ATDEPARTMENT OF HEALTH AND HUMAN SERVICES

FOOD AND DRUG ADMINISTRATION

CENTER FOR DRUG EVALUATION AND RESEARCH

PEDIATRIC SUBCOMMITTEE

OF THE ONCOLOGIC DRUGS ADVISORY COMMITTEE

Tuesday, April 24, 2001

8:10 a.m.

Best Western Washington Gateway Hotel
1251 West Montgomery Avenue
Rockville, Maryland

PARTICIPANTS

Victor M. Santana, M.D., Chairperson
Karen M. Templeton-Somers, Executive Secretary

ODAC MEMBER

Donna Przepiorka, M.D., Ph.D.

AD HOC MEMBERS

James M. Boyett, Ph.D.
Alice Ettinger, MSN, RN, CPON, CPNP
Henry S. Friedman, M.D.
C. Patrick Reynolds, M.D., Ph.D.
	
PATIENT ADVOCATES

Nancy Keene
Susan L. Weiner, Ph.D.

CONSULTANT

Charles Schiffer, M.D.

GUESTS AND GUEST SPEAKERS

Robert J. Arceci, M.D., Ph.D.
Diane C. Arthur, M.D.
Frank M. Balis, M.D.
Irwin D. Bernstein, M.D., (by telecon)
Michael J. Borowitz, M.D., Ph.D.
David Head, M.D.
Robert E. Hutchison, M.D.
Martha S. Linet, M.D.
Sharon B. Murphy, M.D.
Stefania Pittaluga, M.D., Ph.D.
David G. Poplack, M.D.
Malcolm Smith, M.D., Ph.D.
Samuel Waxman, M.D.

FDA
	
Joseph Gootenberg, M.D.
Steven Hirschfeld, M.D., Ph.D.
Richard Pazdur, M.D.

C O N T E N T S

PAGE

Call to Order: Victor Santana, M.D.     	                5

Welcome: Richard Pazdur, M.D.                     	      5

Conflict of Interest Statement:
  Karen M. Templeton-Somers, Ph.D. 	    7

Open Public Hearing 	   11

Charge to the Committee:
  Steven Hirschfeld, M.D., Ph.D. 	   11

Challenges and Considerations in Linking Adult
  and Pediatric Leukemias:
  David Poplack, M.D. 	   27

Challenges and Considerations in Linking Adult
  and Pediatric Lymphomas:
  Sharon B. Murphy, M.D.   	   44

Discussion                                        	   59

Perspectives on Myeloid Leukemias:
  David Head, M.D. 	   78

  Irwin D. Bernstein, M.D. 	   96

Discussion  	   99

Questions to the Committee 	  113

Open Public Hearing 	  139

Perspectives on Lymphoid Leukemias:
  Michael J. Borowitz, M.D, Ph.D. 	  140

  Charles Schiffer, M.D. 	  153

Open Public Hearing
  Wayne R. Rackoff, M.D., Ortho Biotech            	  162

Discussion                                        	    163

Questions to the Committee 	  184

Perspectives on Lymphomas:
  Stefania Pittaluga, M.D., Ph.D.                  	  187

  Robert E. Hutchison, M.D.                        	   197

C O N T E N T S (Continued)

PAGE

Discussion                                         	  207

Questions to the Committee                         	   214

Summary Comments:
  Robert J. Arceci, M.D., Ph.D.                 	      216

P R O C E E D I N G S
Call to Order and Opening Remarks
	DR. SANTANA:  Good morning to everyone.  I know that you all have very busy schedules and I do appreciate, and I am sure the FDA will appreciate, your being here this morning.
	This is a meeting of the Pediatric Subcommittee of the Oncologic Drugs Advisory Committee that has been called to seek the advice and guidance from all of you present here today with some issues in pediatric drug development that the FDA wants to consider both from a scientific and ethical point of view as they get requests from different sponsors in the future for new drugs and new biologics.  I am sure Dr. Pazdur and Dr. Hirschfeld will expand on that.
	What we will do this morning is we will have some brief introductory comments from Dr. Pazdur, then, we will have a conflict of interest statement, and then we will start with our meeting.
	Dr. Pazdur.
Welcome
	DR. PAZDUR:  Thank you very much.
	This is really the second meeting, I believe, of the Pediatric Subcommittee for Oncologic Drugs Advisory Committee, and I would like to thank you all.  This is somewhat of a diverse group since it has both adult medical oncologists and pediatric oncologists here, and I think reflects the issue that we are trying to address here, and that is the 1998 Pediatric Rule.
	Basically, this mandates pediatric studies if the indication in an application under review can be found in children, so I think really we need an active dialogue between not only the pediatric oncology community, but also those of you who represent the adult medical oncology community.
	Most of our applications come, not to develop pediatric drugs, but obviously to hit big tumor types, such as breast cancer, lung cancer, prostate cancer, and pediatric malignancies have somewhat been ignored in the development scheme.
	We have really taken an interest since I arrived at the FDA to try to promote pediatric oncology both through looking at the Pediatric Rule again, but also various incentives that can occur for the pharmaceutical industry in developing drugs in pediatrics.  So, this is really only one part of a more global picture of the FDA's interaction with the pediatric oncology community.
	I am not going to spend a lot of time.  I would just like to thank you for your participation here, and I think I will turn the table over to Steve.
	Steve.
	DR. HIRSCHFELD:  I will in turn defer to Dr. Somers.
Conflict of Interest Statement
	DR. TEMPLETON-SOMERS:  This is the conflict of interest statement.
	The following announcement addresses the issue of the conflict of interest with regard to this meeting and is made a part of the record to preclude even the appearance of such at this meeting.
	Since the issues to be discussed by the subcommittee at this meeting will not have a unique impact on any particular firm or product, but rather may have widespread implications with respect to an entire class of products, in accordance with 18 U.S.C., Section 208(b), waivers have been granted to all members and consultants who have reported interests in any pharmaceutical companies.
	A copy of these waiver statements may be obtained by submitting a written request to the FDA's Freedom of Information Office, Room 12A-30 of the Parklawn Building.
	With respect to FDA's invited guests, there are reported affiliations which we believe should be made public to allow the participants to objectively evaluate their comments.
	Irwin Bernstein, M.D., would like to disclose that he owns stock in Johnson & Johnson, Merck, Bristol-Myers Squibb, and Exelexis.  Wyeth-Ayerst and the Genetics Institute provide research contracts to his employer, the Fred Hutchinson Cancer Research Center, for studies of an agent used to treat acute myeloid leukemia, and he is the principal investigator for the laboratory studies only of the agent.  Dr. Bernstein is the inventor of the agent and is entitled to a share of any royalties that the center receives from Wyeth Ayerst.  Dr. Bernstein is participating by telecon for part of this meeting.
	Michael Borowitz, M.D., would like to disclose that Aventis supports some testing in his laboratory and a very small part of his salary.
	Sharon Murphy, M.D., holds stock in Schering- Plough, Pfizer, Immunex, and ImClone Equity holdings, Rhone-Poulenc Rorer, Pharmacia, Novartis, Sequus, and U.S. Bioscience provide financial support to the Pediatric Oncology Group, and Sanofi provides support to the Children's Memorial Hospital.  Dr. Murphy is the past chair of the Pediatric Oncology Group.  Further, Dr. Murphy receives consulting fees from Biogen.
	David Poplack, M.D., previously received speaker's fees from Chiron and is an unpaid scientific advisor to Astra Corporation.
	In the event that the discussions involve any other products or firms not already on the agenda for which an FDA participant has a financial interest, participants are aware of the need to exclude themselves from such involvement and their exclusion will be noted for the record.
	With respect to all other participants, we ask in the interest of fairness that they address any current or previous involvement with any firm whose products they may wish to comment upon.
	Thank you.
	DR. SANTANA:  For the record, we need to introduce ourselves, so I would ask, starting with Dr. Reynolds to my right, to speak into the microphone their name and their affiliation.
	DR. REYNOLDS:  Patrick Reynolds, Children's Hospital, Los Angeles.
	DR. WEINER:  Susan Weiner, Patient Advocate, the Children's Cause.
	DR. SCHIFFER:  Charles Schiffer, Karmanos Cancer Institute, Wayne State, in Detroit.
	MS. ETTINGER:  Alice Ettinger, St. Peter's University Hospital.
	DR. BALIS:  Frank Balis, Pediatric Oncology Branch, NCI.
	DR. ARTHUR:  Diane Arthur, Laboratory of Pathology, NCI.
	DR. WAXMAN:  Sam Waxman, Mount Sinai, New York.
	DR. PITTALUGA:  Stefania Pittaluga, NCI, Laboratory of Pathology.
	DR. HEAD:  I am David Head, Vanderbilt University Medical Center, Nashville.
	DR. LINET:  Martha Linet, Division of Cancer Epidemiology and Genetics, National Cancer Institute.
	DR. ARCECI:  Bob Arceci, Pediatric Oncology, Johns Hopkins.
	DR. HUTCHISON:  Bob Hutchison, Hematopathology, Syracuse, Upstate University.
	DR. SMITH:  Malcolm Smith, Cancer Therapy Evaluation Program, NCI.
	DR. POPLACK:  David Poplack, Texas Children's Hospital.
	DR. MURPHY:  Sharon Murphy, Children's Memorial Hospital, Northwestern.
	DR. PAZDUR:  Richard Pazdur, FDA.
	DR. HIRSCHFELD:  Steven Hirschfeld, FDA.
	DR. GOOTENBERG:  Joe Gootenberg, Center for Biologics at the FDA.
	DR. PRZEPIORKA:  Donna Przepiorka, Baylor College of Medicine, Cell and Gene Therapy.
	DR. BOYETT:  James Boyett, St. Jude Children's Research Hospital.
	DR. TEMPLETON-SOMERS:  Karen Somers, Executive Secretary to the Committee, FDA.
	DR. SANTANA:  Victor Santana, St. Jude Children's Research Hospital.
Open Public Hearing
	DR. SANTANA:  The next item on the agenda is an open public hearing.  Is there anybody in the audience that wishes to address the committee?  If you wish to do so, there is a microphone in the middle of the room.  Please stand up, state your name, and start your address.
	Anybody in the audience?
	[No response.]
	DR. SANTANA:  If there is nobody in the audience, we will go ahead and get started with the activities today.
	The first presentation will be by Steven Hirschfeld from the FDA.  Steve is going to try to define for us the charge of this committee from the FDA perspective.
Charge to the Committee
	DR. HIRSCHFELD:  Good morning.  I want to thank everyone for coming this morning.
	What I would like to do in just a few minutes is try to give the charge to the committee and attempt to focus the type of advice that we would be soliciting this morning.
	[Slide.]
	I will begin with a brief history of pediatric therapeutic development globally.  Globally, pediatric therapeutic development has never been as thorough or robust as adult therapeutic development, and it is well documented that many therapies are administered to children without adequate study, and furthermore, many therapies are not made available for pediatric study until after adult marketing studies are completed.
	[Slide.]
	The conventional pathway of therapeutic development is to begin with pre-clinical work and then develop an adult indication, and optionally, which is what the spaced dotted line represents, optionally, there may be some pediatric development, but this is not the only paradigm.
	There are other possible paradigms where one may have pre-clinical development followed by concurrent adult and pediatric development, or never seen before in the history of approved pharmaceuticals, but there could be a model where one has pre-clinical development, pediatric development, and then optional adult development if it is warranted scientifically or economically.
	[Slide.]
	The FDA has attempted to address the issue of pediatric therapeutic development through some initiatives.  In 1994, the FDA promulgated a Rule that established a principle of extrapolation for efficacy data from adult population to pediatric population if certain conditions were met.  The Rule was intended to lower the barrier for studies in pediatric therapeutics, but the results were disappointing.
	In 1997, as a provision in the Food and Drug Administration Modernization Act, there was an incentive program for the development of pediatric therapeutics on a By Invitation Only basis, and while we will not discuss this at all this morning, I will mention that compliance with the 1998 Pediatric Rule, which we will discuss, can simultaneously be fused with compliance or an invitation to have an exclusivity extension, and there could be, in complying with the Rule, also a concurrent financial incentive.
	[Slide.]
	So, we will pause now on the 1998 Pediatric Rule.  The 1998 Rule mandates pediatric studies if the indication for an application under review can be found in children.  It applies to drugs and biologicals, and if the indication does not apply to children, then a waiver can be granted.
	There is never an intent, nor should there be a circumstance, where development of a therapeutic for an adult population is in any way delayed or inhibited because of compliance with pediatric priorities.
	This circumstance is specifically addressed by the granting of a deferral for the submission of the pediatric data.
	The 1998 Rule also does not specifically address the question of extrapolation of efficacy.  The 1998 Rule raises the issue of are studies warranted, and that is the focus of what we would be discussing today in the setting of hematological malignancies.
	So, the general question to the committee will be:  How should the 1998 Rule be applied for hematological malignancies?
	[Slide.]
	Our goals, which we recognize may not be obtainable, and we recognize even if obtainable, may not be obtainable today, but our goals, nonetheless, would be to look for recommendations for adult indications that would trigger the Pediatric Rule, specific recommendations for adult indications that should be waived from compliance with the Pediatric Rule, and recommendations for general principles that may be used to apply the Pediatric Rule.
	[Slide.]
	What is intended by this concept of general principles?  Well, one example might be a statement, such as if a lesion is necessary for establishing or maintaining the malignant phenotype, and if a therapy is directed against that lesion, then studies in tumors where the lesion occurs and has the same critical role are warranted.
	With that, I close my presentation and look forward to what I hope will be an informative, interesting, stimulating discussion.
	Thank you.
	DR. SANTANA:  Steve, I think we do have a few minutes, we are ahead of schedule, does anybody have any questions to Steve about the charge of the committee that he can directly address now?  Go ahead.,
	DR. SCHIFFER:  Steve, maybe you can give us some examples of how this has been applied recently, for example, ATRA was studied simultaneously in adults and children.  I mean how has this been done in a practical way?
	DR. HIRSCHFELD:  In a practical way, it actually hasn't come up specifically.  We have looked at it.  As an example, there was a recent approval for arsenic trioxide for therapy, and we have applied some principles, and I will be explicit in how that was applied.
	We wanted to look at defining the diagnosis on a molecular basis, so we defined the diagnosis, not on the basis of a French, American, British classification, but on a cytogenetic lesion.  We wanted to define the place or the role of the therapy, not as something generic as first or second line, but specifically stated that it would be therapy which would follow a retinoid and an anthracycline therapy.
	Then, when we asked how it would be applied to pediatrics, we noted that there were some pediatric patients that were included in the studies which we had encouraged and that there is a commitment to follow up with further pediatric data, and we do have data on file which establishes the pediatric dosing for patients who have that particular constellation of disease plus disease setting.
	Does that answer your question, Dr. Schiffer?
	DR. SCHIFFER:  So, the label doesn't include pediatrics for ATRA and arsenic?
	DR. HIRSCHFELD:  ATRA, no; for arsenic, there is a statement, but it is not a robust pediatric indication per se.  What we are interested in, and I should clarify this, is generating data, and as a byproduct of generating the data, we would be looking for labeling, but having labeling is not as important as having the studies done.
	DR. HUTCHISON:  Steven, a quick question which should help me understand this a little bit better, too, is what kinds of exceptions are implied by this ruling, and how is the term "warranted" interpreted, does that have teeth associated with it or does it not?
	DR. HIRSCHFELD:  Right.  I think I can address that pretty clearly.  The exceptions are for indications.  An indication is a word that we are looking for some guidance in interpreting, but in indications which have up to now automatically generated waivers are colorectal cancer, breast cancer, non-small-cell lung cancer, prostate cancer, diseases which historically are not only not found in children, but we find that there is no linkage on a biological basis with pediatric diseases.
	In terms of the teeth behind the 1998 Pediatric Rule, the redress is through the court system, and although this has never come up, if it should come up, then, the agency has the responsibility and the prerogative to bring an applicant to court and ask the court to either demand that the studies be done, which would be the first position, and the second position would be some other remedy which the court would determine.  Now, since there are no legal precedents, we don't know what will happen.
	Going back to how this has been followed up to now, to try to amplify on Dr. Schiffer's question, the answer is that we have been looking for a way to follow through, and we have not established a policy.
	What we are trying to do through the series of meetings is evolve a policy through public discussion and consensus to guide us on what the circumstances or what the indications would be that would trigger the Pediatric Rule.
	So, the compliance with the Pediatric Rule was not formal until December 2000, and until December 2000, even though the Pediatric Rule was published in December 1998, there was a time window in which all applications could receive an automatic deferral, and that normally got us off the hook, but everyone else off the hook in that we didn't have to make a decision, but rather we could ask that the decision be deferred.
	Time has come now to make some decisions, and we began the series of meetings in September 2000 in anticipation of having to comply with the mandate, and we have been seeking advice on the circumstances, and up until now, for better or worse, we have not had an application that has specifically addressed the 1998 Pediatric Rule.
	DR. PAZDUR:  I just wanted to clarify this because I think it is very important.  When we apply the Pediatric Rule, this is a mandate, so the sponsor must do this, and I think that this is very important when you give us advice to have this consideration in mind.
	We are requiring the sponsor to perform these studies, which is different, for example, from the pediatric incentive programs where we could say it would be nice if you did this, or please consider doing studies.
	When the 1998 Rule is applied, it is a mandate, and as such, it may be questioned because obviously, we are requiring people to do these studies, and therefore, once we start exerting some pressure on people or sponsors, there obviously could be this consideration of what are the indications really that can be extrapolated from the adult situation to pediatrics, how well founded is that in scientific data that would warrant an extrapolation of an indication, an adult indication to a pediatric indication.
	So, it is a much different thing than it would be scientifically interesting to apply this Rule, it is a mandate, and therefore, that carries with it somewhat of a stick.
	DR. SANTANA:  Dr. Weiner.
	DR. WEINER:  Following up on what you said, Dr. Pazdur, I think that there is a very interesting contrast in language and one that I hope people would think about between the language in the example of your principle and the language in the example of the exclusivity provision.
	The language in the exclusivity provision says studies that provide some benefit to children, and here it is a question of where the critical role is warranted.
	I think that, you know, it is important to place the principle in the context.
	DR. SANTANA:  Dr. Schiffer.
	DR. SCHIFFER:  So, if at the end of the day, Rick, we come up with a half dozen diseases that we think are similar biologically, and trials have been done in adults, like STI, for example, that means you would mandate trials in children because the diseases are similar or identical?
	DR. PAZDUR:  Potentially, we could, okay, and here again are we redefining how we define an indication and a disease, and I want to emphasize that this is a mandate as such, and therefore, I think we have to be quite explicit as far as the scientific robustness of the data that makes us make that recommendation, but potentially, that can be mandated.
	DR. SCHIFFER:  Does it go in the other direction?
	DR. HIRSCHFELD:  Yes.  Dr. Schiffer, also, if we could have a list of diseases which should automatically be granted waivers.
	DR. SCHIFFER:  Occasionally, we learn from the pediatricians.
	DR. SMITH:  Steve, could you clarify the comment you made about ATRA, that there is no pediatric section for ATRA, since there is clearly pediatric experience in children, in fact, were in the inner group ATRA trial?
	DR. HIRSCHFELD:  I will begin by stating that product labels often lag behind clinical usage, and all- trans-retinoic acid, trade name Vesanoid, although clinical usage is typically for front-line therapy for acute promyelocytic leukemia, it isn't specifically labeled in that regard, and the same with the pediatric information section.
	That doesn't mean we are not interested, but the development of all-trans-retinoic acid, as well as most of the approximately other 80 drugs which are approved, and the other half dozen at least biologicals that are approved for cancer therapy, all had their evaluations and determinations made before the Pediatric Rule went into effect.
	So, in part, it is to address, not only the absence of the pediatric information in labeling, but specifically to make the drugs or biologicals that are being developed available to investigators and available for study that we are looking to implement the Pediatric Rule.
	Just as we often say studying the past is not a guide to the future, and that was just an example to show how there is a discontinuity between what is published, what is formally in the label, and what clinical usage is.
	Does that answer your question?
	DR. SMITH:  Well, I mean yes and no.  What is also published are the pediatric experience with ATRA, and so, I mean it is a drug that was studied in children and studied in a relatively timely manner in children, so it is then perhaps a situation where the studies were done, and children were able to have the advantage of receiving this agent, but somehow it didn't get into the label even though it made it into the published literature and other sources.
	DR. HIRSCHFELD:  Right.  I would not use ATRA as an example of delayed development.  I think Dr. Schiffer brought it up as just an example of a disease where one can make a linkage between the adult indication and the pediatric indication.
	Now, to go back again to Dr. Schiffer's question, how has the Rule been applied to date, and I think the short answer is it really hasn't, that we are looking for a consistent and predictable approach to apply the Rule.
	DR. SANTANA:  Malcolm, the way that I interpret it is if the sponsor was presenting ATRA today to the FDA for approval, and this committee says APL, or the group of experts says APL is really the same disease in children as it is in adults with many minor differences, and the sponsor wants to, today, obtain approval for ATRA, that the '98 Rule would mandate that those studies have to be done.
	The problem is they can't go back because the Rule was not there yet.  All they can do now, as I gather, is that they can then request for the exclusivity rule, that those studies be submitted to extend the indication.
	Am I correct in that, Richard or Steve?
	DR. HIRSCHFELD:  Yes, I just would want to separate the words "exclusivity" and "rule."  The exclusivity is a separate program which is optional.
	DR. SMITH:  The studies were done, though, it is not that the studies weren't done.  They didn't make it into the label, but the studies were done.
	DR. HIRSCHFELD:  Right.  Dr. Waxman.
	DR. WAXMAN:  The question I would have is when you mandate a pediatric study, does that mean that a drug would not be approved, if the diseases were similar in an adult and in a child, an applicant could not get that drug approved unless it was done in a children's group?
	DR. HIRSCHFELD:  Absolutely not.
	DR. WAXMAN:  What does it mean then?
	DR. HIRSCHFELD:  There is no linkage between the adult approval and doing the pediatric studies, and there would be no delay in the adult approval.  The mandate comes from having the authority to ask, if need be, court enforcement of pediatric studies.
	Dr. Head.
	DR. HEAD:  I have two questions, Steve.
	The first is an operational one.  Are the invited speakers participating in the decision or presenting data to a panel, and the panel makes the decision?
	DR. HIRSCHFELD:  Well, actually, there are no decisions that we expect to be made, so I would hope that everyone would feel comfortable saying whatever it was that they thought was important to say, and we will be reviewing the transcripts and following up on a continuing basis with the people in this room and many others when it actually comes time to making decisions.
	But what we wanted to do is set the framework and have it based on as sound scientific principles as the state of the science allows.
	DR. PAZDUR:  We are looking for recommendations and the scientific data to support those recommendations.
	DR. HEAD:  So, the speakers are here to recommend and provide data.
	I have a second question.  There are several levels that this can be considered at.  The most simplistic level is, is the disease the same in pediatric patients and adults, but there are other considerations, is the host the same, and the hosts are different, are we supposed to consider that or not in our statements?
	In other words, the effect of high-dose ara-C is much different in an elderly person, side effects, than in a young adult, or perhaps things affected in neurological development of infants, skeletal development, et cetera, and are we supposed to consider all of that or just consider the disease?
	DR. HIRSCHFELD:  All of the above.
	DR. HEAD:  To continue this, there may be different therapeutic goals in treating patients of different ages, so, for example, in myelodysplastic syndrome, in an elderly person, it is of great benefit to gain three to four years of life for that individual, whereas, in a child, the hope would be to cure the disease, so quite different goals even though the disease may be very similar.
	Is that also a consideration?
	DR. HIRSCHFELD:  It is a consideration, and I think all the issues, all the points you raise are points which we had hoped to discuss during the course of the day, and then whatever is discussed here would not again be a final determination, but rather just a series of issues and recommendations to follow through with, and the more explicit the recommendations, the more helpful the discussion would be.
	DR. PRZEPIORKA:  A question about the term "studies."  Clearly, there may be no financial incentive to fully develop a drug for a pediatric use, and so I wanted to ask when we think about what the diseases that we recommend you mandate studies in pediatric patients, what degree of studies will this be, just pharmacologic studies or all the way to Phase III randomized studies?
	DR. HIRSCHFELD:  Excellent question, and that foreshadows a meeting which we have planned later this year, and we have what we hope is a logical end-stage process in that we will first discuss the nature of the indications, and once we have some focus and some consensus on which indications, then, we will be having a meeting we hope in September of this year, but the date hasn't been established, where we will discuss the types and formats of studies.
	In some instances, it may be just doing some pharmacokinetics and perhaps some pharmacodynamics, perhaps it will be an issue where one knows enough about the diseases and is comfortable enough with how they are similar, that one could have a combined trial, and in other circumstances, it may require a proof of concept study, but the format of the studies is not something which we will discuss today or decide on, but we have in the back of our minds that it is an important question to address.
	DR. ARCECI:  I hope it is appropriate to just ask Susan to clarify your comments on benefit versus exclusivity, that you were talking about, because it seemed important and right to the point, but I wasn't quite sure exactly where you were going with that.
	DR. WEINER:  I just meant to comment on the contrasting language between the statute and the term "warranted," as Steve has given this example today.  The focus in the congressional language was clearly on the studies that would benefit children, whereas, here, the relationship is several steps away.
	I would just hope that somehow or another that when the studies are discussed and the recommendations come through, that that emphasis is pervasive, that is, that the emphasis on kids and what is going to benefit kids is pervasive.
	DR. ARCECI:  Thank you.
	DR. HIRSCHFELD:  If there are no further questions, I will turn it over to Dr. Santana.
	DR. SANTANA:  Thanks, Steve, for all those clarifications.  I knew they were coming, so I am glad we did it.
	We are going to go ahead and start with the presentations.  Dave Poplack will start us off with the Challenges and Considerations in Linking Adult and Pediatric Leukemias.
	David.
Challenges and Considerations in Linking
Adult and Pediatric Leukemias
David Poplack, M.D.
	DR. POPLACK:  Thanks very much.  I want to compliment Dr. Pazdur and Steven for putting pediatric oncology on the FDA's radar screen and for having this meeting.
	[Slide.]
	What we have been really asked to do by Steven is to explore the relationship between pediatric and adult leukemias, and more specifically, determine areas in which there may be compelling biological evidence of similarities or differences that are useful in guiding the drug development process.
	[Slide.]
	Another way to phrase this is that we are being asked to respond to the question as to whether there are defined subsets of adult and pediatric leukemias that share biologically relevant features that might mandate that they be commonly studied.
	[Slide.]
	What I will try and do very briefly as the first speaker is to give you a brief overview of the situation in terms of adult and pediatric leukemias and to discuss some of the promise and perhaps rationale for asking this question, but yet also to highlight some of the challenges that we might have in trying to address it.
	[Slide.]
	This slide simply illustrates the distribution of adult and pediatric leukemias and provides information that I am sure most of you are aware about, which indicates that, for example, acute lymphocytic leukemia is more common in children than in adults, and that acute myelogenous leukemia is more frequently seen in adults than in children.
	One of the points that Steven mentioned was that we should also suggest situations in which it may be superfluous or inappropriate to consider that simultaneous studies be done.  Certainly, since chronic lymphocytic leukemia is not on the radar screen of pediatric oncologists, and chronic myelogenous leukemia, at least the adult form, is extremely rare, those might be considered situations that would not be appropriate for the type of discussion we are having today.
	[Slide.]
	I think we are all, and you are all, aware of the fact that adults have a worse prognosis.
	[Slide.]
	This slide simply illustrates the survival of adults and children with the two most prominent forms of acute leukemia, and shows you that in both circumstances, children do do better, and the reasons for this, of course, aren't clearly understood.  They may have to do with differences in biology, with pharmacokinetics and pharmacodynamics, clearly with host status, as David Head had suggested, all of these have to be considered.
	[Slide.]
	I think one of the things that we have learned over the last 25 to 30 years in particular is that it is no longer really appropriate to consider the acute leukemias as two separate entities, acute myelogenous and acute lymphocytic, and to lump them together under those headings, because, in fact, these are really a heterogeneous group of diseases.
	[Slide.]
	I would like to illustrate that just through the example of childhood acute lymphoblastic leukemia.  This slide simply illustrates data from the Children's Cancer Group showing the dramatic improvement overall in survival that has occurred in the last 35 to 40 years in treating childhood acute lymphoblastic leukemia.
	Each of these curves represents a different clinical protocol.  We have made tremendous strides, as you can see.  In fact, it is considered one of the true success stories in modern medicine.
	In part, in particular of late, one of the reasons for these successes has been because we have appreciated the fact that acute lymphoblastic leukemia is, in fact, a heterogeneous group of diseases and there are biological differences with the disorders that are lumped under that category.
	[Slide.]
	The evidence for this comes from a variety of studies and a very large literature in a number of fields, that started with the recognition clinically that patients present in different ways and that one could, when one went back retrospectively looking at these types of studies, define certain features evident at the time of diagnosis whether it is the initial white count or patient age, a variety of features that were linked to prognosis.
	Of course, the attempts to classify the disease on the basis of morphology, cytochemistry, immunophenotyping, and there the approaches have become highly sophisticated, and more recently, using cytogenetics and molecular phenotyping, have all just provided increasing evidence that this is really a group of diseases that are distinctly different in terms of their biologies.
	[Slide.]
	What has been the impact of understanding and appreciating this heterogeneity, well, clearly, it has had an impact on therapy in the following way - is that understanding that one can define risk groups for prognosis has allowed investigators to stage patients according to the degree of risk and to actually develop or tailor therapy accordingly, such that low risk patients over recent years have been treated with effective therapies, but less toxic in nature, and high risk patients, those presumed to be at a high risk of relapse, have been treated with more intensive treatment, and generally, this has been a successful strategy, but I want to point out that many of the initial prognostic criteria that were identified by looking back and developing statistical associations, for example, between prognosis and initial white count, et cetera, provided clues, but really little in terms of biological insights into why they were good or poor prognostic factors.
	[Slide.]
	Clearly, however, things are changing and there is no question that now, and as we go forward in terms of technological advances, we have at hand tools which will allow us to really work within a new paradigm where we have tools that are going to allow us to develop more biologically relevant bases for classifying these disorders both in pediatrics and in adults, and also to allow us to identify molecular targets for therapy.
	I think it is important to recognize that this discussion of differences and similarities between adult and pediatric leukemias is occurring on a constantly evolving technological stage.
	[Slide.]
	Just, for example, in the area of cytogenetics, we have made quantum leaps in our ability to define the chromosomal aberrations that occur in these disorders, and this slide simply lists a whole host of different technologies that allow us, with greater refinement, to determine that there are indeed chromosomal aberrations and to define them, and to even go farther in terms of identifying with molecular techniques what is actually happening, for example, at the site of a translocation.
	[Slide.]
	This slide simply illustrates, for those of you not familiar with it, the technology of spectral karyotyping, which in a very highly sophisticated system which involves computerization, individual chromosomes are painted, and one can determine with much greater resolution the presence of translocations.
	Here, you can see a 12-15 translocation in ways that could never be identified previously, so we are able to look at the karyotype in a much more complex and sophisticated way.
	[Slide.]
	Then, naturally, in the area of molecular biology, we now have at hand tools which will allow us to genotype and phenotype and again increasingly sophisticated manners.  We have gone beyond in a sense Southern and Northern and Western Blotting, and PCR technology is at hand, but there is tremendous promise in the concept of using cDNA microarray to determine differential gene expression and the other technologies listed on the slide, hold great promise.
	So, I think we need to recognize and appreciate, as I am sure we all do, that in the future, we are going to better be able to define similarities and differences.  Things are really moving quite rapidly in this area.
	[Slide.]
	This slide simply illustrates panels taken from a microarray, analysis of gene expression in patients with two forms of leukemia, showing differences in gene expression.
	[Slide.]
	This data from a study done by Dr. Judith Margolin in our institution in which she compared the gene expression using microarray of the t(4;11) translocation to pre-B ALL shows that there are different genes expressed.
	[Slide.]
	For example, here, in the t(4;11) circumstance versus CALLA-positive pre-B ALL.
	So these technologies are at hand, and they need to be studied prospectively in both children and in adults.
	[Slide.]
	Given the fact that we are working with a changing playing field, can one at the present time define at least theoretically subsets of adult and pediatric leukemias that might be appropriate for common therapeutic studies?
	I would submit that, in fact, yes, we are able to define certain areas.
	[Slide.]
	For example, in the acute lymphoblastic leukemia category, we are aware, using cytogenetics, and these next slides are going to focus on cytogenetics in particular, entities that are clearly shared between pediatric and adult lymphoblastic leukemia.
	The Philadelphia chromosomal translocation BCR-ABL translation that has been mentioned already, is clearly one of those circumstance.  Patients with a t(4;11) translocation and other 11q23 abnormalities.  B-cell disease characterized by a similar translocation.  All of those are associated with relatively poor prognoses.
	At the bottom of this slide, you see the TEL-AML translocation situation, one which is perceived to be associated with a better prognosis, but even though we may not have the biological information that goes along with the observation that a higher or lower than normal chromosomal number may be associated as in the case of hypodiploidy with a poor prognosis, or hyperdiploidy with a good prognosis, these differences do exist in pediatrics and childhood, ALL, and may be the basis for studies in the future.
	[Slide.]
	In terms of myeloid leukemia, again, the situation of the t(15;17) abnormality and other APL variants is one that has already been studied and would be appropriate to be studied in both circumstances, as would the t(8;21) translocation even though, "it is associated with a better prognosis," in fact, we are really doing quite poorly with this disease, and it may be appropriate to do a combined study.
	Then, I would submit that therapy-associated myeloid disease might be an appropriate focal point for combined studies because we are seeing both in pediatric and in the adult community increasing numbers of patients with this disorder.
	[Slide.]
	Of course, now we are in a new era of molecular targeting and perhaps two examples here are really worth noting, and they have already been mentioned, and that is, that we have already been able to demonstrate that one can target therapy specifically for abnormalities present at these types of translocations, in the case of the STI 571 study occurring in patients with the BCR-ABL translocation, and in the use of ATRA, for example, to treat patients with a t(15;17).
	I think these experiences really are sort of poster children for the concept of targeted therapy, and they provide compelling arguments, I would submit, first of all, in terms of confirming the validity of targeting relevant molecular lesions and also providing a supportive argument for testing targeted agents in all relevant populations.
	[Slide.]
	One of the challenges that Steven asked us to respond to is whether we could actually develop a general principle that might guide the identification of biological subsets that would be suitable for study both in adults and children.
	[Slide.]
	As Dr. Hirschfeld did, I believe that any characteristics that are defined have to be associated with lesions that are linked to either the establishment or development or the maintenance or progression of the malignant phenotype or perhaps linked to the development of resistance to specific treatments for these disorders.  But this will be a subject I think of discussion over the day.
	[Slide.]
	I didn't want to leave you with the impression that it starts and ends with cytogenetics.  There are clearly examples of a whole host of biological features that may be shared by adult and pediatric leukemias that may be worthy points of discrimination between the two, and worthy candidates for combined study.
	They are listed on this slide, but include, for example, gene expression patterns as we learn more about the application of microarray technologies, various receptors, drug resistance genes, tumor suppressor genes, et cetera.
	[Slide.]
	So, in theory, I think I have pointed out that there probably are already lesions that we can identify that would argue, perhaps strongly, that we ought to be able to study them commonly in both adults and pediatrics, but what are the challenges to really designing these types of trials and things can't always be all positive, and clearly they are not.
	It is possible, for example, that the biological basis that we use to select grouping may turn out to be incorrect, and that we just missed the boat in choosing a particular biological target.
	[Slide.]
	Here, for example, I would illustrate the importance of going, if you will, beyond that breakpoint.  We know, for example, that there is heterogeneity in the location of actual fusions or translocations, and there is heterogeneity that occurs in the resulting proteins.
	One need only look at the BCR-ABL situation in which there have been at least two different distinct fusion proteins identified, which may, in fact, be associated with different downstream events.
	We know that in childhood ALL, with the BCR-ABL translocation, that there is a different fusion protein than seen in the majority of adults, and so it may be presumptive for us to believe that a therapy identified or targeted specifically for the translocation may have similar therapeutic results in both populations.
	Also, I would offer as another example the t(1;19) translocation where the translocation may be present, but there have been differences noted and observed in expression, which may be associated with different prognosis.  So, one can't be too simplistic and simply say because there is a translocation, and if we can target it, or the downstream events, that we are going to have similar results in adult or pediatric populations.
	One also has to remember that these lesions usually occur in the context of other genetic changes that are occurring in these diseases, such as concomitant aneuploidy, which may have significant impact on the biological expression of these translocations, so we have to be careful.
	[Slide.]
	The other issue was raised again by David Head, which has to do with host tolerance and differences that relate to toxicities.  When one deals with children, we are dealing with developing tissues, with developing neural tissue, for example, and with a growing organism, and in contrast, the situation is quite different in dealing with the fragilities of individuals at the older age of the spectrum.
	We know already that there are agents that are used even now to treat, for example, acute lymphoblastic leukemia both in adults and in children that have at least widely different clinical impressions of toxicity, and I will offer asparaginase as a perfect example of a drug that appears to be much better tolerated in children than in adults, and where now that aggressive use of asparaginase has become a fairly common theme in childhood leukemias, there has been some resistance to try and apply that in adult ALL because of the fact that adults appear to have greater toxicity.
	So, we always have to be cognizant of the possible issues that relate to toxicity.  Perhaps the major problem, however, is small patient numbers, and it wonderful in theory to define these subgroups, but if you then say, well, how do I really develop a trial, even in BCR-ABL translocation, by my calculations, there probably are only 150 to 200 children in the country who have this type of abnormality.
	Most of these translocations occur in 5 percent or less pediatric patients with ALL, for example, and so therefore, it is going to be extremely difficult for us to develop studies in which we are going to be able to get sufficient numbers, and as the prognosis and as our therapies get better for those different subsets, the studies paradoxically are going to require greater numbers of patients to show validity, so it is not going to be an easy process by any means.
	Another point, I think, is that many of these subsets are already being, if you will, taken out of the study pool by other available therapies, such as transplantation, and where, for example, therapy-related secondary myeloid leukemias in most centers or in many centers are being automatically given bone marrow transplants, and that may be an appropriate therapy, and I am not comment on it, but many of these subgroups may already be defined for different types of therapy, making it more difficult for us to apply new approaches to this subset.
	[Slide.]
	So, are there benefits to attempting to design and implement common adult and pediatric leukemia trials?  Clearly, I think so and obviously, the ultimate benefit would be new and improve therapies for our patients.  Clearly, that has to be, as Susan Weiner pointed out, the factor that motivates all of us.
	Clearly, by doing this, I think we will arrive at a better understanding of the underlying biology of these diseases, but as I pointed out, it is not necessarily going to be easy.
	[Slide.]
	I would like to make a plea for the development even now--and it is wonderful to see pediatric and adult leukemia and lymphoma specialists and experts in the same room, I think we need to do more of this--and I think what we need to start to do at this point is to develop common, comprehensive prospective biological studies of these diseases.
	Hopefully, that can be commonly coordinated using these new and advanced technologies, so that we don't miss the opportunity to be able to use the new technological advances to define with greater certainty biological subsets in the future.
	I would also like to point out that it is important to study, I believe, both the good and the poor prognostic groups.  It is natural and appropriate for us, and certainly from an economic point of view, to focus on where the need is.  We need to learn what is going on with patients who have, for example, a bad translocation, but we also, and particularly I think of the promise of cDNA microarray in gene expression studies, need to learn what has happened in patients who have done well on the therapies that we have, and can we come up with information gleaned from evaluation of those patients using these new technologies that may be relevant and appropriate for us to utilize or give us clues to, treatments that could be utilized in the poor risk groups.
	[Slide.]
	So, in summary, I think even now it is probably possible for us to identify classification techniques in adult and pediatric leukemias that can identify subsets in which joint treatment protocols are justified, but no question that significant caveats to the strategy exist.
	Again, I would make a plea for the development of coordinated prospective biological and clinical studies of adult and pediatric leukemias, using the latest genomic technologies.  I would also suggest that there may be value perhaps stimulated by this meeting here done at the behest of the FDA, and perhaps coordinated either by the FDA or the NCI for the development of a working group or a forum that might begin to take a hard look together at adult and pediatric leukemias and lymphomas, because I think we can only benefit from pooling our knowledge.  For too long we have really sort of done and developed therapies in our own spheres of interest, and I think it is very important to share information.
	I think I will stop here and thank you very much.
	DR. SANTANA:  Thank you, David.  I think you have set the stage for some point that we will catch up in the discussion period, and we will try to answer those questions then.
	I am going to go ahead and invite Dr. Murphy to do her presentation as it relates to adult and pediatric lymphomas.
	Sharon.
Challenges and Considerations in Linking
Adult and Pediatric Lymphomas
Sharon B. Murphy, M.D.
	DR. MURPHY:  Well, Dr. Hirschfeld assigned me the task of describing the potential advantages or pitfalls of linking adult and pediatric lymphomas.  Along with Dr. Poplack, he asked that we provide a global introduction, an overview, if you will, of the advantages and disadvantages of, if you will, lumping versus splitting, and try to identify some principles for defining which criteria for which lymphomas could be considered essentially the same or different in adults and children for the purposes of applying the Pediatric Rule.
	I must say that we were encouraged to talk to each other before this session to harmonize our global introductions.  That opportunity did not arise, but it is nonetheless interesting.  You will hear some themes that we both independently identified, I think.
	Before jumping into lymphoma classification, which I know you are all anxious to do, I want to first give some of my personal perspective about the issues this Pediatric Subcommittee of ODAC is struggling with in applying these new regulatory initiatives which are, after all, aimed at producing health benefits in children.
	Now, I also want to confess--this is like a disclaimer or a disclosure--that I have really been struggling with some very fundamental problems in applying this Rule and preparing this talk that I just find very difficult to reconcile.
	So, upfront, I would like to say that, on the one hand, for my whole professional life as a pediatric oncologist, I have been preaching the mantra, you know, children are not just small adults, and furthermore, that pediatric cancer is very different than adult cancer.  We have all said this a million times.
	But from the standpoint of the Pediatric Rule, it makes sense perhaps to say that, well, the diseases are really the same, not different, so that we can get drugs early on the market with pediatric information as a mandate.
	So, it is clear to me that since the legislation has been enacted, there actually has been a huge increase in pediatric studies for new drugs and for drugs already on the market, drugs that are really quite important to treat pain, asthma, hypertension, seizures, infectious processes, but that the hope for stimulation really of research in pediatric anti-cancer drugs has not materialized whatsoever as we all know, and that is why we are here today, to provide some advice to the FDA, which might help to shape maybe a more flexible interpretation or a liberal application of the Rule or something in order to better realize the original intent of the law, which is to provide more health benefits for children, have incentives for the pharmaceutical industry to conduct these new drug studies, so that children with cancer could benefit from the knowledge gained and have greater access to new treatments.  That is what we all want.
	So, I just want to clarify if we say today that pediatric cancer in general, or leukemias and lymphomas in particular, are different from the diseases in adults, then, the Rules will not apply, and a full or a partial waiver would be extended to the sponsor relieving them of the requirement for these pediatric trials, and that is sort of a politically incorrect outcome for children.  So, we have to be careful of what we say today, but at the same time we have to say what we know to be true based on the evidence and also all of our collective knowledge.  So, I have quite struggled with this conundrum.
	If I can be allowed to make a few more comments of a general nature, I would like to do that, because a lot of people will talk about lymphomas, I am sure.
	[Slide.]
	The advantages obviously of this pediatric provision are to stimulate the development of new therapeutics for pediatric indications, the whole point being to produce public health benefits for children in return for which an exclusivity extension may be granted, which is a financial incentive that has attracted much interest in the pharmaceutical industry.
	We have representatives from the pharmaceutical industry here in the audience today, and I hope that they will chime in, in the discussion period.
	There is also at the bottom here, and I put a question mark, the theoretical advantage of having early access to new agents for children.  As I said, at least in cancer, this has not materialized because I think that the prospect of six more months of additional exclusivity for a company, for a product, that has yet to be approved, and when it is approved, will enjoy up to 15 years or more of freedom from generic competition, it is just not compelling to them, and it just doesn't seem to outweigh the risk I think that industry perceives, that if you let the drugs out early for children, there may be adverse events or adverse experiences that might jeopardize their approval, and the hoped-for widespread application for adult indications, so this has not worked, and there has not been early access to new agents as a result of this legislation.
	[Slide.]
	This next slide is some of the pitfalls and harms of this--potential, these are potential pitfalls, it hasn't really been applied yet, so it is all hypothetical--one problem alluded to by David is the limitation of adequate patients eligible for Phase I/II early trials of pharmacokinetics and pharmacodynamics or for the, if need be, Phase III pivotal trials.
	This is particularly true in pediatric cancer where, as we well know, the success of our front-line therapies, especially in leukemias and lymphomas, markedly reduces the number of children who have recurrent or refractory disease who might even be eligible as candidates for Phase I or II studies of new drugs.
	The numbers actually become even more limiting, and you will see this later in my slides.  When we consider the distribution of different kinds of NHL, because just as NHL is not one disease, it is the same problem as in leukemia, there is lots of different kinds of lymphomas, and when you start slicing up these different kinds, and looking at the numbers, you really get into almost infeasible situations of ever conducting trials.
	I have also listed here under the issue of ethics, the significant problem of protection of vulnerable child subjects of research, and the dubious ethics of the reality or even the perception of profiting from industry-driven studies performed in children.
	Already, in the New York Times and other places, strong concerns have been raised that only blockbuster drugs, like Prozac and Claritin, are being studied, resulting in frankly billions of dollars of additional profits from market exclusivity from the manufacturers.  This tends to leave the rarer illnesses and diseases left out, like leukemias and lymphomas and anti-cancer things.
	So, I just caution we have to be constantly aware of that problem.
	Lastly, I have put the information down that might come up in the discussion, that hasn't yet, and that is, that from the Pediatric Rule, orphan drugs are excluded.  We know pediatric cancer, particularly it is not one disease, but many different kinds of disorders, and actually, each one is kind of an orphan disease if you think about it.
	Wilms' tumor affects 500 or fewer children per year in the United States.  In the case of a common malignancy, like ALL, there is a few thousand kids annually, but of the various different kinds of lymphomas, there is only hundreds or tens of tens affected if we split them down to different kinds, and orphan drugs don't fall under this, but really a lot of adult leukemias and lymphomas are orphan diseases, too, you know, like hairy cell leukemia or certain rarer types of hematologic malignancies seen in adults don't affect lots of people either, so how we are going to do this is a very challenging thing.
	Now, I have just a couple more general slides and then I will get to lymphomas, my assignment, but I thought I would just now focus on pediatric cancer and the pitfalls of applying this provision.
	[Slide.]
	The first is the differences between pediatric cancer and other diseases of childhood, like infectious diseases or asthma or epilepsy, which may fit easier in the Pediatric Rule than does cancer, which is not one disease.
	Then, of course, we have the well-known differences between pediatric and adult cancers, and most important for today's discussion, I think, is a big pitfall, is the lack of validation or evidence of the relevance of the models being proposed to apply the Rule, which we have talked about before, in the previous meeting and Steve's introduction, things like specific mechanisms, pathways, gene expression, profiling, all of these proposed models which might be applicable or designed to apply the Rule have not actually been validated in a strict way, so there will be limits in applying them.  Let's not forget that.
	This brings me back to why we are here today, which is to ask the question is it justified--or why I am here today--is it justified or not to link adult and pediatric lymphomas.
	[Slide.]
	I am going to start with lymphoma classification, this being my favorite simplification, as much as I am going to get into classification.
	There is Hodgkin's disease and there is everything that is not Hodgkin's disease.  Of the non-Hodgkin's lymphomas, we have the B-cell derived, T-cell, and NK-cell derived tumors.
	If we ask ourselves whether, for the purposes of the Pediatric Rule application, lymphomas are the same in adults or in children or different, I would state that Hodgkin's disease is the same, but that non-Hodgkin's lymphomas are mostly different, unless we use the really simplistic argument that lymphomas in adults and children must be the same because they are all derived from lymphoid cells.  No, I don't think so, but there is one way to group them.
	They are all derived from cells of the lymphoid system.  Now, I expect most people to be in general agreement with my statement that Hodgkin's disease is the same, so I really want to spend the rest of my time discussing non-Hodgkin's lymphoma, and I want to approach this discussion from a developmental perspective, if I may.  It is the paradigm I am going to use for my remarks, and I will focus on the cells of origin, first, of B cells, then of T cells, and then give an overview.
	Now, this is where I have to switch media, if I may.  I have some old-style slides that are not on PowerPoint.
	[Slide.]
	This is actually a lovely slide I have taken from Ian McGrath's publications, which I greatly admire, and this is a schema that he has proposed of B-cell differentiation, the vertical pathway being primary differentiation, which is antigen independent, and the horizontal being so-called secondary differentiation, which is antigen dependent and takes place inside the follicular center of the germinal centers.
	Now, on one side of each of the putative cells, you see the markers, and on the other side, you see the counterpart transformed neoplastic lymphoid cancer that might be derived from that normal counterpart, frozen at that point in differentiation.
	So, what you can see, for instance, starting at the top here with some multi-potential lymphoid cell early in differentiation, antigen independent, proceeding along B cell differentiation pre-B, then development of surface immunoglobulin, expression from immunoglobulin gene rearrangements, you see that the counterpart cells are the kinds of things we see in pediatrics, pre-B cell, B precursor ALL, et cetera.
	In contrast, this part of secondary differentiation inside follicular center cells, where you have centroblasts, immunoblasts, differentiating to plasma cells or small memory lymphocytes, these are the phases of differentiation from which the counterpart neoplastic cell is the kind of lymphoma we see among adults, follicular center cells, myeloma, et cetera, so keep that in mind.
	[Slide.]
	Now, switching to the next slide, which is T-cell differentiation, think of this as a box with the box over here being the thymus.  Again, on one side the normal T-cell, the cortical thymocyte or early thymic precursor, the stem cells, and then outside the box is the post-thymic peripheral T cells.
	The counterpart cells again in lineage terms, the earlier cells in the thymus and early phases of T-cell differentiation are the ones we see that produce lymphoblastic lymphomas and leukemias in children.
	The post-thymic, so-called peripheral T cells, like Sezary, mycosis fungoides, CLL, these are the more adult type putting it in a developmental perspective.
	[Slide.]
	This is another paradigm here if you accept this notion I have put forward, and you look at life as the continuum on the age spectrum.  You look here at life starting from childhood to adults, and you look at lymphoid malignancies and their relative frequency, I think it is fair to say that in early childhood and adolescence, the relative frequency of cases of lymphoid malignancies, lymphomas and leukemias, is from precursor cells, and later in life, it is from the mature cells.
	This is also true, I might point out, of other forms of pediatric cancer, which mostly early in life are derived from embryonal cells early in development, neuroblasts, retinoblasts, rhabdomyoblasts, you name it, they are nephroblasts.
	These are really developmentally conditioned tumors in contrast to the more common tumors of fully differentiated mature epithelial tissues that are common in adults, breast, colon, prostate, and lung, and we know, for instance, this is the majority of adult cancer and only 4 percent of pediatric cancers or carcinomas.  So, we have this developmental difference.
	[Slide.]
	Now, why in lymphomas and leukemias do we see this?  Well, the obvious observation again is that the cells of origin in children are, if not actually stem cells, at least they are in proximity to lymphoid stem cells, I think, so the hypothesis, not only mine certainly, but supported by the evidence, would be that childhood lymphomas are the result of somatic mutations occurring at a particular point in time of maximum cellular proliferation, differentiation, and clonal expansion.
	That is a hypothesis supported by some of the genetic evidence where you see these common, non-random, recurring chromosomal abnormalities that characterize pediatric lymphomas and leukemias, and the affected genes at the breakpoints with those loci, which primarily are, for the lymphoblastic lymphomas, T-cell receptor genes juxtaposed to other master genes or transcriptional regulators.
	Small, non-cleaved cell lymphoma, B-cell Burkitt type we know.  We have the immunoglobulin loci, and here we have the only other non-random loci in large cell.
	So, I think it is fair to say that particularly these non-random chromosomal abnormalities are mostly entirely different from the kinds of chromosome changes you see in adult lymphomas, I think there would be little argument about that.  Where the common genes involved are genes like BCL-1 BCL-2, BCL-6, regulating not T-cell receptors or immunoglobulin gene rearrangements, but regulating things like apoptosis and cell cycle control, which are much more common in follicular center cell biology.  So, that is a bit of a developmental argument for how they are mostly different.
	Now, if I may, I would like to stop the slides and go back to just the last few other points here, developmental paradigm for lymphomas.  I want to finish up with some other evidence that relates to this developmental paradigm and the differences in the cell of origin and show how that is reflected in the differences in distribution of the types of lymphomas that are common in adults and children.
	You probably all know this, and I am certain we will have more discussion of it later, but I thought I would hit a few high points.
	[Slide.]
	Now, on this slide, I have listed the relative incidence of the more common types of lymphomas observed in children and in adults.
	In pediatric lymphomas, basically, they are all high grade and about 30 percent or so are lymphoblastic, close to 40 are Burkitt small, non-cleaved, and about a third are large cell.  There is 1 or 2 percent in there that may be other or nodular, but that's it.  We have these three kinds of lymphomas in pediatrics for practical purposes.
	The types of lymphomas prevalent among adults are listed here, taken from the very large International Lymphoma Study Group Classification Project that I have listed the references down here, and you can see that almost 50 percent or nearly 50 percent are B-cell derived, diffuse large cell being the most common, and 22 percent are nodular or follicular.  This is in pretty much the Western World, different in other parts of the world, but let's leave that out.
	There is 6 or 7 percent of marginal zone, multi-peripheral T cell, small lymphocytic lymphomas, the tissue equivalent of CLL, and about 6 percent mantle cell.  You can see that there are fewer than 2 percent, 1 or 2 percent of adult lymphomas with either Burkitt's or precursor T-lymphoblastic, which are the most common, and 18 to 20 percent of lymphomas in adults are other kinds not listed here meaning they are rare in adults, too.
	Let me not show any more slides and in the interest of time, just propose a conundrum that I have tried to think about, how would we apply this Rule.
	I wanted to pick an example of an important new biologic active in adults with B-cell lymphomas, and that is rituximab anti-CD20, which I am sure you all know is approved for use for treatment of indolent lymphomas in adults.
	I am asking myself would it be appropriate even to hypothetically mandate studies of this new agent in children if it were to come up now for a rule, and particularly I am not aware of any good pediatric trials done to date with this compound.  There is only anecdotal use of rituximab in children.
	Now, if you recall, monoclonal antibody therapy for lymphomas was really pioneered by investigators at Stanford, who actually began their biologic treatments of lymphomas with anti-ideotype antibodies, which are patient specific and, of course, more cumbersome and difficult to produce, so it was natural for them to want to try an antibody, a monoclonal antibody that had a broader specificity, wouldn't have to be manufactured for every patient, and so the notion of directing an antibody to some surface antigen like anti-CD20 was a natural one.
	It was logical also to test that approach first in adults with follicular lymphomas, which has a natural history of being very indolent, of relapsing, recurring, going on for years, giving you lots of time to assess responses, and the disease proceeds at a leisurely pace.  In many settings, it is even a watch and wait for those kinds of patients.
	So, how would you do rituximab studies in children or how would you even apply a principle for the mandate to apply, because CD20 is a differentiation antigen, it is not necessary for either establishment of the disease or maintenance of the malignant phenotype certainly, using the Rule proposed, and would we have to mandate studies of anti-CD20 for any lymphoid malignancy expressing CD20?  How strong would the expression have to be?
	I am sure Dr. Borowitz will enlighten us and clarify the point that it is more strongly expressed in adults with follicular lymphomas than in the high-grade B-cell Burkitt type that we see in children, but for the life of me, I can't figure out what kind of principle you would apply, and this is a very important new biologic for treatment of lymphomas, and I just came up stuck with that.
	So, I think I will close and we could have some discussion on how all of this might apply.
	Thank you very much.
Discussion
	DR. SANTANA:  Thanks, Sharon.
	Well, we have had two very challenging presentations and I want to go ahead and open up the discussion.
	Anybody on the table who wants to specifically address issues or questions with David or Sharon?  Donna.
	DR. PRZEPIORKA:  Two questions for Dr. Poplack, one leading to the other essentially.
	You showed a very nice slide, I think the third to the last or second to the last slide, comparing outcome of various types of ALLs between pediatric and adult patients.  Just to follow up on that theme, I know there are not very many pediatric patients with adult type CML, but the prognosis for adult type CML in pediatric patients compared to adults?
	DR. POPLACK:  They do reasonably well actually, the adolescent patients, but heretofore have been treated with transplantation, which is clearly the favored mode.  There aren't very many of them, and I am not sure whether it would make--and I think I stated it--I don't think it would make necessarily much sense in incorporating them, whether we would learn anything different by including them in combined studies.  I think we have learned enough or we are learning from the adult experience.  We don't have evidence of biological differences.
	DR. PRZEPIORKA:  You made a very good statement regarding use of asparaginase in pediatric patients and how it has affected their outcome for ALL, and your table also shows the difference in outcomes for adults in pediatric patients, which one may assume may, in part, be due to the differences in treatment with the children being treated far more aggressively since the adults, especially the older adults, can't tolerate the very difficult therapies.
	What would you consider ethically acceptable when it comes to doing a mandated pediatric study which will, of course, we will have to assume has to start with a Phase I study in a population or in a disease where the adults have a very poor prognosis, but the kids have a much better prognosis?  Just from your table, the example is B-cell ALL with hyperdiploidy where the pediatric patients have a 89 percent survival, and the adults 30 to 50 percent survival.
	Would you really risk a Phase I study in that subgroup of patients?
	DR. POPLACK:  Would I risk a Phase I study?  I think, sure, there is no question that one ought to do it, until we are 100 percent success rate, then, it is appropriate to do Phase I studies.  I think the guiding principle always has to be the concern, obviously benefit, but the concern for toxicity.  If there were toxicities identified early on that were particularly concerning for children, I think people would be very, very concerned about going forward aggressively.
	But as I understand it, this discussion isn't necessarily mandating that studies be done in kids before adults.  We are talking about the need to do studies in both populations.  So, we would still be going forward with Phase I studies first being done in adults and then applied to kids.
	You are talking about the reverse situation, which toxicity would be greater for adults?
	DR. PRZEPIORKA:  No, if I had a drug which we used in one of the populations or diseases in adults which had a poor prognosis and showed a marginal, but definite benefit, would it be considered ethically acceptable, then, to mandate study of that drug and that disease in pediatric population where the current therapy already gives a much better outcome than in the adult population.
	DR. POPLACK:  Again, it depends on the toxicity profile from my perspective.
	DR. SANTANA:  Just a general comment to remind the committee members, whenever you use examples, be careful in the examples that you use for commercially available agents, and that we are not here to give specific advice on the development of those agents, so use them in the context of the general discussion to set forth a principle or a point of discussion.
	Yes.
	MS. ETTINGER:  I just wanted to sort of tie together two things that Sharon and David said, health benefits to children, which I think is something that obviously we are considering.  Toxicity does speak to long-term effects, and I think that when we are talking about children, we always have to remember that, and Dr. Head also brought that up, that we really need to consider not only what the short-term toxicity differences are, but that our patient population in pediatrics are going to live and possibly have long-term effects, which intrigued me in terms of what David said, looking at therapy-related malignancies, which may be some area for us to look at.
	DR. SANTANA:  Charlie.
	DR. SCHIFFER:  The rituximab example that you brought up, I think is an interesting one and brings to my mind what we are talking about.  You know, rituximab targeted a very small--not a small population--but a less than 50 percent of adults, and subsequent studies using this drug in other lymphoma and leukemia subtypes are in progress.
	I think most of us believe that, in general, the most important studies done about how to use a drug occur after the drug is approved.  Certainly the drug is available for both pediatric and adult oncologists to utilize in other disorders if it makes biologic sense.
	So, there is no difference if you go between adults and children with regard to this drug, but a difference, and I think the critical difference, if I was a pediatric oncologist, would be if I could get the stuff to use early, if it makes sense in my patient population to evaluate a new drug early rather than waiting until the development is far advanced, so I can get my hands on it.
	Rituximab, it probably didn't make initial sense to utilize in many of the pediatric B-cell disorders, as you suggest, as initial studies, but might make sense subsequently as it is being tested in non-follicular types of lymphoma in adults.
	I think a real issue that it seems to me is most important is when you can get the drug early to study in children, because it makes the most sense to study it initially in children or the disease is the same in adults and children, and you shouldn't have to wait until the studies are completed in adults.
	DR. MURPHY:  Charlie, I think you have two aspects to your comment there.  One is the early access to new agents, which is for a variety of reasons problematic, and there can be other discussion as to potential benefits or how that could be realized, but I want to go back to the rituximab example, because I was using it just as an illustration of how, if we were to apply the Rule today, how would it be applied.
	That is where I certainly had a problem.  I am not disputing your fact that while once it is available, you can test it in other things if it seems logical, but the question is would there be a mandate for this, and that is a different question, particularly if you are talking about mandates in B-cell pediatric lymphomas, they are all high grade and you don't have a lot of time to assess this, you don't have a lot of patients to assess it either because, you know, 80, 90 percent of children with high-grade B-cell lymphomas of any stage are cured now.
	That was the point I was trying to make.  The early part of it is a whole different thing, not restricted only to rituximab for sure.
	DR. SANTANA:  Sharon, I think somebody in one of the presentations or earlier discussion, I think said something that I noted down, which I think is also a very good guiding principle in making this decision, is the focus should be on where the need is, not to apply it to everything, because we have limited populations of patients, because we have patients that are now being cured, so it limits what patients potentially could go into the drug development process.
	I think that is where we have to give the advice to the regulatory and governmental groups, that we need to tell them where the focus should be based on where the need is, and not just to test it on everything, and it is hard, it is difficult, I appreciate that.
	Bob.
	DR. ARCECI:  I would concur with your comment, Sharon, on the rituximab.  I think that one of the things, however, we miss, and it goes I guess to Charlie's pick up on what you said is the use of these drugs early.
	Once they are approved, I think, and I would love to hear what other people have to say on this, I think we lose an opportunity to study them properly, because what I think happens, of course, is that many of our pediatric patients end up getting treated with the drugs off study for indications that it is unbelievable what a drug like rituximab is being used for now, from autoimmune disease to cancer in children with very, very little data-based, evidence-based studies.
	So, I think that without the ability to introduce these drugs early in the context of proper clinical trials, we will lose that because it is very difficult to get a patient on a clinical trial, very early clinical trial, once the drug is approved, because there is no incentive.  It can be used, and especially with some of the biologics, which have pretty nice toxicity profiles compared to intensive timing, sequential therapy.
	So, I think that there is a potential great, great loss unless we pursue that a little bit further.
	Another comment was on--I would love to hear what David and Sharon particularly have to say about the models, such as the MRC, where they have linked their pediatric and adult trials in a sequential fashion over the years, and is that a model that we should be considering further in this country, and would that help us with this agenda.
	Lastly, I think in terms of what Steven and then Sharon commented upon in terms of the definition of this Rule, I think, biologically speaking, it is not whether a translocation is present.  That is clearly the case, I think as you pointed out, David, just because you have a translocation doesn't mean the protein is being expressed, and there are many examples developmentally where even the same protein in a different developmental context is going to have a different effect on the function of that cell.
	So, the other issue is expression of a protein in those cells.  We have the issue of CD20, the issue of CD33.  These are antigen markers, so maybe we need to think about broadening the intent of that original concept to the purpose of the therapeutic trial, and expression, not just function, because the mere presence of the antigen may be appropriate then to mandate a study in pediatrics if the intent of the therapy is to target that molecule.
	So, it doesn't have to have anything to do with the disease.  It could be a differentiation bystander, as Sharon pointed out.  I think that is very important.  Just doing PCR for translocations is clearly not going to be relevant, as well, because of all these other modifying genes or expressions.
	So, I think we need to think maybe a little bit more about your initial--which I understand was clearly an initial way to start the discussion--but it is far more complex than that, and I think it is not unsolvable, but it would be nice to start thinking in our own minds of laying that out.
	DR. SANTANA:  Go ahead, Sharon.
	DR. MURPHY:  Since you directed that to David, and I just have one small comment about trial designs, although I know that is going to be the subject of another session, I think your allusion to the MRC model, the British model for the leukemia trials, is interesting, and I would entertain--I mean we already have good examples of where there has been cooperation here in the States in doing trials for adult and pediatric APL, and the same way with, well, perhaps not entirely the same, with the Ph-positive STI 571.
	I wouldn't want to see a complete morphing of leukemia trials to all adult and pediatric, because I think we would lose a lot there, but there may be selected subsets for which it makes sense, and I would include also lymphomas in that.
	We have had some discussions, although no action, about working with the adult cooperative groups to study, for instance, the lymphoblastic lymphomas and the Burkitt lymphomas, of which they don't have a real compelling study design to test, and they would just as soon test it on treatment being tested for younger people, and we could do the biology in tandem and collect a lot of good information, and I think that kind of design makes a lot of sense.  Again, it will take a lot of coordination to do it.
	DR. POPLACK:  If I can just also respond, Bob, I think that one of the things we really don't know, we talk about the prognosis being worse in adult patients with, let's say, a disease like ALL, but we also know that therapy can erode and eliminate the impact of many prognostic factors, and there really have been few examples of identical therapy certainly or even similar therapy being given to a cohort of patients that includes adults and pediatrics.
	It is perhaps notable that Dana-Farber now and their consortium are putting together a study where they are going to be putting adults and children with ALL on similar therapy, but I understand as part of the discussions that are going on, the issues of toxicities are playing a very important role.  It is not such an easy thing to do, even if one wanted to, to simply jump into doing identical studies.
	DR. SANTANA:  Malcolm.
	DR. SMITH:  To comment on the rituximab as an example of the challenges that we face, and how it also links the issue of early access with the Rule, rituximab hasn't been systematically studied in children yet, but it is not because the drug wasn't available to study, it really is the limited numbers of patients with the relevant lymphomas.
	So, there will be studies in children in the next year that will be started, but in this case, it is a real challenge how do you study rituximab in children when you have very limited numbers of children who relapse with current therapies, and then what are the questions that you ask once you do study it.
	Perhaps others can address that later, diffuse large B-cell, NHL, in a 15-year-old, what question of therapy do you ask if a rituximab question has been addressed in a 40- or 50- or 60-year-old, what can you extrapolate.
	So, not to beat on a specific drug, but it does illustrate the challenges that we will face when we begin to address these targeted therapies.
	To address Dr. Przepiorka's question about what can you do with the very good risk patients, how do you integrate new therapies there, just my experience in watching the pediatric groups conduct ALL studies for these populations over the past decade, the risks that you take in that population are very limited.
	The questions of therapy that you add have minimal risk associated with them compared to what standard therapy is, and so the question that you might ask in a patient population with Ph-positive ALL with a poor prognosis, that would be very different in terms of the risk associated with it compared to the question for a hyperdiploid or TEL-AML-1 population.
	Again, that is one of the challenges we face is targeted therapies may become available for those patient populations.
	DR. SANTANA:  Malcolm, since you are on that theme, how do you see the interaction between the FDA's mandate to sponsors when these issues come up and what is happening across the street in terms of the NCI/NIH developmental program for pediatric drug development, is there going to be cross-talk between those two, so that the FDA is not requesting that sponsors do studies that aren't possible to do, I mean where is that advice, where is that communication going to be coming from?
	DR. SMITH:  I think there will have to be that cross-talk, and the reality check of what can be done within the clinical trial systems that are available to test new agents, and so it is a dialogue with the NCI, it is a dialogue with the Children's Oncology Group, and with others.
	You can mandate studying five different new targeted therapies for childhood ALL, but if, in reality, only one could be studied in any reasonable length of time, then, you need to step back and have a dialogue to decide which one should go forward.
	DR. SANTANA:  Dr. Boyett.
	DR. BOYETT:  While I know that there certainly is a concern for numbers of patients to study in children, I think that we need to think broader than just the U.S.
	There are international investigators who have collaborated for the past three to four years because they realize that there are rare subsets of children with leukemia that we will not ever learn how to study in Europe or in the U.S. unless we work together, and this collaboration has been going on for some time, so I think we can think that if we have a target and we have a drug that has significant promise, that there will be patients available for us to test in an adequate way.
	DR. SANTANA:  Susan.
	DR. WEINER:  I wanted to pick up on Malcolm's comments and others about the coordination between the FDA and the NCI.  Malcolm had as a primary concern, and Peter Adamson, and others, of course, the question of prioritization of agents, and it is a real issue as to how the Rule will impact on that prioritization and how the prioritization is going to be decided as the pipeline drugs increase in number and the subject populations decrease with higher success rates.
	DR. SANTANA:  Steve.
	DR. HIRSCHFELD:  I wanted to personally express my gratitude for the excellent, excellent presentations that we had from our two initial speakers, and state that other speakers may possibly repeat some of the themes or maybe different, but we want to have an open discussion, and we also recognize that, as Dr. Murphy pointed out, you can keep splitting infinitely and always find differences, but we are looking for practical ways to approach the problem.
	Dr. Murphy brought up a few points which I thought bear some mention, and one is the issue of which drugs are going to be studied, is it only blockbusters, and while they may have been the first ones out of the starting gate or attracted the greatest interest, our analysis of the drugs outside of oncology, which have potential application in pediatrics, is that there are essentially no drugs or major drug classes at least which have not either had studies initiated or have had an interest expressed explicitly in studying them, so the program overall seems to be working.
	In fact, I was interviewed extensively by the Wall Street Journal who wanted to put a headline on this theme, only blockbusters, and when we went systematically through the various therapeutic areas, again outside of oncology, we could not find a single contrary example.
	In terms of the orphan drugs, that is a potential weakness and everyone recognizes it in the application of the Pediatric Rule.  We also have the default state the way the Rule is written that we can always grant a waiver if there are too few patients, so we could categorically exclude all of pediatric oncology and to say there are too few patients and we never have to apply the Rule, and that would be the end of that discussion, but we don't have to do that.  In fact, we would like to do otherwise.
	And why would we want to look as to how we could apply the Rule, and one of the reasons, which Dr. Arceci touched on, and which we have attempted to put the context in both the exclusivity incentives and the Rule, is that we are looking to establish evidence for use.
	We think that using these pediatric initiatives in some cases may be an important catalyst to initiate studies which would provide the types of evidence which we would all like to make our decisions on.
	DR. SANTANA:  Charlie.
	DR. SCHIFFER:  Just picking up on one of Bob's comments, I don't bemoan the off-label use perhaps as much as you stated.  I mean particularly in adult oncology, there are problems with off-label use, particularly of cytotoxics where drugs get just thrown at people one after the other, and you have to bemoan that outside of a study context, but on the other hand, that is how we learn how to use drugs when they are on the market and you study different doses and schedules and how to intercalate them into different regimens, and that is most of the trials that are eventually done in adult oncology because the original licensing trials tend to be very narrow and focused with a single goal in mind.
	Again, particularly with biologics, some cool stuff happens when you try it in autoimmune disease, for example, and it seems to me the nature of discovery is some imaginative people do it in creative ways, make some observations, which then in a more systematic way either get verified or denied, but I don't have perhaps as much concern about that.  I think that is, in fact, how we really learn how to use these drugs.
	DR. ARCECI:  I would certainly agree with the idea of using the drugs in unique ways after they have been approved is how you get creative usages in the future, and sometimes the original indication is not what it is best used for in the end.
	The problem I have is the--and I think we are probably worse at it or better at it in pediatrics, or maybe not--is the anecdotal aspect of doing it off of a study even in the context of a smaller trial, I think detracts from what we are actually going to ultimately learn in these circumstances.
	So, use it in autoimmune disease is a great idea, but don't just give it to a patient and let that result be buried in a clinical record that will never resurface because we never know what the denominator is under those circumstances, so there may be a lot of negatives that never get reported, and, of course, the couple kids who do respond do get reported.  I think what we do is unbalance it, so, yeah, use it in new ways, but I would suggest studying it and reporting both negative and positives.
	Maybe that is one way the Internet will help us in terms of publications.  We can afford electrons maybe more than paper.
	DR. SANTANA:  Dr. Boyett.
	DR. BOYETT:  Another point that might be coloring the reason we think that adult cancers and childhood cancers are different, historically, most children with cancer have been treated on clinical trials in university settings.  Certainly, you cannot say that for adults, and being a statistician, one wonders just how representative are the 2 to 4 percent of adults with cancers that are treated on clinical trials.
	Perhaps if we had 90 percent of the adults with cancers treated on clinical trials, we would really have a better picture of how different or how similar these diseases might be.
	DR. SANTANA:  One last comment.
	DR. WAXMAN:  I would like to echo what you are saying.  I think the need for studying small numbers of patients like you do in pediatrics well brings a great deal of information that in adult oncology and hematology, we just don't get because there too small number of people are on trial.
	So, one of the things we should consider is making these drugs available early, even if it is just a couple of patients that you people study, we are going to learn a great deal and help those children at the same time.
	So, I don't think we should worry about the numbers.  I think we should worry about getting quality information and having the drugs available for that purpose.
	DR. SANTANA:  Well, it has been a very interesting discussion, and we will continue during the day.  We are by schedule supposed to have a 15-minute break, so we will reconvene at 20 after 10:00.
	[Recess.]
	DR. SANTANA:  We are going to start now on the session on myeloid leukemias.  We are going to go ahead and get started because I want to stick to the time limits as best as possible.
	David Head is going to give us his perspective on myeloid leukemias and differences or similarities between adult and children.
	David.
Perspectives on Myeloid Leukemias
David Head, M.D.
	DR. HEAD:  Thank you, Victor.
	My name is David Head.  I am the Vice Chairman of Pathology at Vanderbilt.  Before that, I was at St. Jude Children's Research Hospital for 10 years, and I have worked for longer than I will admit in the federal record with the Pediatric Oncology Group, now part of the Children's Oncology Group and the Southwest Oncology Group and Adult Group.  I am a pathologist.
	First, let me thank the organizers, Dr. Pazdur, Dr. Hirschfeld, Dr. Santana, and Dr. Somers for arranging this session.  I am going to give my perspective of AML classification whether pediatric and adult diseases or the same or different.  I think the perspective is slightly different than the perspective that Dr. Murphy gave for lymphoid malignancies, and I will address that a little bit.
	Dr. Irv Bernstein is participating, I think, by telephone, although he is not hooked up yet, but I am going to show a few slides of Irv's, one, initially this, and then I will show it again at the end.
	Dr. Bernstein, can you hear us?  We can't hear you except sporadically.
	I am going to try and address a historical perspective of our understanding of myeloid diseases and a more current perspective.
	[Slide.]
	One of our charges is to compare adult and pediatric disease.  This is work that Dr. Bernstein did in Seattle at Fred Hutchinson Cancer Center, developing CMA-676, also known as Mylotarg, which is an anti-CD33 antibody with calicheamicin attached to it, I believe, that is aimed at killing myeloid cells.
	The point of this slide is to show that when he looked at colony formation by leukemic marrow cells from adult versus pediatric patients with AML, that the Mylotarg was actually more effective in the pediatric patients at inhibiting colony formation than in adult patients.  Well, how can that be?
	With this in mind, let me pose the questions that I posed earlier in open discussion, and that is, the general question, do pediatric and adult AML differ, and I think there are multiple levels to ask this question, do the hosts differ, and we have already discussed the hosts actually do differ.  Do the treatment goals differ?  The treatment goals may differ depending on the disease, how it is treated, how old the patient is, et cetera.
	I am not going to address either of those specifically, but I am going to address two other points.  One is do the exact diseases differ, disease defined on a genetic biological basis, not just generic AML, and the second is do the pathogenesis of the diseases differ, and by "pathogenesis," I don't mean how does, for example, 15;17 cause APL, but what causes the 15;17 to occur, not how does monosomy 7 cause AML or MDS, but what causes the monosomy 7 to occur, so pathogenesis at the level of creating whatever the genetic events are that actually caused the disease.
	[Slide.]
	So, from my perspective, AML is divisible, from my perspective, into two broad groups of disease.  There may be more, but we can at least define, I think, two broad groups of disease.
	One has an approximately flat incidence throughout life, and I say "approximate" because we don't know exactly because the studies haven't been done.
	The other has an exponential curve with progressive age.
	The same general sets of disease occur in the entire patient range.  This is a different set of curves than what Sharon Murphy showed for lymphomas, but the ratio of the two differs depending on where you are in the curve.  If you are out here, it is all this MDR-AML or 95 percent, and if you are over here, it is 85 percent TDN-AML.
	So, what do I mean by these two sets of disease?  The block show the agents and its AML for population at risk, per 100,000 population at risk per year.
	[Slide.]
	Much of this is published and it is in the folder that was distributed.  So, these are the general characteristics of these two sets of disease.  More common in the elderly versus relatively flat incidence, often has prior MDS, never has prior MDS, myelodysplastic syndrome, MDS.  MDS-like cytogenetics, recurring translocations, multilineage dysplasia and background to hematopoietic cells absent, often clonal background hematopoiesis both at diagnosis and complete remission, nonclonal hematopoiesis, generally poor response to chemotherapy, potentially cured with cytotoxic chemotherapy, differences in MDR1 expression, multidrug resistance gene 1 expression, putatively a different cell of origin, a more primitive stem cell versus at least in some cases a more differentiated stem cell, and we have iatrogenic models of both of these.  Alkylating agents, topo II inhibitors.
	Now, some of this is surmised from literature, not much of this was done in prospective study.  This is an attempt to garner some kind of logical synthesis out of available data.
	[Slide.]
	This is quite different than the historical approach to AML, embodied in the FAB classification of AML.  This was a very useful exercise generated by a working group of morphologists, the French-American-British group in 1976, with the stated reason if this was to allow evaluation of the efficacy of this historical approach, which was not new with them.
	This approach began in the year 1900, and that is not an exaggeration.  In 1900, Naegli described myelomonocytic leukemia.  That is M4.  In 1913, Schilling described monoblastic leukemia.  So, we have been doing this for 100 years now, this approach.
	[Slide.]
	This approach is based on the presumption dating back even to the 1850s that we can characterize malignancies based on how they recapitulate normal cells.  This is a hematopoietic tree, and are the cells erythroblasts or megakaryoblasts, myeloblasts, monoblasts, et cetera.  So, this is the historical approach to classification.
	Is this approach relevant?  Well, this was published in 1976.  This is the Southwest Oncology Group study, started in 1978, and I think you can see that there aren't any big messages here, it does not discriminate disease subsets that have different response to at least chemotherapy used on this protocol, and this has been repeated over and over and over again in other studies, so it is clinically, substantially an irrelevant approach.
	[Slide.]
	This is a different Southwest Oncology Group study, the critical study here being 81;24, that used high-dose anthracycline, high-dose daunorubicin, and it showed a remarkably good outcome in one subset of AML, promyelocytic leukemia.
	So, this was initially used to endorse the FAB classification, well, gee, it means something because look at this, but I will just point out that M3--I will come back to this later--but M3 is essentially a morphogenotype, 95 percent of promyelocytic leukemia or FABM3 as a single cytogenetic translocation that appears to be the driving factor in creating this disease.
	So what is important, is it the genotype or is it the morphology?  I would submit it is the genotype based on further developments, for example, with all-trans-retinoic acid.
	[Slide.]
	From the standpoint of our mission today, although this is different subsets, this is young patients meaning less than 60, I believe, on this study, who got high-dose anthracycline, and this is other patients, young and old, who got low-dose anthracycline, and whether young or old, they had basically the same treatment response for anthracycline dosage, but the high-dose anthracycline was not given to elderly patients, illustrating it was because of presumed host differences, but this would suggest the disease is probably the same disease even though the host differs.
	[Slide.]
	So, I mentioned AML cytogenetics, in particular 15;17 in promyelocytic leukemia, so let's take a minute to look at cytogenetics in AML.  This is far from an inclusive list, but it is one illustration point.
	There are a series of recurring translocations that have been described in AML.  All of these have now been cloned, the genes have been identified.  They are at the breakpoints.  There is extensive study in multiple labs about how can these transform, are the single events sufficient to transform or are other events needed to transform, and if so, what are the other events in each case.  So, there is extensive study going on with this set of diseases from t(6;9) up.
	There are correlates if you start with the cytogenetics and move to the right.  So, for example, 8;21 usually has M2 morphology in FAB, but it is not always, it may be other morphologies.  9;11 typically has M5, but it may be a lot of others; 15;17 is 95 percent M3, and version 16, about 50 percent M4eo, but I would suggest that that is not the point of the historical classification, it is not, well, if you know something else, you can go this way, it is if you know this, can you go this way and predict anything.
	I suggest you can't predict very much except for this line here, if you have got M2, what does that mean?  Well, it is on almost every line, so even though there are some correlates moving right to left, there are a few correlates moving left to right that hold up.  So, I think that is a further indictment of the historical approach.
	The second point is from 6;9 up, the median age of all of those is in the 30s, which is the median age of the population.  They all have approximately flat incidence in childhood and young adults, but they all persist into the elderly at a diminishing percent of total cases, so this has led me to suggest these must have an approximately flat incidence throughout life, and I think what data are available will support that, although we need more data to corroborate that.
	As opposed to that, the second set is found mainly in elderly patients.  It is not restricted to them, it is found in younger patients also, 5q- being a possible exception, which is rare in pediatric patients, but generally, -7,7q-, trisomy 8, complex cytogenetics, and a whole litany of other things are found in AML throughout life, but they exhibit this progressive exponential increase in frequency with progressive age.
	A second point is there is essentially no correlation between morphology and these.
	[Slide.]
	This is the age incidence of AML for population at risk.  I showed you that.  This is the population in the United States just a few years old.  There are the baby-boomers, and they have moved over to here somewhere now, but nevertheless, the curve stays about the same, and if you integrate all this, the median age of AML in the United States and Western Europe is in the 60s, I believe it is 63.  As the population ages, it is going to predictably move up because the incidence goes up.
	The median age of those recurring translocations is in the 30s, which happens to be the median age of the population, as I mentioned earlier, and the median age of something out here, the rest of the cases must be even greater than 63, must be in the 70s or 80s even.
	[Slide.]
	This is the age incidence of MDS.
	[Slide.]
	Let me back up again.  This disease in the elderly, that is increasing in incidence for population at risk, and is at least half of AML, has the following characteristics - it is resistant to cytotoxic chemotherapy, it tends to have clonal hematopoiesis, it tends to have clonal remissions, the background marrow is overly sensitive to chemotherapy, so the patients have prolonged cytopenias with aggressive chemotherapy.  If they get into remission, the remissions are short-lived, tend to be clonal, and the patient relapses with the same disease.
	Although that is what I have just described as AML in the elderly, it also has MDS-like cytogenetics, I left that out, monosomy 7 and 5q-, for example.  Although I described that story for the elderly, that story is virtually the same in young patients who have monosomy 7, they just occur at lower incidence.
	Over here, that group is 95 percent of the disease, over here it is 15 percent of the disease, but the characteristics of the disease are virtually the same.  The only way to cure that set of patients right now appears to be an allogeneic transplant, which we luckily can do over here, we can't do that over here, and there is basically no curative approach to this set of disease.  I think most adult oncologists would agree with that now.
	[Slide.]
	So, this set of data led me to propose, well, we are dealing with two different sets of disease here.  That is in the paper, in the handout.  One, I call myelodysplasia related to AML because it has features to suggest it is related to myelodysplasia.  It has monosomy 7, 5q-,+8, has background dysplastic morphology.  When it enters remission, it often looks like MDS, and the disease shares multiple features that I just described with AML following overt MDS.
	[Slide.]
	And given this age incidence of MDS and the fact that 10 to 40 percent of these are going to progress to AML we know, I think, that is this set of disease.
	The other set is the set with a median age in the 30s, and there is one important additional point to garner from this slide.
	[Slide.]
	That is, this is the age incidence of a disease at least that can be explained by a multi-step, random multi-step pathogenesis, for example, colon cancer.
	An age incidence like this was used to predict that colon cancer has a random multi-step pathogenesis, and this has been largely borne out in studies coming from Johns Hopkins, for example, and other institutions over the last decade.
	So, this doesn't prove a random multi-step pathogenesis, but it does have implications about the pathogenesis, whatever it is.  Whatever the pathogenesis ends up being has to explain this age incidence.
	If this is, for example, a multi-step pathogenesis, what is this, and this cannot be a random multi-step pathogenesis, it can't, because that gives you this curve.
	So, without even knowing what the pathogenesis of either of these sets of disease is, we can say, I think with some assurance, the pathogenesis has to differ in these two sets of disease, and this has to be some fairly simple rate controlling pathogenesis.
	For example, in some cases, this could be a recurring translocation even if the recurring translocation is insufficient to explain the disease.  It can still be the rate-limiting effect, and once you get that, other events happen, and you then develop whatever disease is characterized by that translocation.
	[Slide.]
	So, how does the FAB--I have given you a model here of AML--how does the FAB classification work with this model?  This is a very simple study we did in SWOG comparing patients less than 50, who should be predominantly true de novo AML, and greater than 50, who should be predominantly myelodysplasia-related AML.
	I think you can see the historical approach abjectly fails to spot these differences, which I would submit are much more important clinically and biologically than whether the case is myeloblastic leukemia with minimal or more differentiation or myelomonocytic leukemia or monocytic leukemia, for example
	So, the historical approach totally misses these very important clinical and biological discriminants, so from my perspective, although this is very useful for pathologists and morphologists for recognizing the morphologic variants of AML, for diagnosing AML, at that point it becomes substantially irrelevant, and we need another classification, which I have proposed.
	[Slide.]
	Let me just use promyelocytic leukemia to illustrate the true de novo subset.  This is a classic picture for promyelocytic leukemia, I won't go into the details, but hypergranular cells and lots of Auer rods, for example, very characteristic.
	[Slide.]
	It has a recurring translocation, ignore this down here, it is obsolete, but the picture is correct, the 15;17 translocation.
	[Slide.]
	Genes have been cloned, PML and chromosome 15, RAR-alpha and chromosome 17.  We have identified that these both appear to be important maturation regulators although especially for PML, we don't understand quite what it is doing yet.
	We have characterized these translocations.  There are three different translocations that occur.  Extensive work is going in the study and other de novo subtypes of leukemia.
	[Slide.]
	We did an extensive analysis combining cases from St. Jude and the Pediatric Oncology Group, pediatric patients, and the Southwest Oncology Group, adult patients, and we basically couldn't see a difference in the two subsets from the standpoint of morphology, cytogenetics, and molecular testing.
	These are the participants in the study.  Of 71 cases that had confirmed 15;17, 68 were acute promyelocytic leukemia.  I will point out, though, that 3 were not acute promyelocytic leukemia, and this type of case still responds to all-trans-retinoic acid in the literature, and there were other cases that had promyelocytic morphology, but lacked the 15;17.  These cases were entered in the first U.S. ATRA study because entry was based on morphology, not on genetics, and those cases do not respond to ATRA.
	So, I would suggest that for this morphogenotype that appeared at first to corroborate the historical approach to AML classification, that, in fact, it is the genetics that are important, it is not whether they are actually promyelocytes or not.  That is simply a secondary feature of the genetics in most cases.
	[Slide.]
	So, this leads to two different models for leukemia.  For the true de novo subtypes, there is some kind of initiating event that starts cells growing in a transformed state.
	This doesn't say whether there was one event or several concomitant events, but it appears that once you transform a cell and perhaps escape immune surveillance, these cells just start dividing, 1, 2, 4, 8, 16, 32 until you get to about 1012 cells.  The only difference there is you now have a tumor burden that gives you clinical symptoms, but you have had the disease for a long time.  If you can spot this disease early, you should treat it early, as soon as you are sure you have an uncontrolled proliferation with one of these characteristics, that is leukemia.
	So, to speak of, as is known in the literature, myelodysplastic syndrome with favorable cytogenetics meaning disease with an 8;21 translocation and a low blast count, 10 percent less, no, that is not myelodysplastic syndrome, that is AML, and you just were lucky enough to catch the patient early.  It is still true de novo AML, and it should be treated as such, and that same story is true whether you are dealing with an adult patient, a pediatric patient, or an elderly patient.
	If an elderly patient has one of these diseases, the disease responds the same to the treatment regardless of age.  The host may differ, but the disease is the same.
	As opposed to that, the other set of disease is very complex and is receiving very little study right now even though it is half of AML.  These cases are vastly under-represented in adult oncology trials because they are very difficult to treat, the treatment is very unsatisfactory, but also, very little is being done to try and ferret out the biology of these diseases.
	We have no idea in most cases what the initiating events are.  There are some clues from some pediatric syndromes, Fanconi's anemia develops this set of disease, severe congenital neutropenia, Kostman's syndrome develops this set of disease.  We know that some drugs cause this set of disease, other drugs cause this set of disease, so epipodophyllotoxins tend to cause in particular where to go.
	MLL/AF9, for example this set of disease, MLL translocations, alkylating agents, various cross-linking agents cause this set of disease, but once we get past that point, we have little idea what the pathogenesis of this set of disease is.
	We know there are multiple steps.  We can define a low-grade MDS, a high-grade MDS.  We can probably define some events that happen when this progresses to leukemia, like EVI-1 dysregulation in RAS point mutations, perhaps C-fems point mutations.
	But what happens over here and what causes all these just remain a mystery right now.
	[Slide.]
	So, let me then close.  I have given you my assessment of the historical approach, a different approach that I have proposed, published in 1996, that we use now in the Southwest Oncology Group and to some extent in the Children's Oncology Group, we are evaluating these.
	This is the World Health Organization, new World Health Organization classification of AML.  I sit on the subcommittee.  Other members of the subcommittee are John Bennett of the FAB group, George Flandron of the FAB group, Estelle Matutes, who works with Daniel Catofsky in London, of the FAB group, Richard Drumming, the chairman, and myself, and we did not reach 100 percent agreement, and ended up with a compromise, but I will present the compromise.
	There are four subsets in this classification, AML with recurrent translocations, which corresponds approximately to my true de novo AML; AML with multilineage dysplasia, which corresponds approximately to my MDS-related AML; AML and myelodysplastic syndrome therapy related, and I have described that there are, in fact, iatrogenic models of these two unfortunately, and that is what this group is, alkylating agents for this set and cross-linkers; and epipodophyllotoxins and some other drugs for this set, and then AML not otherwise categorized, and I will come back to that in a minute.
	[Slide.]
	So, this is some of the recurrent cytogenetic abnormalities.  For reasons I don't completely understand, we didn't list all of them, but we just listed these four, but nevertheless, it is basically true de novo AML in my classification.
	[Slide.]
	Acute leukemia with multilineage dysplasia was limited to these two settings.  I would have included AML with monosomy 7, trisomy 8, complex cytogenetics.
	[Slide.]
	And MDS and AML therapy related.
	[Slide.]
	And before I show the next slide, one directive we were given was this is the World Health Organization classification, it is not just the United States, Western Europe, and Japan classification, so we had to create something that was to some extent applicable around the world where they don't have access to many of the more refined technologies that we use, so a fourth category was added, and this is basically a slightly refined FAB classification of AML.
	So, what we have then is a classification based on two different sets of ideas, attempted to be melded into one classification, but this is the genesis of WHO classification of AML.
	[Slide.]
	I have one more slide.  This is Dr. Bernstein's slide, again.  I will ask Irv--are you there, Irv?
	DR. BERNSTEIN:  Yes, I am.  Can you hear me?
	DR. HEAD:  Yes, we can.  Would you care to comment on your PMA 676 inhibition slide?
	DR. BERNSTEIN:  Maybe I will just make two points.  The first is that I agree with what you said.  But, given that, it is clear that in the future we will be looking at comparability between adult and pediatric disease even more based on genetic abnormalities.
	I would just want to point out that although we don't know the complementing events that occur with known translocations or the events with leukemias, we are rapidly learning mutations, for example, cytokine mutations.
	One has to believe as new drugs are being developed that will target pathways that are affected by these mutant cytokine receptors, that one would really define leukemias between adult and pediatric based on the lesion of the particular molecular pathway.
	So, although we need a classification, in the future, one way of defining will be abnormalities of the pathway that new drugs will specifically target, and that is clearly an area of interest.
	In terms of functional effects of drugs, the one thing I would want to point out is that in the development of Mylotarg, this is the gemtuzamab ozogamicin or the anti-CD33 antibody calicheamicin conjugate, that, in fact, was developed based on the notion that for at least most pediatric and young adult patients, disease was unipotent, that is, usually limited to granulocyte and monocyte differentiation as opposed to more frequently seen in the elderly patient where there is multilineage disease.
	So, based on that concept that was worked out by Phil Fialco, looking at G6 PD polymorphisms at a clonal marker, there was a notion that precursor cell involvement may be greater at the committed myeloid stage for patients with unipotent disease, and it was based on that, that we thought that targeting committed precursors would be useful with anti-CD33 antibody.
	I think the important point is that since that disease was a disease of younger adults and pediatric patients, we, in developing this conjugate, selected linkers based on their ability to kill leukemic colony-forming cells in vitro from pediatric and young adult patients, younger than 60.
	In fact, if you have the slide up, what you can see is that we selected a linker to join the drug and the antibody, such that the killing that we observed was, in fact, greater for pediatric patients than for adult.
	So, here is an example where a drug was developed on a concept that applied to young adults and pediatric patients, that was, in fact, most optimized for pediatric patients and really for evidence of functional information about a drug that probably should have been tested in kids first and adults second, but obviously, it was done the opposite way, so I think that best made the case for testing in pediatric disease, as well.
	Otherwise, I have no other comments to make unless I can answer any questions.
	DR. HEAD:  Thank you, Irv.
	I agree completely with Dr. Bernstein's comments, and I don't mean to minimize in my presentation the importance of secondary events in these leukemias, but what I have tried to present is an overview model, an overriding model to allow us to synthesize data in the future.
	In my overview in which I attempt to create a different structure to look at leukemias, I am not saying secondary events after an 8;21 translocation or a 9;11, et cetera, are not important, and may actually have therapeutic benefit or clinical relevance, but I think to get to that point, we first have to get to the point of accepting these are each different diseases that we need to look at separately.
	I would just make one last point, and that is, in my estimation, to make progress in treating these diseases, we are going to have to admit that these are multiple different diseases, 9;11 AML is not the same as 8;21 AML.  They may have different chemotherapy response profiles, and they are going to certainly have different biological response profiles, and we are going to have to figure out how to do studies for specific genetic diseases.
	I have suggested that at least there is a basis for treating the specific genetic diseases very similarly or identically in young patients versus older patients.
Discussion
	DR. SANTANA:  Now we have time for direct questions and discussion with David's presentation and Dr. Bernstein's comments.
	I want to have a brief comment, David.  One concern that I have with this WHO classification is that that last category seems to be the excuse category, that you can't do the cytogenetics, you don't have that other information, and therefore, you fall back on the old principle of using morphology, and the concern is that if this classification is used widely for study design, then, you are really going to be into trouble, because you are going to have patients that are not truly representative of the best.
	Do you see what I am saying, that you are going to be then having information on some patients based on trial design that are specific for a cytogenetic issue, but then a great proportion of those patients in which you don't have that information for whatever reason, how did those patients get treated, and what do you learn from those patients.
	DR. HEAD:  I agree with that point completely, and think the last category should only be used when a sincere attempt for studies in the United States, after a sincere attempt to place the patient in the first three categories fails, that the patient does not have a recurring translocation and you can't decide which category to place the patient in.  I agree with you completely.
	DR. SANTANA:  Dr. Arceci.
	DR. ARCECI:  A couple quick comments, I think, and actually questions.
	One is the idea of the hematopoietic stem cell leading to a leukemic stem cell in this situation.  I know certainly Irv and I, in our strategy group, have discussed this at length, but in fact, in some of the data that is occurring, maybe, it is not, in fact, the stem cell that is either further back or further forward with the exception possibly of APL, but it is really what lesion occurs in that stem cell that leads it into your two categories.
	So, it is not how far back you go in lineage necessarily, but it is what lesion you acquire in that setting.  I would be curious to know what you thought about that because I think it has implications in terms of your last point in terms of genetic targeting.
	The other question is can we, are we at a point where we can define potential therapies or classification just on the molecular genetics of these lesions?  For instance, TEL was originally cloned out of a myeloproliferative disorder, not ALL, where it's a good prognostic feature, and I think that if you just had a PCR result on a chromosome 12 TEL-related event, and you didn't have anything else, I think you could make the wrong therapeutic decision based upon that molecular lesion depending upon what cellular context that lesion took place in.  It is really a question.  I don't know the answer.
	DR. HEAD:  From the standpoint of the first question about how primitive the stem cell is, I think in myelodysplasia-related diseases, the stem cell involved has to be at least a multipotential myeloid stem cell because the cases have multilineage dysplasia.
	So, if you have dysplastic megakaryocytes, granulocytes, and erythroid cells, the lesion must be in their precursor or more primitive.  For the true de novo cases, as more data become available, it is not clear how primitive the stem cell involved is.
	Promyelocytic leukemia may be an exception.  It appears to be a fairly committed myeloid stem cell there.  The 8;21 translocation appears to have and also in a multipotential myeloid stem cell, so can you speculate, well, what are the differences, and I can only speculate.
	I speculate that the differences in the underlying pathogenesis of the process, that actually the real unifying feature in MDS and that sort of disease is that they are a mutator phenotype and get progressive complex genetic damage that leads to leukemia, but that is speculation.
	DR. BERNSTEIN:  If I could add one point on that, Bob is absolutely correct that we really can't tell where that lesion occurs.  I think what the experience speaks to is either where the lesion occurs or where unregulated expansion of the cell occurs, and that would be where, whatever this lesion is, would affect the context of signaling in that cell.
	So, in fact, when John Dick's animal models claim that early, very primitive precursors are involved in the leukemic process, that is probably correct.  The differences probably are that the unregulated expansion of precursors doesn't occur until a particular stage of differentiation of multipotent or unipotent cells.
	So, in a sense, both answers are correct, and the differences are probably quantitative differences in the involvement of the earlier cells.  It is not clear how to translate all of this, but at least it is a concept to think of.
	DR. ARCECI:  And what about Down's syndrome and infant leukemia, could you guys comment on that because those may be exceptions to what we are talking about.
	DR. HEAD:  I will comment first and then if Irv has comments, Down's syndrome is a perplexing exception because it appears to develop, has a high incidence of AML, and the AML is often preceded by what appears to be myelodysplastic syndrome, and yet, in total contrast to all the rest of myelodysplastic syndrome and MDS-related AML, AML in Down's syndrome has an outstanding prognosis, and I don't know how to explain that.
	The second, infant AML, I didn't mention infant AML, but it is very interesting.  AML, less than one year of age, has a different set of recurring cytogenetic features than AML after approximately one year of age.  Less than one year of age, well over 50 percent of AML has an MLL translocation, and after one year of age it reverts to the approximate frequency throughout the remainder of adult life, which is on the order of 4 to 5 percent.
	There is a second subtype of AML, megakaryoblastic leukemia with the 1;22 translocation that appears to be confined to patients less than one year of age.
	So, there have some interesting biological implications, also suggests some interesting pathological implications that these translocations are not just stochastic events happening by chance, there are factors influencing their happening even though we don't know them, and whatever those factors are appear to change from the in-utero environment to the ex-utero environment.
	DR. ARCECI:  But the MLL of infants, would you target that the same way you would target the MLL of the older child in terms of this conference?
	DR. HEAD:  And I don't know the answer to that.
	DR. SANTANA:  Dr. Boyett.
	DR. BOYETT:  A question for Dr. Bernstein.  I am sure you have mentioned it, and I missed it, but in your data for the CMA-676 analysis where you had adult and pediatric AML cases, what was the defining genetic defect, and was it the same in both samples?
	DR. BERNSTEIN:  That actually was not looked at in those samples, and we actually don't know the impact of genetic defects on the effectiveness of the conjugate.
	DR. SANTANA:  Dr. Borowitz.
	DR. BOROWITZ:  Could I ask Dr. Bernstein, do you have any comments on Dr. Arceci's previous questions?
	DR. BERNSTEIN:  The only thing I could say is that MLL defects in infant leukemia, you know those are interesting abnormalities because they clearly arise in utero, they can be transplanted in twins from one to the other, so they may be single events leading to that leukemia.
	It is interesting that the prognosis of older children with AML is quite different, so one might speculate that there are differences, the context that arises at a later time, but obviously, there is something we don't know very much about except the striking difference in prognosis.
	DR. BOROWITZ:  Yes, sort of a comment and maybe to comment back, it picks up on something you said, David, about thinking about every one of these diseases as a unique entity.
	I don't in any way want to minimize what we have learned or the importance of understanding the mechanisms of specific translocations and how downstream events may lead these to leukemia, but when you step back a bit and talk about therapy, and talking about designing targeting agents, it seems to me that if that is the overweening strategy that one uses for treating leukemia, that you wind up with a bunch of orphan drugs.
	I think the contrast between ATRA as a therapeutic agent and Mylotarg as a therapeutic agent, I think are striking because Mylotarg looks at some common phenotypic property that all of these leukemias, I won't say irrespective of their genetics, but likely lumping several of the similar genetic lesions end up sharing an important phenotypic property.
	I think in terms of rational design for therapy, we are all, as we sort of explode our knowledge of the detailed mechanisms of leukemias, it is always attractive to look towards very specific genetic targets, but I think we should be trying to look downstream in commonalities of these things because I think over the long haul, we will wind up with more effective agents.
	DR. HEAD:  That is a very good point, very practical.
	DR. SANTANA:  Dr. Hirschfeld.
	DR. HIRSCHFELD:  I had a very specific question to Drs. Head and Bernstein.
	There is some speculation that the MLL translocations--and it relates in a way to Dr. Arceci's comment, too--the MLL translocations in infants may be similar to the type of translocations seen secondary to exposure to cytotoxic therapy.
	I wanted to hear your sense as to the credibility of that speculation and whether one should consider these types of leukemias to be in the type of classification scheme that Dr. Head is discussing, to be in the same category.
	DR. HEAD:  Irv, can you comment on that?
	DR. BERNSTEIN:  I can say there are epidemiology studies asking about exposure of mothers to topo II inhibitors, and I can't really comment on that.
	Molecularly, can anybody comment whether the breakpoints are precisely the same or different between the two entities?
	DR. SANTANA:  Dr. Arthur?
	DR. ARTHUR:  I know that Dr. Rowley was conducting some studies particularly into that, thinking of the breakpoints in the treatment-associated patients might be different, but I don't know if that has been definitively decided.
	DR. HEAD:  The extent of my knowledge, which I have been remembering while I asked people to speak, Dr. Rowley's group, and also Dr. Peter Domer, have looked at the specific intronic break in post epipodophyllotoxin AML versus infant AML to see if the breaks were in similar portions of the intron, and I believe the conclusion was although it was an attractive hypothesis, that maybe there were topo II inhibitors in utero that were leading to this secondary MLL disease.
	I believe the conclusion was the breaks in the infant disease were at different sites in the introns and the breaks post epipodophyllotoxin, which then suggests that at least infants versus secondary epipodophyllotoxin MLL translocations may have a different pathogenesis even though they both result in similar translocations.
	DR. SANTANA:  Dr. Poplack.
	DR. POPLACK:  I was just going to make a comment in follow up to Michael's statement about the search for common downstream events.
	I think that is clearly the ideal, but it actually may be that as we search downstream, we find less commonality and more uniqueness, and if so, perish the thought, we may be talking about AML, for example, as a disease that ultimately is optimally treated by 35 different specific targeted approaches and a clinical trialist's nightmare.
	So, yes, we always have to look for the common, but we may have to be prepared for the fact that for us to get to 100 percent across the board may require a totally different paradigm than we have used in the past.
	DR. BERNSTEIN:  Could I make a comment on that?
	DR. SANTANA:  Yes.
	DR. BERNSTEIN:  You know, it is correct that if one looks at the computations of mix and match, for example, 8;21 plus a second or a perhaps third mutation, that one will have a myriad of diseases, but, you know, if one looks, for example, at FLT-3 tandem repeats, you have a substantial percentage of patients who have this, where one really could envision targeting specific lesions where the complementing lesions in a particular leukemia may be very different.
	So, I don't think it is far-fetched in one set of circumstances in development of very specific drugs, that one really could define large groups that may benefit.
	As far as looking at the whole of leukemias, it is still possible that for very powerful cytotoxic agents that kill in general, that the differences, the discriminators between adult and pediatric may be the opportunity to develop resistance mechanisms, for example, the substantial differences in MDR in patients at diagnosis, you know, younger versus older.
	I think one, rather than limit oneself with classifications, really needs to ask some very specific questions about if it is a very specific targeted therapy for a pathway, one could look at that pathway independent of other events, and if it is a general cytotoxic agent, then, one could not only ask molecular specific, but needs to pay attention to what might be a resistance mechanism that may be common or dissimilar between pediatric and adult.
	DR. SANTANA:  What is likely to happen, though, my own simplistic view, what is likely to happen in the next couple of years is that as the fields evolve or complement each other, that we are not going to abandon the traditional cytotoxic, neither are the sponsors, and the new specific molecular targets will be identified, drugs will be developed or biologics to that, and they will be complementary to a certain degree to what we already do.  I mean that is my own simplistic logic here.
	Bob.
	DR. ARCECI:  I would actually hope that we do abandon them and that--you do, too, I know you do, Vic--
	DR. SANTANA:  I just don't know, I don't have enough information.
	DR. ARCECI:  But in some respect we may have a different backbone, such as non-genotoxic, cytotoxic agent, such as the farnesyl transferase inhibitors or monoclonals, those approaches to cytoreduce generically, but then I think, as David pointed out, in terms of what you are saying, Michael, and the specificity of these lesions, I think that as you look further downstream in terms of signal transduction, for instance, you are going to find more commonalities that are going to also be more common to normal hematopoietic and other cells in the body.
	So, for instance, internal tandem duplications of FLT-3, will induce certain signals downstream.  A different mutation in the c-kit receptor will also initiate and up-regulate those downstream signals, for instance, STAT-3.
	So, if you target the STAT-3, you are going to affect normal cells potentially, and I think that is where Irv was talking in terms of drug resistance.  Mostly normal cells are going to be more resistant.
	However, the issue here is if you target FLT-3 with a specific drug, you will more likely affect those cells with less toxicity to normal tissues, whereas, that may not work in those with c-kit mutations.
	So, I think it is going to be a balance, and if we have to, in a sense, put clinical trialists out of business by going to more molecular approaches, so be it.  I think we would all be unhappy with that if we ended up that way.
	DR. SANTANA:  Charles.
	DR. SCHIFFER:  To get back to why we are here, if we have a drug that for some reason we think targets 8;21 or MLL, I would propose that that drug should be developed, particularly if it is a targeted drug, simultaneously in adults and children, and possibly in the same trials.  I mean that is what you want out of this, I think.
	As Sharon said, there is certainly precedent for this.  The APL trial is a very good example.  These are relatively uncommon phenotypes, et cetera.
	One of the nice things about the highly targeted drugs so far is that you didn't need statisticians, you needed two patients, and you knew you were on to something, and the subsequent trials were to determine how best to use the drugs, and I would suspect that if you develop small molecule inhibitors of many of these discrete, necessary, but not sufficient mutations, we are going to see the same thing.
	But even if there is a difference in infants with 4;11 or MLLs, well, then, it will fall out.  You know, when you have such a hypothesis and a discrete target with good in vitro data, then, include them all and see what happens, and build on the APL model and do it quickly, and I think that pharmaceutical companies should hear this also.
	DR. SANTANA:  Dr. Borowitz, you had a comment or question?
	DR. BOROWITZ:  I just sort of wanted to return to my comment that has elicited some response, and I didn't mean to suggest that when I say look at downstream commonalities, that doesn't mean that I am suggesting that we go back to conventional chemotherapy strategies.
	The idea is if we focus just on the sort of cytogenic translocation, and not the downstream common pathway elements, I think we miss an opportunity to do more intelligent design, and they could either signal transduction pathways or apoptosis pathways, or things like that, and I think we can't get too sucked into our advances in classification and assume that that is going to be the only answer to our therapeutic approaches.
Questions to the Committee
	DR. SANTANA:  If there are no further comments, I want to go ahead and start addressing the questions because the FDA has posed some questions for us that we need to advise them on.  I think that we have covered some of it kind of here and there during the discussion, but I want to be more formal and go through them.
	My first comment is I don't think you are asking us to endorse one classification system versus another with the first question, you just want some general comments in terms of if we were to use the FAB classification, how that could potentially be used in children and adults, and so on, and so forth.
	DR. HIRSCHFELD:  Right.
	DR. SANTANA:  So, let's try to deal with the first one then.
	DR. HIRSCHFELD:  May I just comment that the intent is not to make one point of view "the official FDA point of view," but rather just to elicit comments, and we are not asking for votes on any of these questions, but just would like the issues that the questions raised aired.
	DR. SANTANA:  The first question is - For myeloid leukemias and myelodysplastic syndrome:  A.  Should the FAB classification be used as a basis for relating adult and pediatric myeloid malignancies?  If you think not, what other criteria should be used?
	Dr. Arceci, do you want to start addressing that?
	DR. ARCECI:  I think that David and Michael would agree that that is probably an inadequate classification to make those decisions on.  I think you would have to take it to the next level, as I think David and others have pointed out.  So, I would say no.
	DR. SANTANA:  David, do you want to comment on that or follow up?
	DR. HEAD:  I agree completely.  That was the point of my talk.  I think we need to move beyond that.  I have suggested two broad groups that I think are more relevant.  To the extent we can define those two groups, I think we should use those two groups.
	When we can define groups more specifically, for example, t(8;21), t(15;17), I think we should use those.
	DR. SANTANA:  So, what you are saying is that the corollary note to that answer is that the other criteria that should be used, should be some cytogenetic criteria or molecular criteria?
	DR. HEAD:  Should be cytogenetic, molecular, if such are available.  Those are not necessarily available for myelodysplasia-related disease because 40 percent have normal cytogenetics, for example, and we don't know what the molecular events are in this set of disease.
	So, in some settings, it needs to be based on other parameters, for example, history of MDS, history of drug exposure, background dysplasia, which is used in the WHO classification, if you can do it and corroborate my synthesis of the data, clonality, if hematopoiesis, may be something that could be used, at least in females, et cetera.
	DR. SANTANA:  Sharon, you had a comment?
	DR. MURPHY:  I think David is being very modest.  I think he has presented a wealth of data, and it has been now widely shown the FAB classification should not be a basis for making decisions.
	The criteria, at least for starters, should be this broad separation, I think, between true de novo AML, characterized by these chimeric proteins and specific translocations versus the myelodysplastic-related AMLs for a starter.
	I applaud his contributions and the fact of getting us all to think about a new way of thinking about AML.  I mean I have decided I am going to stop teaching the FAB classification is my plan.
	DR. SANTANA:  Dr. Bernstein, do you have any comments on this?
	DR. BERNSTEIN:  I agree with those last comments.
	DR. SANTANA:  We can hardly hear you.  You said you agree?
	DR. BERNSTEIN:  I agree with those comments.
	DR. SANTANA:  Any other comments to subpart A?
	Subpart B.  What general principles could then be used to relate myeloid malignancies in adults to myeloid malignancies in children?
	Charlie, do you want to address that?
	DR. SCHIFFER:  I think the cyto and molecular genetic findings when they are homogeneous.  The problem is that there are large numbers of patients who fall in between or who don't have such findings, and there the results in adults and children are approximately the same and equally poor.
	It is going to be difficult to target if you don't have a chimeric protein unless, in fact, something like the FLT-3 represents a target, and you might be talking in this arena about a new cytotoxic, whether it be a semi-targeted one like a CD33 antibody or whether it might be a new drug, although I can't think of the last new drug that has come along for AML in the last 30 years.
	But I think it is this group of patients in the middle who exist for both adults and children, i.e., you don't have one of the obvious cytogenetic classifications, they are not obviously myelodysplastic.  In adults, it may be as high as 30 or 40 percent of patients, it may even be a higher percentage in children.
	I think the relevant question there is if some new drug comes along that gets tested, for example, in relapse disease, which Mylotarg has set up a nice target for a new drug in relapse disease, and then gets accepted because it appears to have activity comparable to or better, should the same results apply in adults and children, do you think the results would be the same.
	I would think they probably would be the same, but it may be that such trials would not be conducted simultaneously in adults and children, so then should this be a mandated area, for example, because this is a very substantial fraction of patients with AML in both age groups.
	DR. HEAD:  Could I make one comment affirming what Charlie just said, and that is, that we have no definitive way of spotting MDS-related disease, and we are not sure we have definitive ways of spotting all true de novo AML, and I will just use 12;21 ALL as an example, can't be spotted cytogenetically, you have to do molecular testing to spot it, and if you don't know to look for it, you never see it, and there may be similar categories of true de novo AML that are yet to be defined, and we don't have any specific test we can do for MDS-related disease.
	We can only look at secondary features if they have developed monosomy 7, trisomy 8, complex cytogenetics, but these are all secondary events, and they don't necessarily happen in each patient.  Forty percent of the patients, we can't figure out where to put them in these two categories right now except by age, and that is not the best way to do it, but that is all we have got.
	DR. SANTANA:  Dr. Borowitz.
	DR. BOROWITZ:  I think there is a principle at stake here, that if we sort of turn the question around and say under what circumstances would it be legitimate to have a waiver, and not apply the Pediatric Rule in AML, I think the cases where they share a common translocation of one of the true de novo AMLs, it is easy to say, but it is this intermediate group that is more difficult.
	My bias, and maybe this is what Charlie was saying, is that in these cases where you can't clearly demonstrate that it's MDS-related AML, and therefore, a disease that is much more likely to be seen in adults than childhood, you should err on the side of saying that the leukemias are the same unless you have compelling evidence to suggest that they are different.
	I think that this opens up a much larger envelope of cases where you can start looking at common therapies than if you just restrict it to those sets of diseases where you have demonstrably identical translocations.
	DR. SANTANA:  Sharon, you had a comment.  I know you have had your hand up for a while.
	DR. MURPHY:  That's all right.  Actually, we are all kind of converging, I think.  So, I would answer the question the general principles would be, one, if they clearly share a specific molecular marker, translocation, or whatever, then, they are the same, like APL, RAR-alpha, AML, that is the same in adults and children.
	Then, there is the ones that don't clearly share anything, and are the great NOS, otherwise unwashed, broad category of AML that we all face, and a drug is targeted to AML, not a specific maybe molecular designer drug, but a general AML like Mylotarg or something else down the line, then, they should also be considered the same.
	I am having trouble thinking of where they are clearly different unless it's an entity that occurs only in AML in children, like megakaryoblastic leukemia and Down's syndrome, which is, you know, angels on the head of a pin here, and/or something specific, can you think of a kind of AML that only occurs in adults.
	I mean some of the more myelodysplastic forms might be granted a waiver, because myelodysplasia is so rare in pediatrics, I mean it is just impractical to try to mandate studies.  That would be my answer.
	DR. SANTANA:  Dr. Waxman.
	DR. WAXMAN:  I just want to expand on what you said, that the malignant phenotype may be the same despite not having the same abnormality in translocation.  So, I think if a drug is being targeted to a specific malignant phenotype, such as an amplified c-myc, or an over-expressed BCL-2, or you are trying to overcome MDR, that principle should hold right across the board whether it is an adult or a pediatric case, if you are targeting a drug that way, and it should be similarly tested as can you--back to leukemia--overexpresses that, you are going to attack that, actually, I think it should go across the board.
	DR. MURPHY:  But could you clarify, though?  I mean the examples you used, for instance, overexpression of BCL-2 is not something we see in pediatrics.
	DR. WAXMAN:  No, I was using that as an example that if it's not BCL-2, then, it's BFLA-1, so that we know more and more about what we are trying to attack downstream as it was brought up before.  It may not be a primary event, but a secondary event of transformation, and so that is a target, and it goes across the board.
	DR. SCHIFFER:  Actually, BCL-2, not mutated, but BCL-2 is overexpressed in many, if not most, AMLs, and might actually represent a target which would go across age groups.
	DR. MURPHY:  I was thinking with the lymphomas.
	DR. SCHIFFER:  I understand.
	DR. SANTANA:  Dr. Pazdur, you had a comment?
	DR. PAZDUR:  I wanted to follow up on something that Sharon was mentioning for clarification.  Bringing this down to what is going on now in drug development where many drugs are not being developed for a specific target, but many times we are seeing conventional cytotoxic drugs, for example, me-too anthracyclines, me-too ara-Cs, et cetera.
	If somebody was developing a drug, for example, for refractory AML without a specific molecular marker at this time, should we exert our regulatory authority in mandating that drug to be examined in pediatric AML?
	DR. SANTANA:  Comments?  Dr. Borowitz.
	DR. BOROWITZ:  Just a comment about that, and I think it does reflect part of the problem between how drug development works and what refractory AML is.  I mean I think, as David pointed out, myelodysplasia-related AML is very highly resistant to conventional chemotherapeutic agents, so in a protocol for refractory AML, in the typical adult population, you would expect that population to be highly over-represented with the kind of AML that doesn't occur in children.
	So, my own bias is if that is the target for drug development, that may not be the most fruitful place to invoke the Rule.
	DR. PAZDUR:  I am just giving that example because in adult indications, most of the drugs are developed in refractory diseases and then brought forward, but the intention usually is to take the drug then and develop it further in adults in that first-line setting, et cetera.
	But the point that I am trying to get across is that yes, these molecular markers are being evolved and therapies are being evolved against them, nevertheless, in a real world situation, we are still dealing with conventional cytotoxic drugs and how should we look at those drugs also.
	DR. SANTANA:  Dr. Reynolds.
	DR. REYNOLDS:  I would agree with you, and I have heard several comments here that basically is arguing for lumping rather than splitting on this, and I think that if you are using general cytotoxic agents, what we haven't heard on this in terms of all of the cytogenetics and molecular markers that have been able to differentiate between survival outcome in these groups, we haven't seen any data that has been distinguishing the response rates in Phase II trials.
	I think if you are taking a new molecular entity forward, especially a general cytotoxic agent, the real question is could you on any of these data presuppose that the response rate would be different between pediatric and adults, and I don't think that would be the case.
	So, it would seem that we would be better off to apply the Pediatric Rule and obtain that data and that agent rather than have the agent languishing while we are waiting to figure out what the exact molecular relationships are.
	DR. SANTANA:  Dr. Arceci and then Dr. Smith.
	DR. ARCECI:  The one area that is somewhat confusing here, though, if we co-develop, you know, "rudolphomycin," or whatever one is coming down the pike, the issue in my mind is where do we start Phase I trials in pediatrics if we don't have any information prior to starting those trials in terms of dose finding, and it is a thing that we have worried about in pediatrics because of what I think Susan brought up earlier in terms of benefit.
	Although most Phase I's don't result in long-term benefit necessarily, we have probably spared enrolling some children at very, very low doses based upon the fact that we start at a dose 80 percent of the adult.
	I would be curious, I think it's an important area, if we are going to recommend mandating co-development of some of these agents, then, we probably need to think how we are going to do that in pediatrics.
	DR. SCHIFFER:  Why is that less of an ethical problem in adults?
	DR. ARCECI:  Because they can give consent, a pediatric patient cannot, and it really goes back to McIntyre's, you know, whose justice, whose rationality.
	DR. SANTANA:  I mean you could turn it around and say, for example, for biologics, MTD dosing is completely irrelevant.
	DR. ARCECI:  I think that gives us a huge opportunity, but for the other agents, I think, I am not sure how we do this or how we deal with it.
	DR. SANTANA:  Malcolm.
	DR. SMITH:  To Rick's question about what do you do with another cytotoxic, it gets back to the issue of the need for a dialogue.  There are a limited number of Phase II studies that can be done in recurrent AML, and it may be that the best thing available is a new anthracycline, you know, who knows, but it may be that that is competing with three or four other agents that have not been tested before for their distinctive mechanism of action.
	So, a mandate to study the former may, in fact, now contribute to overall development of new therapies for AML.
	DR. SANTANA:  Good point.
	Dr. Boyett.
	DR. BOYETT:  Similar to Dr. Borowitz's comment for perhaps a different reason, I think I would like to be a bit more conservative about applying the mandatory rule at this point in time, and maybe restrict it to those things where we know we have some genetic definitions.
	In the future, the groups of AML patients that we cannot now distinguish because of some lack of genetic markers, I think we will have techniques in the future.
	I would be concerned about mandating it to the broad category and then having studies come out that not be productive and actually killed it, when, in fact, if we restrict it to those where we have some hope of some targeted intervention where we really believe that perhaps the adult and the childhood AML is the same, I think we need to produce some positive results to build upon.
	DR. SANTANA:  Yes, I think this goes back to the issue of a conversation that has been occurring in terms of prioritization and dialogue.  I mean at some point, a community, whoever that community is defined, FDA, NCI, cooperative groups, individual sponsors, needs to decide what the priorities are because we are not going to be able to test everything that we want to test.
	I think those priorities have to be established through a dialogue, and not through individual sponsors or individual groups.
	Steven, you had a question or a comment.
	DR. HIRSCHFELD:  I think every comment is a question that can be a question unto itself, to take off on Dr. Arceci's commentary.
	Well, I wanted to put out a speculation, and again this is not a formal position, it is just a speculation for discussion, that to interpret the word "studies" may not necessarily mean clinical studies, and the speculation I would want to propose is if one says studies should be mandated, and we had--and this is another supposition--an effective screening mechanism for looking at inactive drugs, that is, if there was a method where we had with a great deal of certainty lack of activity in the screening method, whatever that may be, correlated with lack of clinical activity, then, we might consider asking for studies in the screening method, because I think the data to support that because there is in vitro activity, there will be clinical activity is much shakier.
	But if there was a possibility of having negative data translated into negative data, then, that might address some of the priorities and some of the circumstances where one isn't sure.
	DR. MURPHY:  Since you want to be provocative, I am trying to imagine what are you thinking, and what screen possibly could be validated, and so I am guessing, is he thinking, you know, the current trendy gene expression profiling with chips and stuff, and the hypothesis, you know, increased expression, it might work or not.
	I don't think we have a shred of evidence to go forward on those kinds of screens in real human disease and responses to treatment, and I would worry about using something that is not validated in a pre-clinical way to mandate rules myself.  Maybe you would like to tell us what you are thinking.  You must have something you are guessing at.
	DR. HIRSCHFELD:  Sure.  It would be absolutely contingent on some validation.  So, I will take an example, not from AML, because I think that is much harder, but if we go to, let's say, the solid tumor circumstance, and we would say that--this is again just a speculation--but if we had a xenograft where we had confidence that lack of activity in the xenograft would correlate with lack of activity in the clinical circumstance, then, we might raise that as a possibility.
	DR. MURPHY:  A xenograft is one tumor, Steve.
	DR. HIRSCHFELD:  We recognize that, but I raise it as a possibility, and this is speculation.
	DR. SANTANA:  Donna, you have had your hand up for a while.
	DR. PRZEPIORKA:  I wanted to agree totally with Dr. Reynolds' comments that for non-targeted therapies, that we should be as inclusive as possible until we prove otherwise independent of the dialogue that needs to take place regarding priorities.
	I would also like to agree with the fact that if we have a targeted therapy, it should be targeted towards patients in both populations who have that target, but I think Dr. Hirschfeld just made a very good point, and I was very happy that he said that, because this is one of the questions that I wanted to raise, and that is, what happens if there is in vitro data that suggests that it is not effective, and I think Dr. Poplack pointed out that, you know, breakpoints, everybody is talking about breakpoints, but, in fact, beyond the breakpoints cytogenetically, molecularly, there may be differences.
	So, 9;22s may look different in ALLs in adults or pediatric patients if you go and look at the size of the protein, and with very specific targeted tyrosine kinase inhibitors nowadays, one of those tyrosine kinase inhibitors may inhibit one of those tyrosine kinases, but not the other, despite the fact that the breakpoint looks the same.
	So, I am happy to hear that the FDA would accept in vitro data to show that, hey, our drug isn't going to work in this pediatric population, let's not do the clinical study.
	DR. HIRSCHFELD:  I wouldn't quite go so far as to say the FDA will accept.  I just wanted to raise the possibility as to another approach to the issue.  For all we know, there might be some matrix hybridization schema that would evolve sometime in the fairly immediate future that we could have confidence in.
	So, I wouldn't want to close the door on that.
	DR. SANTANA:  Dr. Schiffer.
	DR. SCHIFFER:  It is going to take a lot to destroy empiricism in oncology, and actually that is probably okay, because a lot of very important observations came out as a consequence.
	Back to this mandate business, I am new to thinking about drugs and pediatrics, so excuse me if I step in it, but if we have a drug that is active in relapsed AML, a traditional cytotoxic drug, but you are not allowed to test it or you are late to the plate because you are unable to do the Phase I trials until there is an adult dose, the second that drug shows activity, that is going to be the priority drug for pediatricians and adults with AML.
	So, it seems to me that the problem or the issue is not whether you mandate those trials, the pediatricians would be dumb--and they are not--to pick up something immediately that has been shown to be active in adult disease.
	It seems to me the issue goes back to how early the drug can be or rapidly the drug could be applied to children, and that is more a consequence of dose, and I guess I really hadn't thought about this 80 percent issue, and you need the adult dose to start in kids, et cetera, but it seems to me that for traditional cytotoxics, and maybe even biologics, that is something that needs a focus.
	DR. SANTANA:  Dr. Reynolds.
	DR. REYNOLDS:  One thing in this discussion I haven't heard is the interactions with the cooperative group, and we now have one national cooperative group for pediatric oncology.  The Developmental Therapeutics Committee within that cooperative group is very committed to interactions with each of the disease committees, so for AML or neuroblastoma, or any of these, there are liaison people between those groups.
	It would seem that in the case of the FDA, where they are trying to decide whether or not to apply the Pediatric Rule versus the questions that have been raised like Dr. Arceci's, well, how early should we do this, and questions raised by Dr. Weiner about whether or not children should be at risk for doing this study, that maybe a dialogue between FDA and Developmental Therapeutics and the cooperative group would serve to provide some guidance for this.
	DR. PAZDUR:  We are all for dialogue, and as we developed in the exclusivity aspects, interactions between industry, the NCI, and Pediatric Cooperative Group.
	One point that is a very practical point that I must emphasize, though, although this dialogue can occur, and there could be a dialogue about what agents should be selected, it has to be a fair and level playing field for all of the sponsors, in other words, we can't just select, well, this drug, because the pediatric oncology community thinks it is hot, we will exert the Pediatric Rule in.
	There has to be some overlying general principles that we could apply to the industry because it has to be perceived as fair and equitable to all sponsors.
	DR. SANTANA:  Sharon.
	DR. MURPHY:  Just to amplify the point, Pat, and for those who may not know, I mean I think there is, in the new Children's Oncology Group, already a mechanism, a platform by which the dialogue can take place, and it already has taken place.
	There has been formed an industry advisory group, some members of which are here in the audience, that meet regularly with cooperative group investigators who are in the same room with FDA and NCI, so this is already a forum.
	It can be used to facilitate the kind of dialogue that everyone wants to have, and it will, I am sure, and I hope later, some of the--I mean this is formalized already, so it is going to happen, but the point is, well, how are we going to make sure that it isn't just emotional or trendy or some other kind of thing.  We have got to have some kind of framework on which to move these discussions forward to prioritize.
	DR. SANTANA:  I want to get back to the questions.  Is that okay, Dr. Hirschfeld?
	DR. HIRSCHFELD:  I was going to say Part C, I think we have discussed that.
	DR. SANTANA:  I was going to say, Part C, we have discredited the FAB, so we would all say that for APL, probably that is okay, but we have discredited B already, so there is no reason to discuss that.
	For the chronic leukemias, do you want any comments on those specifically for Ph-positive CML?  Anybody in the audience, Bob Arceci, or anybody else?
	DR. ARCECI:  I think as several people have already echoed, it is 9;22 and CML, they are so similar.  It is the host that really matters in that situation, I think, but not the target.
	DR. SANTANA:  Lastly, are there any pediatric myeloid leukemias that have an adult counterpart that is not commonly classified as an adult leukemia?  I would like to clarify that question, I didn't understand it when I read it.  Can somebody from the FDA help me with it?
	DR. HIRSCHFELD:  I could try to clarify that.
	DR. SANTANA:  What are you wanting?
	DR. HIRSCHFELD:  Sometimes or at least we could conceive of a circumstance where there might be a target.  We will make something up, but we will say a particular receptor that is absolutely critical for a malignancy to maintain its phenotype.
	There could be, at least in theory, a circumstance where there is not an adult counterpart, that is a leukemia, but the adult counterpart might be a solid tumor, it might be a lung tumor, it might be a breast tumor, it might be something else, and so we just wanted to raise the question, turning it around, is there some other tumor that if let's say we get an application that comes in for small-cell lung cancer, and we should immediately say, well, children don't get lung cancer, but there is a disease that is similar, which manifests in the bone marrow, or a histiocytosis, or something of that effect.
	DR. SANTANA:  Help me clarify, either you or Richard can help me clarify, I thought the FDA gave approvals based on specific indications, and not broad indications.  You help me with this.  I don't understand how the agency in its current structure would say we are approving this drug for anything that expresses Y.
	DR. HIRSCHFELD:  Right, but the FDA has, and I think our trend is to approve or define an indication or describe the indication in terms which are fairly specific.  So, it might be anatomic, and it potentially even could be histologically independent.  It might be tumors--and this we haven't done, but it's a hypothetical--tumors that have a particular expression pattern or tumors that have a particular lesion, and that is how an indication in the future--
	DR. SANTANA:  But the problem there is how does that relate to the actual tumorigenesis, and it may be completely irrelevant.
	DR. HIRSCHFELD:  It could be, and then if that is the comment, then, that is the comment, but we wanted to raise the issue.
	DR. ARCECI:  I think it is a fascinating question in a way because there may be, in fact, some developmentally expressed genes that are going to be quite unique to the pediatric setting.  I can't think of many right now, but I think possibly one is--Charlie, you have to correct me on this in terms of the work in adults--but, for instance, the elastase mutations that are contributory to congenital neutropenias, that may contribute also to AML, may be a target that is really quite unique in pediatrics.
	DR. SANTANA:  I was thinking of the ATM story.
	DR. ARCECI:  ATM is potentially another, Fanconi anemia.  There are some lesions that may be, in fact, very unique to the pediatric situation.
	DR. SANTANA:  Charlie.
	DR. SCHIFFER:  I don't think you need the FDA for that.  I think that is where clever clinicians and clever doctors come in.  You have the example of the patient who discovered for herself or himself about the c-kit mutations in GISTs.
	DR. PAZDUR:  I think that would have been probably very hard probably to mandate.
	DR. SCHIFFER:  Well, that is exactly the point.  I don't think it is necessary to mandate.  I think the progress will happen.
	DR. PAZDUR:  The indication is the population, to answer your question, that is studied in the clinical trials in general, and I think that if we would--don't forget this is a mandate, okay, as I mentioned before, that we are requiring people to do this.
	That link has to be well made and scientifically based and accepted by the scientific community, and I think that that is an underlying principle.  It is not just, well, this is an interesting phenomena that may be an epiphenomena, how really intricate is it in the pathogenesis, because in essence what we are doing here is redefining a disease and how we define a disease.
	DR. SANTANA:  Steve.
	DR. HIRSCHFELD:  I would just would want to before we have our lunch break, make one point about the timing of the triggering of the Pediatric Rule, and that is in the lifetime of the development of a therapeutic.
	The timing of the Pediatric Rule would be essentially near or at the time of NDA filing, so we already know that there is sufficient data in someone's mind to potentially register the product for either a new molecular entity or for a new use.
	We would presumably have some body of data, and it would be at this time that we would ask the question, well, should your data support pediatric use, and it wouldn't be necessarily earlier in the development.
	DR. POPLACK:  Just one comment.  I particularly find intriguing this last discussion about having similar targets and the indication being, in that case, the target, and I think that is a very, very important concept here that we can't lose sight of.
	DR. SANTANA:  Thinking outside the box.
	DR. POPLACK:  We have to think outside the box, and not think about histological similarities, and I really think it is a very important point you raise.
	DR. SANTANA:  But I think the issue is what Richard said, that has to be scientifically validated to make it real.
	DR. PAZDUR:  Mandate obviously.
	DR. POPLACK:  Malcolm was mentioning track expression, for example, in lung cancer and neuroblastoma, and there are probably other examples, but the leukemia ones are evading us for the moment.
	DR. SANTANA:  Susan.
	DR. WEINER:  I just didn't want us to lose the notion given who has gathered here today, lose the notion that we do need a platform for making these decisions.  The notion of scientific community is very vague.
	The notion of how this is going to get done and how these priorities are going to get set, either through the COG or through some interaction.  Obviously, it has to be a multiple interaction, and we have to go ahead at some point, perhaps not in this forum, but those recommendations have to be made.
	DR. SANTANA:  I think we have tried to answer your questions and giving you the advice we were going to give you this morning, so we will adjourn for lunch, and we will reconvene at 12:30.
	[Whereupon, at 12:00 noon, the proceedings were recessed, to be resumed at 12:30 p.m.]

AFTERNOON PROCEEDINGS
[12:40 p.m.]
	DR. SANTANA:  Let's go ahead and reconvene. There were three individuals that joined us after we had done the introductions this morning.  For the record, we need to have those individuals introduce themselves - Dr. Friedman, Dr. Borowitz and Nancy Keene.  Please state your name and your affiliation into one of the microphones for the record, please.
	DR. FRIEDMAN:  I am Henry Friedman.  I am from Duke.
	DR. BOROWITZ:  I am Mike Borowitz from the Department of Pathology at Johns Hopkins.
	DR. KEENE:  I am Nancy Keene.  I am one of the patient advocates on the committee.
	DR. SANTANA:  Thank you.  Anybody else join us?  I think that everyone else was here this morning.
	Let's go ahead and start the afternoon session.  This afternoon, we are going to follow the same format.  We are going to have two presentations followed by a series of questions and then there will be a summary comment at the end from Dr. Arceci later this afternoon.
Open Public Hearing
	DR. SANTANA:  As required, we have an open public hearing, a time allotment.  Is there anybody in the audience that wishes to address the committee? If you wish to do so, please state your name into the microphone in the middle of the room.
	[No response.]
	DR. SANTANA:  If there is nobody who wants to make a public statement, we will go ahead and get started with this session.
	DR. HIRSCHFELD:  As you may tell by the fact I am in uniform, I belong to a team, and in this case the organization of this particular meeting is a result of a team, and I wanted to acknowledge and thank the members of that team, and I will begin with our division director, Dr. Richard Pazdur.  Our team leaders, Dr. Allison Martin, Dr. Donna Griebel, and Dr. Grant Williams, and in absentia, Dr. John Johnson, and the other pediatric colleagues at the FDA, Dr. Ramsey Dagger, Dr. Al Shapiro, Dr. Joe Gootenberg, Dr. Karen Weiss.
	Without their efforts, we wouldn't have the quality meeting that we have today.  Thank you.
	DR. SANTANA:  Thanks, Steve.
	So, let's get started with the Perspective on Lymphoid Leukemias, Dr. Borowitz, please.
Perspectives on Lymphoid Leukemias
Michael J. Borowitz, M.D.
	DR. BOROWITZ:  I would like to start this afternoon off with a not very extensive discussion about classification, and really sort of slant the overall classification of lymphoid leukemias heavily towards the issues at hand, namely, pediatric leukemia.
	I don't propose this as any kind of an official classification, but just a framework for the discussion for today.
	[Slide.]
	Basically, in the broadest sense, lymphoid leukemia can be divided into acute and chronic.  In the case of pediatric leukemia, obviously, it is heavily weighted towards the acute lymphoid leukemias, which are divided into three important groups, one derived from a precursor B cell, as we heard before, and that that is further subdivided, as we will see, and has already been alluded to by many speakers, completely in parallel to the situation in myeloid leukemia, it is further subdivided on the basis of specific molecular abnormalities.
	Precursor T-ALL is a little bit more controversial, how or if to subdivide that, but I think most people would still, from a biological perspective, separate that out from the larger group of precursor B-ALL, and then there is a special case of Burkitt's leukemia, which we will come back to again, and other speakers will deal with when talking about the lymphomas, because Burkitt's leukemia and Burkitt's lymphoma are really the same disease.
	The chronic lymphoid leukemias in children we can dispense with the most quickly.  There is, for our purposes, you don't even have to subdivide this, because these things don't really occur in childhood, but I have put down CLL and a whole variety of others.
	[Slide.]
	I think the one point I will make, and then we will dismiss this, is that for all intents and purposes, CLL doesn't occur in children, and I have run a reference laboratory, as many of you know, for many years and gotten leukemic samples from the Cooperative Oncology Groups and seen more than 5,000 cases, and of the cases sent to my reference lab, have actually seen two cases of CLL, so I don't think we have to--if there were ever an orphan disease, CLL in children I think would qualify.
	There are a few other chronic lymphoproliferative disorders and maybe some of those will come up in the context of the lymphomas, but again these are all rare.
	[Slide.]
	So, let's turn our attention to acute lymphoid leukemia and talk about the important entities.  I think in precursor B-ALL, everyone recognizes that the four major translocations account for, in aggregate, about 40 percent of cases of childhood ALL, and these include the 9;22, those involving the MLL gene most commonly with AF-4 on chromosome 4 is the partner oncogene, but with others, as well, the t(1;19) and the t(12;21), as have been alluded to before.
	A subgroup of ALL that hasn't been talked about much because even though it has been around a long time, and its prognostic significance has been known a long time, we really don't understand the mechanism of this leukemia or what the reason for its prognostic significance is, but that is hyperdiploid ALL, and there is a growing awareness that it is not just simple hyperdiploidy, but, in fact, the specific chromosomes that are duplicated that seem to be most important in determining the prognosis in this lesion, and I think we can discuss that more if there is interest, but I don't think for purposes of today's discussion that that is necessarily a track which we have to go down.
	Then, hypodiploidy, by contrast, clearly must have a very different mechanism of leukemogenesis, and does carry with it in everybody's series, a particularly poor prognosis, and is sorted out, but is a very rare group of ALL.
	On the other side, precursor T-ALL, as we saw from I guess it was Sharon's slides, about cytogenetic abnormalities in T-lymphoblastic lymphoma, which is really the other side of the same coin, have a lot of different oncogenes involved, and in contrast to the model of precursor B-ALL, where most of these translocations involve production of specific fusion proteins which contribute to the leukemic phenotype, in T-ALL, the mechanism of leukemogenesis seems to be different in that it involves up-regulation of normal cellular oncogenes either by translocation to the T-cell receptor, locus, or by other mechanisms that we don't know, and certainly many cases of T-ALL have abnormal expression of many oncogenes even in the absence of demonstrable translocations.
	The important ones are SCL1 or TAL, HOX11, and probably LYL1 and the LMO1 and 2, in particular, are involved in a lot of translocations, but their role in producing leukemogenesis is a little less clear.
	There is starting to be some emerging suggestion that maybe some of these have different prognoses, but I think those data are all pretty premature at this stage.
	I have put down at the bottom of the slide as a separate category the idea of a primitive T-ALL, and this is a bias of mine that is supported a little bit by the data in the literature, but it is more anecdotal than anything else, and that is that people have divided T-ALL for a long time on the basis of expression of different kinds of differentiation antigens in the hope that this would be very revealing for the underlying biology.
	In general, that has not been a very fruitful exercise with one exception, and that is that there seem to be cases of what we call T-cell ALL that express very little in the way of markers that clearly indicate T-cell differentiation, and seem to share some properties in many cases with myeloid leukemias.
	It is my own bias that the home for these leukemias may not be within the greater confines of what we call T-ALL, but this is still an emerging area.
	[Slide.]
	To sort of get to the essential points here, and that is what we were asked for, what are the differences between adult and childhood ALL, I think T-ALL is in some ways the hardest to deal with, and in some ways the easiest to deal with.
	It is the hardest to deal with because there really aren't really good data on frequency differences among genetically defined groups.  There is cytogenetic data that compares T-ALL in adults and children, but as I said before, it is not always the cytogenetic abnormality that drives the molecular abnormality, and we really don't know to what extent these things are the same, but again there is really not any good data that any of these genetically defined groups represent drastically different diseases in terms of the phenotype as dictated by the patient outcome.
	I think if we start getting to issues of drug targeting for particular molecular abnormalities in T-cell disease, we will have to start to revisit these questions, and there really aren't a lot of good data.
	But I think that for current purposes I would submit that T-ALL in adults and children in aggregate are likely the same disease.  Whether in the end there will be more children that use HOX11 and more adults that use SCL TAL, I don't know, but I don't think those data are at hand.
	The other thing is that the frequency of T-ALL overall seems to be higher in adults than children, but that is really a false elevation because it has to do with the fact, as we will see in a second, that some of the most common kinds of B-precursor ALL are not found in adults.
	[Slide.]
	So, let's turn to precursor B-ALL, where there are more data and more ways of thinking about this.  If you look at the cytogenetic abnormalities that we talked about before, and you look at the sort of comparative frequencies, the one thing that stands out is that BCR-ABL-associated ALL, the single most common translocation in adult ALL, and it is a rare lesion, a relatively rare lesion in children, seen in about 4 percent of cases.
	By contrast, the single most common cytogenetic translocation in children, the TEL-AML1 translocation, is a very rare lesion in adults.
	So, to some extent, the difference between, if you would step back 2,000 feet, the biggest difference between ALL in adults and children is that in adults, they have a lot of Ph-positive or BCR-ABL ALL, in children, have a lot of TEL-AML1 ALL.
	If I skip down to the bottom, you will see that hyperdiploid ALL also shows this relative increased incidence in children compared to adults, although it has been reported in adulthood.
	The other translocations, E2A-PBX1 and MLL translocations seem to be a little bit different between adults and children, but probably not significantly so, and when you sort of take into account the distribution of other lesions, those numbers really aren't that different.
	[Slide.]
	So, the important thing is that these in children, is that these genetically defined lesions in B precursor ALL carry with them important prognostic significance.  The most important of these is the hyperdiploidy, particularly those involving chromosomes 4, 10, and 17, and the TEL-AML1 are associated with very good prognosis.  Remember, those lesions are found with very low frequency in adults
	By contract, BCR-ABL ALL and to a lesser extent the MLL-associated ALLs are associated with a poor prognosis, and again those diseases, particularly BCR-ABL, are more common in adults.
	Finally, the E2A-PBX1, now with current therapy, although that used to be considered a poor prognosis lesion, with current therapy I think it carries the prognosis of any other standard risk child with ALL or high risk depending upon the clinical features.
	Then, I don't want to underemphasize the fact that we have still only accounted for about 60 percent of children with ALL with all of these abnormalities, and there is a whole group of cases out there that we have not yet characterized.  We know they have recurring cytogenetic lesions in some cases, but we don't really understand much about the underlying mechanism.
	[Slide.]
	So if I were to just summarize the important points here, first is that the good prognosis genetic lesions that are so characteristic of children, the TEL-AML1  and the hyperdiploidy, are rare lesions in adults and, for all intents and purposes, I think should be considered different diseases.
	I think because they are 	good prognosis lesions, they are less likely to be targets of new therapy.  The great majority of these patients are cured with conventional therapy, and in some sense, when you think about talking about treating children with ALL, or being experimental protocols, you are not talking about treating these children anyway, because we have excellent therapy for this group of diseases.
	On the other hand, I would submit that there are really no significant differences between adult or childhood Burkitt's leukemia, adult or childhood T-ALL, or adult or childhood with BCR-ABL or MLL abnormalities, so that any protocols targeting these diseases are fair game for both children and adults.
	This leaves the remaining 40 percent of childhood precursor B-ALL.   As far as we know, and this hasn't been investigated in detail, we can't pull out, once we take all the kinds of leukemias where we know the underlying molecular abnormalities, we can't discern any biological difference between adults and children with ALL once you take out all of these other abnormalities I mentioned above, but the important thing is that children still fare better.
	And we really don't have a good handle on why that is, whether it has to do with differences in the host or, as Sharon Murphy said, differences in the doctors, but I think that is an important point as we think about targeting therapies to ALL not otherwise specified, we have to take in mind the fact that in contrast to AML, where children and adults fare equally poorly, in ALL, we are talking about this group of diseases where children still fare very well.
	The other thing that I don't have on my slide, that I sort of want to say, is that another kind of ALL that we sort of don't think about in classification is relapsed ALL.  Relapsed ALL, if you sort of step back a little bit, is the fourth most common cancer in children because even though we do very well in treating children with ALL, the frequency of ALL compared to other diseases is so high that there is still a significant number of patients who relapse.
	I think that we don't have a good handle.  Relapses occur in every group including the best prognostic group, and I don't think we have a handle on the biology of relapse per se, and I think as we go forward, thinking about the biology of relapse as a way of thinking about targeting drug therapy, may be a more fruitful approach even than breaking it down by these lesions.
	That is all I have to say.
	DR. SANTANA:  Thanks, Mike.
	I am going to go ahead and ask Dr. Schiffer to do his presentation, and then we will have plenty of time for discussion.
	DR. SCHIFFER:  It will take a minute to rearrange these slides.
	DR. HIRSCHFELD:  I have one more public comment, and that is I wanted to acknowledge the professionalism and assistance that Karen Somers has given to this committee and to everyone else who had to make arrangements or to work out any logistical details, so thank you, Karen.
	DR. POPLACK:  Can we ask questions while we are waiting?
	DR. SANTANA:  Yes, go ahead.
	DR. POPLACK:  Michael, one of the things I find curious is that the concept of thinking about relapse ALL as one group, regardless of the unique biologies of these, seems to be going in a backwards direction rather than in a forwards direction.
	It is ignoring what we now know and have the potential to know about the biological characteristics of these patients, so why choose to lump them and specifically for the purposes of this meeting where we are looking for indications, of what value is that?
	DR. BOROWITZ:  I will answer that in two ways.  First, in the second practical way, if I had a patient who was good prognosis ALL by all hyperdiploid with all the favorable trisomies, and yet that patient relapsed, that patient is no longer a good prognosis ALL that is manifest.
	So, I don't want to label that patient just on the basis of their favorable cytogenetics as a good prognosis lesion.  Clearly, something has happened to that patient that has overcome the otherwise good prognosis biology.
	The issue of what that might be, I don't know, but I do know, for example, that an approach to some of the newer biologic studies with some of the DNA microarray data, for example, or other things, are to try to look for features that distinguish, given a particular genetic abnormality, patients who relapse from patients who don't relapse.
	If, across genetic abnormalities, one can find some common threads, then, it may be that it is worth putting those together.  On the other hand, it may be that  the patient with TEL-AML1, who relapses, relapses for a different reason than somebody with Ph.
	As of yet, we just don't know.  All I am saying is that because we don't know, we shouldn't just shut our eyes to the notion of, well, you know, everything there is to know, we know from upfront genetic characterization.
	DR. POPLACK:  I agree with you 100 percent, we have to look harder in that group, but I don't know what the value is of lumping them at that point.
	I think those are the patients that have the clues to why we are not curing 100 percent, we have to look harder for more information, genetic or molecular, rather than just put them into one group.  I guess I misunderstood what you were getting at with the concept of putting them all together as relapse.
	DR. SANTANA:  Any other comments?
	Are you ready Dr. Schiffer?
	DR. SCHIFFER:  Yes, I am ready.
	DR. SANTANA:  Okay.
Charles Schiffer, M.D.
	DR. SCHIFFER:  I am finding it a challenge to say something new, that hasn't been said already.  I don't know whether I will say it differently, probably worse, but there are a number of points I think perhaps still to be made.
	[Slide.]
	There are differences between adults and children.  We see an awful lot of this, you don't see it at all maybe except if you look in the mirror every once in a while, but this represents an enormous challenge to those of us treating hematologic disorders in adults and--I had a slide of a child, but you get the point.
	[Slide.]
	Mike talked about this already.  The biologic differences and similarities, we have stated.  There is a profound difference in the incidence of TEL-AML in adults and children and hyperdiploidy.  In fact, I think that estimate of 5 to 10 percent of adults being hyperdiploid is very high.  It is much higher than we just published in the CLTB where it didn't even show up in the listing of cytogenetic abnormalities in 200 patients with ALL, and, of course, the bete noire of the Philadelphia chromosome.
	The frequency in probably the impact of the MLL and the mutations are probably the same in adults and children, and we can talk a little bit more about that when we talk about Burkitt's lymphoma and why we do well with adults, but not quite as well as you all seem to do.
	These are incredibly rare in adults, that is, hypodiploidy and 1;19, well less than 1 percent of patients, but I would agree with Mike's comments that, in fact, you can extrapolate these discrete abnormalities just as we said in AML from adults to children for the purposes of this discussion.
	[Slide.]
	There are obvious differences in adults and children and even young adults, and we can't ignore it.  Adults have other medical conditions, and a lot of those are subclinical and we haven't the foggiest idea of what that does in terms of drug disposition, very subtle abnormalities of hepatic, cardiac, or renal function, and all the clinical trials that are ever submitted to the FDA don't have real adults, that is, they have perfectly well patients with cancer, and that is not what we see in the clinic as soon as a drug is approved.
	Children remind me of those little toys, you know, where you bang it up and down and they keep coming back, well, you can't do that to adults.  It is very difficult to give intensive repetitive courses of therapy to adults.  It is not just L-asparaginase, it's high-dose methotrexate, it's high-dose ara-C, it's stuff that causes mucositis.
	Adults are much less physically, and perhaps even emotionally, less tolerant, and while we would love to have a focus on long-term toxicities in adults, unfortunately, that is rarely our problem, but it is a very major problem in pediatric oncology.
	But this whole issue of extrapolating dose from adults to children is, of course, problematic, and we have alluded to it, but in general, children can tolerate much higher doses of drugs than can adults, and we face this question at times in adult oncology.
	[Slide.]
	In the STI studies, everyone gets the same dose.  This is the NBA playoffs - so we give Shaquille O'Neal and Mugsy Bogues the same dose simply because they are 18 or 21, however old you have to be to vote, and obviously, the extrapolation to children is there.
	I notice actually in the Phase I studies that are being done with STI in children, it is being somewhat more rationally dosed on a mean square basis rather than the same dose for everyone.  It turns out for a biologic agent like this, fortunately, the dose that was chosen exceeds the therapeutic threshold in both Shaquille and Mugsy, but that is not going to commonly happen with anti-neoplastic therapy.
	[Slide.]
	These are the results you see in adults, all comers with ALL.  It is very age dependent.  In the 20 percent of people who are this old, there are very, very few cures, and that is predominantly because they are almost all Philadelphia positive.  If you break it down even further, this largely reflects the incidence of Philadelphia chromosome positivity.
	The same issues with regard to T and B lineage ALL.  These are the Ts.  They used to be our worse group and now our best group as a consequence of intensification of therapy, actually based on some of the pediatric models, but still not as good as you all do, and no understanding, as Michael said, of whether the different genetic subtypes offer an advantage or a disadvantage.
	These all the BCR-ABLs and the 411s, and most of those people have been transplanted.  That is how they got out there.  Very few survive without transplant.
	This is that very difficult group that I think deserves some discussion, as Michael said, of the other Bs, do half as well at the most as you all do in pediatrics.
	[Slide.]
	Now, what are some of the possible differences and can we do trials together?  Well, there was this very disturbing abstract that was presented at the American Society of Hematology, which should have been on the plenary session, but wasn't, which represented the CCG and CALGB, comparing the outcome in adolescents and young adults with ALL treated either on pediatric or adult protocols.
	[Slide.]
	196 adolescents, 103 treated by CALGB, approximately the same time period.  Interestingly, they are identical CR rates, and I will get back to why I think that may be important, but a little more than half the event free survival in patients treated on the adult protocol by adult oncologists.
	[Slide.]
	What are some of the reasons?  Probably not risk factors.  The groups were reasonably well balanced, the adults were a little bit worse.  This may account for about 5 percent of the difference.
	The regimens are different, the pediatric regimens were more asparagine intense, but I will say that we designed the CALGB regimen attempting to take the most intensive of what were the extant pediatric regimens at that time and tried to apply them to adults.
	So, I am not certain how much difference there was in the regimens.  That remains to be looked at.  We haven't the foggiest idea, however, about the doses delivered.  We know the doses delivered in induction, that is easy.  People are in the hospital, you read the protocol, you give them the drugs, but the ALL regimens are very, very complicated.  They have very tight schedules, which may or may not be necessary, but they are written as such, and we haven't the slightest idea of the drug delivery rate or total drug given by pediatricians versus adults.
	But there is a very big difference.  All of the people treated in the CCG studies were treated by people who do ALL for a living, it's their bread and butter, they do nothing else.  They don't have to look at the protocols, they have got it memorized.  The nature of adult oncology is different.
	I am not certain what percentage of these adolescents were treated in cancer centers or transplant centers where there were people who were devoted to leukemia as opposed to being treated in the community by doctors who are more general oncologists and they do colon and breast and lung at the same time, and it may very well be that it is not necessarily the doctors, but the type of doctors who are delivering the care to this type of patient.
	I must say we have seen the same thing or I have seen the same thing in evaluating patients treated with interferon for CML in the STI studies or I have seen sometimes rather bizarre patterns of care generally administered by people who were not hematologic oncologists, so not all the patients who you see treated in that comparative study, which is really very, very important, were treated by hematologic oncologists.
	Many were treated by more general medical oncologists, and I think these data need a lot more digging into to see what the real cause of those various differences are, and it may also have some implications with regard to doing parallel trials in subgroups of patients with ALL.
	I don't think it pertains as much to AML.  AML is sort of easy.  Things are in blocks, and you do it, and adults are pretty good at that, adult oncologists.  ALL just might be very, very different.
	[Slide.]
	Now, what about the types of agents that we might be talking about, comparing adults and children?  The stuff on the top I think is pretty straightforward.  The next STI or the next highly targeted antisense will have a target which I think we have a consensus should be applied to both adults and children if that target is there.
	The same thing might apply to antibodies, such as anti-CD33 or the next one that comes along as long as the cell expresses that antigen in an adequate enough fashion.
	There are going to be two different types of cytotoxics, some that may have a little bit of specificity if it turns out to be true of this 506U for T lineage ALL, and one might imagine, although there are toxicity differences again between adults and children, that the results might be extrapolated from one group to the other.
	We have already talked about what I call plain old new drugs.  That is simply because many new drugs are variations, unfortunately, on old drugs, and there aren't too many new, new drugs.
	There are also issues in leukemia with regards to supportive care, that is, myeloid cytokines to attenuate neutropenia, et cetera, were studied predominantly, if not exclusively, in adults first, and then children, and they may be very different because the intensity of the regimens are different and the cardioprotectants, which are much, much more of an issue in children, were actually studied backwards, because it is not a public health hazard in adults whereas, it may very well be dose and life-limiting n children, and then there is this whole other group of compounds, anti-angiogenesis I just list as one possibility, which are broad and may not be as specific and probably should be studied, I think differently in adults and children perhaps.
	[Slide.]
	Lastly, I was struck in listening to the conversations about pediatrics about how this--with children--this is parallel to thoughts I have been having about what happens with the next STI and how do you develop that.  I have been involved in those trials, found it to be one of the most exciting things I have ever done, and like everybody, I am looking forward to the next one.
	But the question is that these are very rare disorders.  CML is pretty uncommon, but has a high prevalence because people live five, six, seven years, but t(8;21s) and MLLs, and all that, are very, very uncommon diseases even if you pool adults, children, and adolescents, and it is not clear what the stimulus for pharmaceutical companies will be to develop things that are so highly targeted, but on the other hand, this is the major goal of what we are hoping to get out of all of this fancy molecular biology, that is, small molecules.
	We have the example of STI that are going to discretely target these lesions which are obviously critical to many of these diseases, but how is our society going to provide an inducement for the large expenses that are necessary to develop such molecules?
	I think we need some creative thinking between government and between the pharmaceutical industry to figure out models for how this can be done expeditiously because obviously, this is the kind of therapies that we want out of all the science that we are paying for.
	I think I will stop there without an answer certainly to this.
	DR. SANTANA:  Thanks, Dr. Schiffer.
	Since there was a request for public hearing, is there anybody in the audience that wishes to address the committee?  Please come to the microphone in the middle, state your name and affiliation.
Open Public Hearing
	DR. RACKOFF:  Wayne Rackoff from Ortho Biotech Oncology.  I am speaking today on behalf of, one, my colleagues on the COG Industry Relations Committee, Raj Malik and Alan Malamud, Raj from BMS and Alan from Lilly.
	Just to respond to some of the comments this morning and our meeting just this past Saturday, first of all, the COG Industry Relations Committee has been constituted to try and get at just some of the issues that have been discussed today.  I know Malcolm Smith has participated, Rich Pazdur and Steve Hirschfeld have both participated, as have some other members of the panel.
	In discussing this over lunch, which is why we were late, when you had the first call, we had to go outside the hotel, because you guys had the lunchroom closed off there, the Pediatric Rules had a couple of unintended effects, I think.
	One is that there are now 12 premarketed agents in COG Phase I studies and 5 pending the opening of protocols, and I think that is unprecedented just in my short history in pediatric oncology.  The second is that there are probably at least that many pediatric oncologists working in industry.  I don't think those two things are unrelated.
	So, although the specifics of how the Pediatric Rule is going to be applied are still being discussed, I think the effects of the Pediatric Rule are already being manifest and really they are unintended effects.
	The second is this timing issue, that the Pediatric Rule, no matter what happens, the way the law is written, the way it is has been interpreted, it does not affect timing as we understand it.  In fact, if it does, it really affects it quite late in the game.
	So, a number of the agents are being tested in pediatrics well prior to filings being prepared, and that is not going to be affected really by any of the discussions we have had today.
	The third thing we talked about at lunch was the fact that although there is a lot of talk about targeting and targeted drug therapy, on the other side of the aisle, if you will, drugs are being identified or molecules are being identified using these molecular targets, and they are being identified as lead candidates, but to cross the threshold from discovery into development in human trials, really, the drugs are being subjected to traditional screening against cells and xenografts.
	So, what we might think of as a very targeted drug coming through the pipeline because it is targeted to geranyl geranylase may turn out once it is put into animals with various tumors, not to be working by the mechanism of action.
	So, I think we would argue for a fair, level, sort of broader approach to thinking about these things in terms of diseases where therapy is similar in adults and children.  Ara-C, we still don't know the exact mechanism for maybe not ara-C, but for prednisone in leukemia--David, you could correct me if I am wrong--but we still know that if it works in adult Hodgkin's disease, it is probably going to work in pediatric Hodgkin's disease.
	So, those are just some thoughts in response to Sharon's request that we speak up a little bit, that we wanted to put out there from the industry perspective.
	The one other thing that came up at lunch, and really for the FDA to consider, is this idea of setting priorities.  This is something we are working on in COG, and this is going to have to be a collaborative effort.
	You know, there is liposomal doxorubicin, there is another doxorubicin, Doxil, there is doxorubicin, there is epirubicin, there is adriamycin, and do you put each--you know, you want to level the playing field, as Rich Pazdur said, but on the other hand, you don't want to take up all the patients in studies.
	The final point, and this really comes mostly as a consumer, somebody who lost a brother to cancer, is that Malcolm Smith has been sort of the protector of kids over the years, maybe not Malcolm alone, but CTEP, in terms of looking at safety, so as we approach this timing issue, I think we really have to balance that against safety and appropriate medical need in terms of bringing these agents into children at a younger age.
	DR. SANTANA:  Appreciate your comments.
	Anybody on the committee want to add further to that?
	DR. RACKOFF:  Did we cover all the Burger King conversation?  Okay.  If you are going to have it in a hotel and close the restaurant, you have got to give us like 10 more minutes to get back.
	DR. SANTANA:  We didn't close the restaurant.  We ate in here, a box lunch.  Our lunch was boxed.
	[Laughter.]
	DR. SANTANA:  Malcolm, do you have a comment?
Discussion
	DR. SMITH:  I will just say, one, on behalf of CTEP and I think on behalf of COG, as well, we certainly appreciated the efforts of the pharmaceutical companies who have been participating in the COG Pharmaceutical Committee, Industry Relations Committee.
	The other, this would be a question to the FDA, it really has struck me that a number of these agents before they are approved, are being studied in children with cancer, and that, in fact, we are being relatively successful, at least in the recent 12 to 18 months, in doing this.
	So, it would perhaps be interesting to compare the success at doing this in childhood cancer with some of the other situations that you are facing with exclusivity, how many of those are pre-approval studies that are being done as opposed to marketed drug.
	I think that is a tribute to a lot of people.  You know, the efforts of the FDA, the pediatric oncologists who are working in the pharmaceutical sector now, the advocate community, the pediatric investigators who identify needs and advocate for children to have a particular drug tested.
	So, you know, it is half full, half empty, but I think right now there are a number of very interesting agents that we have access to at a relatively early stage, and we keep working at that.
	DR. HIRSCHFELD:  I, first of all, appreciate Wayne Rackoff's comments and those of his colleagues that he was the spokesperson for, and in answer to the question that Dr. Smith raised, there are areas outside of oncology where drugs are being developed for children prior to approval in most of the therapeutic areas, but I think this is another case where oncology may be leading the field, and that the proportion of drugs which are being developed are drugs which are in the early stages of development.
	There are relatively few, although there are some approved drugs which are being revisited or being developed in new paradigms for pediatrics.
	DR. PAZDUR:  I would just like to address two aspects, the first being selection of agents to go forward into clinical trials.  I really think that that is not only a problem for pediatrics although it is more acute in pediatrics because of the limited patient resources.
	It is also one that I think adult medical oncologists have to come to terms with, how many aromatase inhibitors do we need on the market, can we prioritize the development of drugs better in adult medical oncology, and that is one thing that we have, as an oncology community rather than just a regulatory agency, have to come into play with, because to take an agent to demonstrate clinical benefit, to get a drug approval is a very expensive process, and just because one has a drug, is it really going to make an impact, and perhaps there needs to be greater thinking on a national level in conjunction with the NCI, et cetera, of how to better utilize clinical trials' resources rather than it is there, therefore, we must develop it.
	The other comment I want to address is Dr. Schiffer's comment about changing paradigms for new drugs that come out in clinical development for them.  Should we have different endpoints for drugs that have unique mechanisms?
	As you know, for the approval of a drug, our major emphasis has been the demonstration of clinical benefit, and it is kind of a mantra in the regulatory agencies throughout the world, clinical benefit, clinical benefit, clinical benefit.
	These usually require large trials.  Why?  Because many times the treatment effect is so, so minimal, you need large trials, large survival trials if you are trying to find a very small difference.
	Hopefully, with relatively selective therapies, where you are actually selecting a target out, that will improve the response rates, the survival of a given population, so the treatment effect will be much greater, and therefore, enable us to still answer questions of clinical benefit with limited numbers of patients.
	You know, if you are improving survival by 100 percent or 120 percent, that is going to be a much different population than by a 10 percent or a 20 percent difference in survival just based on patient numbers.
	So, I think, hopefully, you know, some of these questions will answer themselves.  The question that we always have to grapple with because we are under a great pressure of it is should we change the approval criteria for drugs with unique mechanisms of actions, such as cytostatic agents, angiogenesis inhibitors.
	So far, basically, we have kind of stated that clinical benefit is clinical benefit, and we really want to see these endpoints, but I think they need not be unattainable if these agents really are used in populations that are selective in a sense.
	DR. SANTANA:  Richard, can you further clarify for me because I thought in one of the regulations, particularly when you are extrapolating adult data, that the requirement was demonstration of activity in pediatric studies.  To me, it is not a play of words, but to me, activity is very different from survival.
	DR. HIRSCHFELD:  I think you are referring to the principle, which was first enunciated in the 1994 Pediatric Rule, which says that in order to register a product for pediatric use, that if certain conditions were met in terms of the disease having similarities between the adults and the children, and the mechanism of action of the drug having certain similarities, that there would be a decreased burden on demonstrating efficacy because it was felt and believed that you could extrapolate some of the efficacy data, and therefore, would just need to do the pharmacokinetic and some safety data.
	In oncology, that has never been used, and in other arenas, it has rarely been used, so we look on it as an attempt which sounded like a good idea at the time, but hasn't proved to be practical.
	DR. PAZDUR:  What I was referring to by the clinical benefit basically is the initial approval of a molecular agent or new molecular entity or a supplemental approval in an adult indication, where they are usually having the initial approval rather than an extrapolation of data.
	But I think that these are questions that we are continually grappling with, as well as the oncology community in general, because there is various steps in the development of an agent.  It is not only the identification of biological activity, number one, it is the selection of agents that one should take forward for further clinical development, which usually in adult medical oncology is a very muddy area.  Number three, the actual demonstration of clinical benefit.
	But once you start skipping around here between these three steps, it becomes problematic.
	DR. GOOTENBERG:  I just wanted to take the opportunity to make it clear that in biologics, we feel that we are going to have a lot of the novel mechanisms of the future, and that these questions are going to be even more compelling when we get to cellular therapies, gene therapies, and the more advanced cytokines.
	DR. SCHIFFER:  With regard to your comments, Rick, first, there certainly is precedent for approving home runs based on relatively modest data, and ATRA is an example, the hairy cell drugs are an example.  It was pretty obvious what was going on, and I would assume that that is what you are referring to, and that that is going to happen in the future as we have more home runs.
	DR. PAZDUR:  We have no problem in using surrogate endpoints in a sense, but the point that I was trying to get across, if you could select out a group of patients from, for example, the total denominator of lung cancer patients that was destined to have a good response to therapy, that effect is going to be so much greater, and the numbers of patients that you would need to answer that question is going to be so much less that these trials will be easier to do, and therefore, we necessarily don't have to go away from traditional endpoints although we are willing to look at different endpoints for different diseases.
	DR. SCHIFFER:  With regard to the prioritization issue, things are very different in children and adults.  The children's group have all the patients, period.  In adults, in fact, the Cooperative Groups do relatively few of what might be called licensing trials except as they get picked up by pharmaceutical companies in retrospect.
	The large prospective trials, if a pharmaceutical company thinks there is money to be made with another aromatase inhibitor, are done by putting together these large ad-hoc groups of highly organized practitioners who do these trials very well, and actually, probably more rapid than the Cooperative Groups.  One reason that they don't go to the Adult Cooperative Groups sometimes is the absence of speed--
	DR. PAZDUR:  Or control.
	DR. SCHIFFER:  Or control--with which these things can get done, but with regard to prioritization, it is a totally different issue in pediatrics and adult oncology.
	DR. SANTANA:  Dr. Arceci.
	DR. ARCECI:  I would be curious to know, and I think, Malcolm, because of your role at CTEP, I would be curious to know your opinion, can we do surrogate marker endpoints in new agents for pediatric patients, is that a legitimate approach in a setting that is a little different than what we have done in the past?  It may be okay, but I would be curious to know what people think.
	DR. SMITH:  What do you mean, give me an example of a study.
	DR. ARCECI:  Well, is it adequate to set up a study to look at the inhibition of farnesylation without a clinical endpoint, can we look at demethylation without necessarily a clinical endpoint being the priority in such a study?  We have grappled with these questions, and don't really have an answer.
	DR. SMITH:  I mean it is a real challenge.  The studies that have been done in adults, for example, the current wave of anti-angiogenesis studies where you are getting samples before and after, perhaps multiple times during therapy, it is very difficult to do those in a pediatric population.
	There are solutions that have been found, for example, Henry's studies with benzo guanine where a dose is determined in adults that affects the target sufficiently, the pharmacokinetics are understood in adults, and then the dose is identified in children that achieves those same levels of the drug.
	So, there is an extrapolation there, but a reasonable extrapolation.  The FTI studies, instead of using tumor tissue, might use buccal cells or another source of normal tissue as a surrogate endpoint to show that the target has been affected.  Of course, it is easier to do surrogate endpoint studies in the leukemia population than in the solid tumor population, so those types of studies are possible, some solutions are possible, but there will be times when it is just very difficult to do that.
	DR. SANTANA:  But what I heard from the FDA was, at least what I heard was it is okay to do those studies, but those studies are not sufficient enough.
	DR. PAZDUR:  Well, it really depends, you know, what is the purpose of the study, are you trying to determine biological activity or is this a trial to demonstrate clinical benefit in a situation.  Obviously, you know, it is where the science is at this time.
	If somebody came to us at this time and said given the science now, if we inhibit enzyme Q, will you approve the drug, and this is in isolation, probably that is not going to be the case because the approval for a new molecular entity at this time still revolves around the demonstration of clinical benefit.
	Can I say we will never accept that?  No, if the science evolves to that point where we believe that this is a very reliable surrogate endpoint and we are very comfortable in accepting it, then, we would be happy to revisit that situation.
	DR. SANTANA:  Sharon.
	DR. MURPHY:  Actually, I have been taking a list of a few comments, if I may, that really lead us from the general discussion back to the topic that Charlie and Mike had, may I?  Just a few.
	DR. SANTANA:  Go ahead.
	DR. MURPHY:  The first one, on the end of this discussion, the hoped for, I would say, is that yes, sometime there may be flexibility to have different endpoints for approval, even surrogate endpoints, but as far as the surrogate ones, I am sure there would be need to be validation of their relevance before they could be accepted, and I am not sure there is that in all the cases yet or in many, but I hope we will have novel endpoints for some biologics especially, Joe, because they are not going to be judged by the usual parameters of efficacy.  That was point one.
	The second point I would like to make, I think as we are focusing too much--and I am picking on Charlie now, which is not something I am known to do--I like to think about and to see differences, as you clearly demonstrated in outcome and reviewing the ASH abstract about between adults and children, but today, I think we are spending too much time on whether the responses to treatment are similar or different, or the responses in terms of the toxicity profile.  That is missing the point I think of what we are talking about because we expect the responses to be different, and that is why we want to do pediatric studies.
	So, why are we talking so much about showing differences in responses, that really has nothing to do with the mechanisms of action or safety or the disease process.  There are always going to be differences, and we shouldn't focus on what the survivals are.  That is looking at it from the wrong direction, I would say, for this discussion.
	DR. SCHIFFER:  I put that up as a point.  Let's say we are going to stick something in the middle of a complicated ALL regiment because we think it has T-cell specificity, let's say 506U, the cytotoxic, turns out to be the case.
	Can we do a combined trial in children and adults?  Maybe we can, maybe we can't, but I think that is why I brought up that point as to whether or not we could combine those data in that fashion.  I am fairly confident we could in AML and probably the lymphomas, but I think that important abstract raises that point.
	I don't think it raises that point on an STI or an MLL inhibitor, for example.
	DR. MURPHY:  Okay.  I understand better the point now.  You are clearly right, and it really goes to the feasibility, then, of doing trials, should we even decide that they should be the same or different.
	Then, turning to I think an answer perhaps to one of the first questions here about lymphoblastic disorders, what general principles could be used, I would like to echo and support Michael's suggestion that at least for the molecularly defined ALL subgroups, if they exist in adult and pediatric, they are the same.
	Also, I like the notion for the 40 percent or so of ALLs not otherwise specified between adults and children lacking a specific marker, call them the same, and the same way with refractory ALL, recognizing the importance of learning from that subgroup, still for drug testing, call them the same.
	In that way, it is striking that if we said that at the end of the day as a proposal, that would be a nice parallelism to the AML.  That is exactly what we said for AML.  I think that is consistent at least, it may not be right, but at least it is consistent.
	DR. POPLACK:  Just one question about that, Sharon, and that is, what do you do if a product is available that targets a specific lesion, which may be only 3 percent of the population, and one possible indication is refractory ALL, which is a much larger percentage, I believe, who makes the decision as to what the indication is for that drug from the company?
	A company is more likely to want to go for an indication where they are going to be encompassing a wider group of individuals rather than necessarily for a small and specific track, so I guess when the rubber meets the road, how do you deal with that type of a classification?
	DR. MURPHY:  I am not going to answer that.
	DR. SANTANA:  Sharon, do you want to comment on that?
	DR. MURPHY:  No, I have no idea.
	DR. HIRSCHFELD:  I am going to offer an absolutely uninformative, but correct answer, and it is case by case.
	DR. SANTANA:  Charlie?
	DR. SCHIFFER:  Companies want their drugs approved, and they will pick a target where they perceive it is simpler to demonstrate efficacy, and, of course, that is why you see all these approvals in desperate situations both in adult solid tumors.
	To get back to Rituxan, I think that is a great example of what happens when a drug gets approved for a very, very narrow window in terms of what happened subsequently.  You know, it is now called vitamin R for better or for worse, it is incredibly widely applied for every B-cell lymphoproliferative disorder.  In some cases, it is clearly for worse.
	But watching, almost looking at the ASH abstracts is sort of fascinating for Rituxan, watch the original Phase I, the so-called pivotal trial and stuff, and then the numbers that have increased, not only in numbers of patients, the numbers of abstracts, but numbers of diseases, and then it is going to do this, and, you know, get back to where it belongs.
	But it is a nice model actually of watching what happens when a drug with possible wide applicability gets out there and see how it is used, and companies recognize this.
	DR. SANTANA:  Dr. Boyett, you had a comment?
	DR. MURPHY:  Can I have my last one?
	DR. SANTANA:  I gave you an opportunity before, Sharon.
	DR. MURPHY:  Sorry.
	DR. SANTANA:  That's all right.  Go ahead, go ahead.  I am teasing you, Sharon.  Go ahead.
	[Laughter.]
	DR. MURPHY:  Last point.  In reflecting on some of the comments made about prognosis and I think, Michael, you last slide where you said you were lumping, your summary slide, where you had the very good prognosis, hyperdiploid and TEL-AML subgroups of ALL, and you said something like, well, nobody would ever study these or do trials in these because standard treatments are so successful anyhow, and it struck me that they are curative, but they are not necessarily satisfactory treatments.
	When you get to the point of Charlie's point, it raises this issue of how can we develop novel therapeutics for disorders that really have small populations, because really, I mean, you know, if we could encourage that, and it may be through the RAID program or other things because these are not economic targets by any means, but we would really want to prioritize the types of trials for those rare subgroups even if they are highly cured with standard treatment, because if you could replace it with something that is specific, that would be very, very important.
	So, I don't think we should just focus on the poor prognosis things either, we have to prioritize the good things even if it is like Wilms' tumor where everybody is cured.  If you had something that reversed imprinting in the WT-1 gene, hey, that would be cool.
	DR. BOROWITZ:  Just to comment on that, Sharon, I think it gets back a little bit to the ethical questions that were raised earlier and also just some observations I have made as a non-therapist outsider looking at the workings of the Cooperative Oncology Groups, is that there is a much greater reluctance to back off from successful therapy than there is to try something new.
	I don't discount the possibility of doing it, but from a realistic perspective, I think people would have to have a very compelling reason.
	DR. MURPHY:  I agree with that.
	DR. BOROWITZ:  So, I think if somebody comes up with a TEL-AML one specific agent, it will first be tried in those patients who happen to relapse with TEL-AML1.  Of course, based on my comments before, the reason they relapse may have nothing to do with their TEL-AML1, and we may lose an opportunity to have a good drug, but I don't see a really good way around that.
	DR. SANTANA:  Dr. Boyett has had his hand up for a while.
	DR. BOYETT:  This is a question for Dr. Borowitz.
	In your classification scheme for childhood B lineage ALL, you didn't mention anything about children diagnosed under the age of one, and while we are sitting here trying to discuss how we want to treat children with the same type of genetic diagnosis of ALL as adults or vice versa, it seems that in the pediatric oncology community, infants with B lineage ALL under the age of one similarly diagnosed are treated differently than those over the age of one.
	DR. BOROWITZ:  I think you are quite right.  I think all of the answers are not in, in that group.  Clearly, a portion of that has to do with the very high frequency of leukemias associated with MLL rearrangements, and if you take those patients out, in general, children with ALL under the age of one will do a little bit better, but I think it is also true that they don't achieve the success rate that older children do, and conversely, older children with MLL rearrangements don't seem to have the same dismal prognosis of the infants.
	So, I guess what I am saying is to some extent, the things we know about biology explain some of the differences, and so to the extent that we have biologically driven classifications of therapies, that will take care of part of the problem, but I think you are quite right that that doesn't take care of all the problem, and infants are a particularly knotty problem as anyone who has dealt with them knows.
	DR. SANTANA:  Dr. Poplack.
	DR. POPLACK:  I think what Michael was discussing previously is sort of a conundrum because to some extent, I agree practically.  If you get something that is good for a specific subtype of ALL, cytogenetic subtype, that happens to be doing well with the conventional therapy, it is again a nightmare for the clinical trialist to try and come up with a way of demonstrating it.
	On the one hand, you can say how is it ethical to consider doing that, changing midstream, however, you can make a strong argument to the contrary, which is that we know that many of the therapies that cure kids are associated with toxicities, and if you have something that is more specific, that may have fewer toxicities, we may be ethically bound to study that versus the combination therapies that may cure all, but have--you know, the cure is not in a sense the final answer here, it is being able to cure with minimal toxicity, I guess, that will be the ultimate barometer.
	DR. SANTANA:  I think we want to get back to the questions.  Malcolm, do you have a final comment?
	DR. SMITH:  I want just to clarify the comment about surrogate endpoints.  Someone earlier today, one of the first speakers, had a slide about the difference between childhood cancer treatment and some of the adult cancer treatment and cure versus palliation.
	I would encourage us as we talk about surrogate endpoints and alternative endpoints, that our bar not be lowered, that what we are looking for is cure and agents that improve the cure rates with improved toxicity profiles.
	So, while palliation may be particularly attractive in some adult populations, it is much less attractive in a young childhood population.
	DR. SANTANA:  I would support that statement.
	DR. SCHIFFER:  It is not attractive in adult populations.
	DR. SANTANA:  Because there is no other option, right.
Questions to the Committee
	DR. SANTANA:  Okay.  Let's get to the questions.  We are on Question No. II for lymphoblastic leukemias.  A.  What general principles could be used to relate lymphoblastic malignancies in adults to lymphoblastic malignancies in children?
	I think Sharon took an answer to this by in essence saying that for the individual defined subgroups, they are really the same, and they should be treated the same; for the refractory, they should be considered the same; for the not otherwise specified, they should be the same.
	So, in essence, the parallel she was trying to propose as a comment was that they all should be grouped together as the same and looked at the same in terms of therapeutic trials.
	Does that summarize well your comment, Sharon?
	DR. MURPHY:  Just the last sentence is that it leaves its parallel between what we said in AML and what we are saying in ALL.
	DR. SANTANA:  That is correct.
	DR. MURPHY:  Which is nice symmetry, whether it is correct or not.
	DR. SANTANA:  Does anybody else want to comment on that?  Yes.
	DR. ARTHUR:  I had a question.  One of the things that Dr. Borowitz brought up is that probably for all intents and purposes, T lineage, ALL should be considered the same in adults as children, and I don't know if you considered that.
	DR. MURPHY:  I didn't say anything about that.  Let's discuss it more.
	DR. ARTHUR:  I was going to ask you if you thought it was the same.  I am deferring to you.
	DR. MURPHY:  Well, I don't want--I mean probably not exactly.
	DR. POPLACK:  I am not sure it is, and I think that what you mentioned is we don't have a lot of information.  There are some studies that have been done which show that there are clearly differences in the translocations that are seen in adult T cell and pediatric.
	There is not a lot of data to this extent.  I think it is somewhat early to make that as a definitive conclusion, but I thought you said given the information we have at the moment, there is not a lot of--
	DR. BOROWITZ:  I would agree with that.  I don't think we have any compelling data to suggest that they are different, and the way I would approach that is the same way I approach the 40 percent of children that we really don't know.
	Absent clear differences between adults and children, my bias is to say they are the same, but certainly we know enough about T-cell leukemias to know that there are some different mechanisms at play and maybe those will turn out to be important, and they may differ between adults and children and we just don't know, but until we know, my bias would be to say that they are the same.
	DR. SANTANA:  Steven.
	DR. HIRSCHFELD:  I would just try to clarify the point by stating that what we are asking advice on is whether studies should be done, not whether the diseases are the same or whether we should approve it for children given that we might approve it for adults, but should we investigate, and that should be the trigger.
	DR. SCHIFFER:  At least in ALL, it is more likely that most compounds will be going from children to adults first rather the other way around.  There might be an exception, maybe STI, but certainly there are more children.
	DR. POPLACK:  But they are doing better, and I think from the point of view of it is hard to do a study to demonstrate that the addition of a new agent is really going to make a difference in a disease where your figures are so good overall in terms of success rate.
	So, it is easy to do that in populations obviously where patients are doing quite as well.
	DR. SANTANA:  Any other comments?  Let's do subpart B.  Which of the following adult diseases has a pediatric counterpart and what is the basis for making this association?
	[Fire alarm.]
	DR. SANTANA:  I guess we need to evacuate the room for a while.
	[Recess.]
Perspectives on Lymphomas
Stefania Pittaluga, M.D.
	DR. PITTALUGA:  I am Stefania Pittaluga, pathologist, working at the NCI, together Dr. Lane Jeffrey in the Immunopathology Section.  As a pathologist, I will go through the extensive review of the WHO classification entity by entity.
	I will skip the first ones here that we have already discussed.
	[Slide.]
	As everybody in the audience knows, the WHO classification is based on a similar principle as the real classification that was developed, and is based upon identification of disease entity based on morphology, phenotype, cytogenetic data, and clinical presentation.
	[Slide.]
	The precursor to B-cell neoplasia, B and T has been already discussed.  Among the mature peripheral B-cell neoplasm, I highlighted here that the nodal marginal zone B- cell lymphoma and follicular lymphoma have been described and can occur in children, while most of the others, as everybody have already mentioned, they occur predominantly in the adult population.
	It is of interest that although they are relatively rare compared to what we see in the adult population, there are some distinctive features that kind of separates them from what we see in the adults.
	[Slide.]
	In the more aggressive category of the diffuse large B-cell lymphoma, Burkitt lymphoma/Burkitt cell leukemias, those are the ones that occur more frequently in children, as has been already pointed out, although they represent only 1 to 2 percent that we see in adult populations.
	[Slide.]
	Regarding the mature peripheral T-cell neoplasm, aggressive NK-cell leukemia can occur in children, young adults especially in Japan, although here we don't see them that frequently, and hepatosplenic gamma delta T-cell lymphoma can also occur in the young population, as well as subcutaneous panniculitis-like T-cell lymphomas.  Although again these are very rare in the adult population, I just want to point out that they can occur also in children.
	The largest group of peripheral T-cell lymphoma that occur in the children population is represented by anaplastic large cell lymphoma or T and null cell phenotype, which is a systemic disease contrary to the cutaneous primary anaplastic large cell lymphoma.
	It is of interest that this particular type of lymphoma has been grouped in the past within the diffuse large cell lymphoma, and has a distinctive clinical behavior and characteristics.
	[Slide.]
	Regarding Hodgkin's lymphomas, the three highlighted are the ones that we see in children, as already pointed out.  They are similar to what we see in adults.  I just want to mention that the nodular lymphocyte predominant in Hodgkin's lymphoma is a B-cell lymphoma and has characteristic morphology phenotype not expressed in CD15 and 30 contrary to the classical Hodgkin's disease, and it is described and seen in children, and has similar characteristics as we saw in adult population, predominantly occurs in young males and has similar clinical features.
	[Slide.]
	I will just briefly mention the pediatric follicular lymphoma because we believe it is a rare lymphoma subtype that occurs in children at 1 to 2 percent.  It has some distinctive features that we can see, contrary to what we see in the follicular lymphoma in adults.
	They usually present in the head and neck, the majority of them, but they can involve other sites, particularly GI tract or gonads.  The other difference is that usually they are of Grade II or III.  They are higher grade than what we see in the adult population.
	They are usually BCL-2 negative both by molecular studies, as well by protein.  There is a predominance male over female at 3 to 1, and 85 percent of those present with Stage I or II disease, and they achieve CR in 75 percent with a low relapse rate.
	Because of all these features, we believe that pediatric follicular lymphoma might present a distinct entity that is different than what we observe in the adult population.
	Similarly, there are some difference in the nodal marginal zone.  We just collected a series at the NCI, and it is of interest that they also have features that are morphologically distinctive from nodal marginal zone in adult population.  They tend to have very good clinical behavior.
	[Slide.]
	Regarding the more aggressive type, and I refer specifically to the Burkitt lymphomas/leukemias, in children I think that the issues on the borderline with large B-cell lymphoma, and therefore, the category that is called Burkitt-like, that is an overlap, a continuum of progression between Burkitt lymphoma and large B-cell lymphoma is less of a problem than what we have in studying the adult population in which the percentage of diffuse large B-cell lymphoma is much broader and much larger, and therefore, this overlapping in the group that we call Burkitt-like or Burkitt with the typical features is much more a problematic entity, if it is an entity.
	[Slide.]
	Therefore, the question that we have often is Burkitt-like lymphoma, should it exist, and if we have Burkitt-like lymphoma, should those be included with the diffuse large B-cell lymphoma or should those be considered as morphologic variant of Burkitt lymphoma.
	This is one of the issues that has been hotly debated at the WHO classification.
	[Slide.]
	Now, we have several points that point towards the fact that Burkitt's and Burkitt-like lymphoma, they are both derived from a germinal center, they both can show follicular colonization, the cells in both entities resemble the dark zone of the small blasts of the germinal centers.
	The fact that there is detectable high rate of somatic mutation in immunoglobulin gene reveals that those cells might have been exposed to antigen.  The positivity for BCL-6 and CD10 strongly supports the idea that those are indeed derivation of germinal center.
	[Slide.]
	Therefore, the additional parameter that we use to define Burkitt-like lymphoma, which as I mentioned I think is more of an issue in the adult population, they are similar to Burkitt, they show usually greater variation in nuclear morphology.
	One of the features that they try to tighten it up, the group, is to show that there should be a proliferative rate, which is kind of a surrogate marker for the expression of c-myc, that the proliferation rate should about 100 percent.  They are usually CD10 positive and are almost all BCL-2 negative.
	Of course, cytogenetics or molecular genetics demonstrated a c-myc translocation is desirable for diagnosis, and to put this group in this category, and this morphologic variant is also more commonly seen in immunodeficiency states.
	[Slide.]
	Therefore, in the WHO classification, the term "Burkitt-like lymphoma" is retained and is considered to be a variant of Burkitt lymphoma, and the major criteria that we will use to put this into the category of Burkitt's is the intermediate morphology of the nuclear features, the presence of c-myc translocations, and as I said, as a surrogate marker, the high proliferative fraction.
	Therefore, if you have a lesion which has shown 99 percent of high proliferative rate, it is going to be put within this category assuming that the marker I mentioned before are such.
	[Slide.]
	The Burkitt lymphoma therefore will be divided with the morphologic variants, which comprise the classic Burkitt lymphoma, atypical Burkitt or Burkitt-like, and Burkitt's with plasmacytoid differentiation, which is most commonly seen in HIV-associated condition.
	Moreover, there are subtypes related to the difference in the clinical presentation and genetic aspects, as well as the characteristic of the c-myc translocation, and those are what are known as the endemic form, the sporadic, and immunodeficiency-associated.
	[Slide.]
	The second of the lymphomas that I would like to discuss, and that is the anaplastic large cell lymphoma, which is basically represented like the paradigm of the process that we use to define disease entities in the real specification.
	In fact, this disease was originally described based on morphology and the sinusoidal growth, and antigenic phenotype, which was the presence of the CD30, and therefore was called CD30 positive or K-1 lymphomas.
	The molecular pathogenesis led to the identification and actually translocation was earlier described, and it was associated what at that time was called malignant histiocytosis originally, but the molecular pathogenesis brought in the possibility of detecting the translocation by RT-PCR and further, the development of a monoclonal antibody against the ALK-1 protein give us new diagnostic tools to better define the borders of this disease.
	[Slide.]
	It is predominantly a disease that occurs in children or young adults, and it is of interest that most of them, they occur as a nodal disease, however, cutaneous involvement could be present, as well as at extranodal sites.
	In frequency, it presents with B symptoms, which is less predicting the clinical outcome in contrast to other non-Hodgkin's lymphoma, and moreover, although it has an aggressive natural history, they have a good response to chemotherapy.
	[Slide.]
	This is just taken from a publication by an international study group on a large series of 267 cases of anaplastic large cell lymphoma, which they showed that the predominant population is present is in the first two decades of life.  Plotted here is the presence of the translocation, its variants, or the expression of ALK-1.  It actually reflects exactly the same distribution meaning that the majority of cases in children are ALI-1 positive.
	[Slide.]
	That leads to the survival curves, an overall survival of 154 of those patients in which it clearly shows that the ALI-1 positive children actually have a much better behavior than not the one that we observe in the ALK-negative cases.
	[Slide.]
	Therefore, in conclusion, the ALK-1 ALCL is probably a distinct disease entity of its own, that this should be separated from the ALK-1 negative cases, and I mentioned, this is of particular interest to this group since this occurs predominantly in children and young adults.
	Thank you.
	DR. PRZEPIORKA:  Thank you, Dr. Pittaluga.
	Our next speaker, Dr. Hutchison for Upstate Medical University.
	Is there a question for Dr. Pittaluga while Dr. Hutchison is getting ready?
	DR. BROSS:  Just a brief question.  I understood there was some new molecular marker for prognosis in large cell lymphoma, and I believe this is more in adults, and I think that came from the NCI, but I can't remember the source.
	Are you familiar with this?
	DR. PITTALUGA:  I am sorry, which one?
	DR. BROSS:  A molecular marker for prognosis in large cell lymphoma.
	DR. PITTALUGA:  In the marker array data from Dr. Stulz's group, the diffuse large cell lymphoma segregated in two major clusters.  One is poor prognostic indicator which has inactivated B-cell phenotype versus the one that resemble more the germinal center phenotype, there is a series of genes that have been named, however, I don't know which one is being tested at the moment frankly.
	The one that they have always chosen in presentations are genes that we usually follow in those particular cases like CD10, BCL-2, BCL-6, IRF-4.  So, those are known pattern already within pathology, that might segregate between the two groups, but I don't know of new genes that have recently come out.
	DR. BROSS:  I think I am supposed to give my name and affiliation.  I am Peter Bross.  I am with the FDA DODP.
	Thanks.
	DR. PRZEPIORKA:  Any other questions?
	Dr. Hutchison.
Robert E. Hutchison, M.D.
	DR. HUTCHISON:  I think Dr. Murphy already summarized what I have to say, and that is that Hodgkin's disease is probably the same, and non-Hodgkin's lymphoma is probably different between adults and children.
	Dr. Pittaluga basically said some of the things that I am going to say, but I am just going to go through this and show you some pictures and some numbers.
	[Slide.]
	As you know, lymphomas are derived by lymphoid cells which come from the lymph nodes and the extranodal lymphoid tissues, which include B cells, follicular center B cells, mantle cells, interfollicular T cells, and a whole host of subtypes of all of those, and so it is not surprising that we have a lot of different types of diseases.
	[Slide.]
	Hodgkin's disease has been classified pretty well for a long time since probably really the fifties, although the classification that we currently use goes back to the late sixties.
	There is really four main types, which we will go into in a minute.  Although non-Hodgkin's lymphomas are almost equal in number in children, there are really a lot of different types of non-Hodgkin's lymphomas to deal with.
	This is a partial listing, and I think in the WHO classification, there are either 28 or 30 classes, in the REAL, there is 26.
	[Slide.]
	That makes a problem when you try to summarize anything about non-Hodgkin's lymphoma, they are very diverse.
	I just pulled out some raw data.  This is not official data, but this just happens to be the types of cases that the Pediatric Oncology Group has enrolled on studies in the last three years, and you can see that nodular sclerosis Hodgkin's disease is the most common with small, non-cleaved cell Burkitt and non-Burkitt lymphoma being second, lymphoblastic lymphoma being third, and diffuse large B-cell lymphoma and anaplastic large cell lymphoma each tied in there.
	Other forms even of Hodgkin's disease are relatively uncommon compared to the rest of these, and you don't see any of the rare 26 classifications in this at all.
	[Slide.]
	This is just Hodgkin's, and the only reason that I show this slide is to point out that his work was based on the anatomic presentation of the disease, it had nothing to do with molecular or phenotypic or even microscopic morphology, but his observations have borne out very well over all these years.
	[Slide.]
	Hodgkin's really is four types - mixed cellularity, lymphocyte depleted, and nodular sclerosis is the most common and lymphocyte predominant.
	[Slide.]
	All of which have in common one thing which is the Reed Sternberg cell which is shown here in a variety of ways.  The Reed Sternberg cell is something which we have only recently started to know a little bit about, and the paradigm is evolving that it is derived from, a B cell, probably a follicle-center B cell which has undergone some sort of crippling mutations or some sort of abnormal process in that it will not produce immunoglobulin RNA.
	[Slide.]
	Hodgkin's disease incidence is actually relatively flat throughout life.  It peaks in young adulthood and in old age.  In young adulthood, the peak is nodular sclerosis Hodgkin's, which tends to occur in young women with mediastinal involvement, but it does occur in males also.
	Lymphocyte depleted Hodgkin's disease is the one which tends to occur in older people, and actually mixed cellularity and lymphocyte predominant are relatively flat throughout age, so this is a disease which does occur in both adults and children.
	I think I am going to skip over a lot of this stuff, and if anybody has questions about it, we can get back to it, and I will go right to the non-Hodgkin's lymphoma, and like I said, we can address some things if there are questions.
	[Slide.]
	I have summarized all the 26 kinds of non-Hodgkin's lymphoma into basically seven groups, that is, the small lymphocytic and related lymphomas, the mantle cell lymphomas, Burkitt's lymphoma, lymphoblastic lymphoma, follicular lymphomas, large B-cell lymphomas, and the peripheral T-cell lymphomas including anaplastic large cell lymphoma.
	[Slide.]
	With clear classification schemes, we really need phenotype to be precise in our diagnoses, and we can use phenotype not only to classify lymphomas, but potentially in the future to identify targets, such as alkaline expression anaplastic large cell lymphoma, BCL-2 expression in a variety of lymphomas, not necessarily related to BCL-2 translocations.
	[Slide.]
	Non-Hodgkin's lymphoma, I pulled this out, it is a relatively recent reference based on SEER data, and I was a little bit surprised to see that in the U.S., that diffuse large B-cell lymphoma is by far the most common at the current time.  I had thought actually that follicular lymphoma was the most common, but according to this reference, it is diffuse large B-cell lymphoma.
	Now since in adults, NHL is approximately 15 times as common as it is in children, this is largely going to be adult data.  The interesting thing is that the high grade lymphomas are relatively uncommon in adults, but these constitute virtually all of the lymphomas in children.
	[Slide.]
	In children, the published data shows this to have about 5 to 10 cases per million children, whereas, the adult data is per 100,000, so there is at least a log difference in the incidence.  This is just to show in the POG in the last three years, the same set of data that I showed before.
	The distribution is almost equal between small, uncleaved Burkitt's and non-Burkitt's, lymphoblastic, large B cell, and anaplastic large cell lymphoma.  So, these are the four predominant players in pediatric lymphoma.
	[Slide.]
	Burkitt's lymphoma is really a fairly homogeneous thing, which is associated with a translocation involving c-myc and one of the immunoglobulin genes.  There are really multiple types of Burkitt's lymphoma, that is, there is the endemic Burkitt's, there is the sporadic Burkitt's that we see in pediatric patients mostly.  There is also those Burkitt's which are associated with immune deficiency, either HIV or post-transplant, which are a little different in terms of the breakpoint and the insertion site of EBV.
	The reason this may be important is that a lot of the data, a lot of the biologic data on Burkitt's lymphoma actually come from those which are EBV associated, which tend to grow well in culture, whereas, the sporadic Burkitt's, which do not have EBV, do not like to grow in culture, and there is not a lot of cell culture data on those cases.
	Another kind is large B-cell lymphoma, and this is a disease which we saw is the most common in adults, and it is one of the more common in children, but there may be differences between large B cell found in adults and children, too.
	I am not sure, there is not a lot of good data on large B-cell lymphoma in children, and as a matter of fact, we did not even know the distribution of T and B cell phenotype in large cell lymphoma in children until paraffin reactive monoclonal antibodies became available in the late 1980s.  There is not a lot of flow cytometry data, there is not a lot of biology data, and so whether or not this is the same as large B-cell lymphoma in adults can be easily argued.
	These tend to have a higher proliferative fraction, not as high as Burkitt's, but approaching that.  They tend to have c-myc expression by immunohistochemistry.
	Burkitt-like lymphoma, again to reiterate what Dr. Pittaluga said, is a borderline between Burkitt and large cell.  Some of them are actually variant Burkitt's, some of them are probably large B cell.  My feeling is that in this spectrum, that there is a great spectrum between Burkitt's and large B cell, and then really dividing them into three categories is not necessarily accurate, but it is the best we can do at this time.
	[Slide.]
	Now, just to mention the rare lymphomas in children - small lymphocytic lymphoma just like CLL that Dr. Borowitz mentioned is exceedingly rare in children, but it has been described.
	[Slide.]
	There are six or seven cases that I saw in the relatively recent literature.  Three of those had a consistent translocation.  My guess is that this is not the same thing we are going to see in adults because I haven't seen that translocation in adult small lymphocytic lymphoma.  So, it is a rare disease, does exist.
	One thing I learned as an early pathology resident is that every disease occurs in every organ at every age if you look hard enough, but generally, those are rare.
	[Slide.]
	Follicular lymphomas are probably the most common of the rare lymphomas in children.  They are very common in adults, but they do occur in children also.
	[Slide.]
	Most of these, as we have already heard, are of the larger cell type, either mixed or large cell.  Most of the ones I have seen have been large cell.
	They really constitute up to about 1 percent of pediatric lymphomas, but I think they are different diseases.  If you look at the literature critically, very few patients ever relapse with follicular lymphoma in the pediatric population while virtually all patients in adult populations relapse, and that alone makes it very different.
	Those few who actually have failed therapy in the world's literature have progressed to diffuse large B-cell  lymphoma, and what we may be seeing is a follicular and diffuse large B-cell lymphoma, which may behave more like, in some cases, like diffuse large B-cell lymphoma.  There are not enough cases to really know.
	[Slide.]
	Marginal zone lymphomas, which are probably the lowest grade of the adult lymphomas, do occur in children.  At least half of the cases which have been reported have been in HIV cases, but there seems to be an increased smattering of reports of these things occurring in non-immunosuppressed people.
	[Slide.]
	Those rare cases tend to mimic the ones in adults, in the GI tract and the spleen and the salivary glands, a few in the lung, but they are also quite rare.
	[Slide.]
	Mantle cell lymphoma, which we greatly fear in adults, I don't think occurs in children.  I have never seen it and I have never seen it reported, and someone else might know of that.  I thought I saw a case once, but it turned out to be a cutaneous B lymphoblastic, and it wasn't.
	[Slide.]
	Now, T-cell lymphomas other than anaplastic large cell lymphoma and lymphoblastic lymphoma are rare in children, just like they are uncommon in adults, and there is not a whole lot to say about them.  I will skip over that.
	[Slide.]
	Lymphoblastic lymphoma, we have heard a little bit about.  It is actually quite common in children, and it is turning out to be one of the lower prognosis forms of non-Hodgkin's lymphoma in children as we get better results with the B-cell lymphomas.
	[Slide.]
	Anaplastic large cell is the one that most pathologists have been interested in, in children, and we think that we can generally identify this one now with the monoclonal antibodies, and there are some actually good polyclonal antibodies, but most people are using monoclonal ALK-1 to identify the so-called "alkalomas."
	This is a characteristic case.  This is actually about half of large cell lymphomas in children.  Now, the fact that ALK-1 positive anaplastics do better than ALK-negative anaplastics may or may not be related to the disease itself.
	There is an age thing in there, and most reports of anaplastic large cell lymphoma include a spectrum from adults to children, and with most of the ALK-positive ones being under age 35, and most of the ALK-negative ones being over 30.  So, it is very hard to compare survival data between patients who have a median age of 20 or 18 and a median age of 50 or 60.
	We really don't know.  We are looking at this in the COG to see if there is a difference, and we haven't demonstrated any difference between ALK expression or not.
	[Slide.]
	We do know, though, that most anaplastic large cell lymphomas in children express ALK.  This is CD30 positive large cell lymphomas, and the majority of them express ALK.  That has been published in a variety of ways.  That particular piece of data is raw, though.
	[Slide.]
	So, non-anaplastic peripheral T-cell lymphomas are rare.  Anecdotally, people say they don't do well, and that is probably true.
	That is basically it.  We have four types of lymphoma that we are dealing with.
	DR. PRZEPIORKA:  Thank you.
Discussion
	DR. MURPHY:  Aside from admiring the pictures of Lugarno [ph] and the masterful encyclopedic classification now with the REAL and the WHO, neither of you commented--perhaps you would--on whether you want to come down on how the Rule should be applied, which is why we are here today, and I am wondering if I heard the subtext here that each of these real entities is really different from each other, and really they should all be considered separately, or what words would you put in your own mouths as to how to apply the Rule to these entities?  That's the question, right?
	DR. HUTCHISON:  Before I sit down, since I have a microphone in my hand, I will give my view on that if I can.
	I think that a drug that is derived or produced for follicular lymphoma does not apply to children, and when it is derived and developed for CLL, it does not apply to children.  I think that we really don't know in the other categories if they are the same diseases or not, and we probably have to assume that large B-cell lymphoma, anaplastic large cell lymphoma, lymphoblastic lymphoma may be the same, and the Rule may apply in those.
	DR. PRZEPIORKA:  Dr. Pittaluga?
	DR. PITTALUGA:  I would think that some of them like Burkitt's lymphoma or lymphoblastic are more common in children, are more homogeneous, and I think that those are entities that they are similar to the one that we see in the adults, although much less frequently.
	There might be some subtle differences within the Burkitt's in different groups, but I think that overall clinically there is behavior much more similarly.
	Regarding the anaplastic large cell lymphoma, I think it is very interesting the point you raised that the majority of the ALK-negative, they are in the adult population, and therefore, it might be that this is indeed a disease that is strictly confined to children, and we might not have an adult counterpart although there are sporadic cases that are ALK-positive in the adult population, but those are really anecdotal, so it is kind of the reverse that we have seen in most other lymphomas.
	The other entities, I think they are real and they exist, and the affect mostly the adult population, and there are definitely biological reasons why these occur.  I would agree that I would not use drugs that you use for adults translating them into children, and follicular lymphoma, for instance, relatively rare, we believe that indeed there is a distinct disease, and has nothing to do with what we see in adults, and it might be that even the nodal marginal zone, which is very rare in adults, but it also might have some distinct features that are typical of children.
	DR. MURPHY:  I think it just emphasizes the practical aspects and the difficulty of applying the rules here, because of the plethora of real different types of non-Hodgkin's lymphomas, now readily recognizable by expert clinicians and hematopathologists, each one very rare.
	DR. PRZEPIORKA:  Dr. Schiffer.
	DR. SCHIFFER:  We will trade you the mantle cells for almost anything.  In the ones where there may be overlapping, particularly the small non-cleaved, where we have so much trouble in adult oncology distinguishing it between Burkitt's-like and large cell, and there is also probably a major therapeutic implication with regard to that distinction, as well.
	Should these be defined as whether they are myc-mutated or not?  Is there sufficient data to make that distinction, and if so, would those be analogous to the Burkitt's or the pediatric experience, because again with the small, non-cleaved in adults, if we use these short intensive regimens, we cure 50 percent, we don't cure 90 percent, and some of it may be who is doing the treating, but I don't think so, I think it is really more that there may be heterogeneity.
	DR. MURPHY:  Just on that point and not belabor it, I mean it is how you define it, I think, and how strict you are in making distinctions for protocol eligibility between Burkitt-like or pure monomorphic Burkitt c-myc translocated, and because I think a lot of adult trials where this distinction between large B cell and Burkitt-like is a lot harder than it is in kids where we have a purer entity, I think maybe that is why the cure rates aren't as high.  There is a mixture of cases, as well as differences in the host.
	You know, again, we shouldn't focus too much on the outcomes, it is whether the entities are alike, and during the WHO Clinical Advisory Committee meetings at which I participate at the Airlie House, there was long arguments whether even Burkitt-like would stay in the classification.
	Enough experienced adult clinicians argued yes, it has to because it does have therapeutic implications, that it survived being otherwise thrown out.  It was a close call.
	DR. SCHIFFER:  In the adults, there are no good data about what percentage of those are myc mutated.
	DR. MURPHY:  Right, that is why I think they are mixed up.
	DR. SCHIFFER:  Right, but which may, in fact, eventually define which side of the line they go on.
	DR. MURPHY:  Right.
	DR. SCHIFFER:  How many of the children have myc mutations with small, non-cleaved?
	DR. MURPHY:  It is not 100 percent.
	DR. HUTCHISON:  I can answer that.  We don't know.  You mean myc-translocated or myc-mutated?
	DR. SCHIFFER:  I am sorry, I meant mutated.
	DR. HUTCHISON:  You mean translocated because myc tends not to mutate.
	DR. SCHIFFER:  I am sorry, I meant H-14 or its variant.
	DR. HUTCHISON:  Right, and one of the problems with pediatric lymphomas is its sample size tends to be very small and it is has not been traditional for primary treating institutions where the diagnosis is usually made to do cytogenetics on Burkitt's.  It is actually kind of hard to do it.  You have to be very fast and do direct unstimulated preps to get a karyotype off of Burkitt's.
	We don't really know, and we have proposed in the COG now that we have some paraffin-reactive FISH probes to look at that, because we really don't know.  I think most of the data is really based on cell cultures and on L3 leukemias even in the adult population.
	I do know that myc is activated and expressed in virtually all pediatric B-cell lymphomas including large B cell, so you can't use that.
	DR. SCHIFFER:  I wonder then, that it might be premature until these data are forthcoming to lump the adult and the pediatric small non-cleaved on the assumption that these data will be coming soon.
	DR. HUTCHISON:  If I may, in the adult lymphoma, large B-cell lymphoma tends to respond pretty well to CHOP, and that is what people use usually, and the Burkitt's lymphomas, some people feel that they need more aggressive therapy, and that is why you want to separate it.
	In the pediatric groups, the tendency now is to treat all B-cell lymphomas the same with Burkitt type therapy, that is the trend, and that may be over-treatment for adult large B-cell lymphoma.  We don't really even know if adult large B-cell and pediatric large B-cell lymphoma are the same.
	DR. PRZEPIORKA:  Dr. Borowitz.
	DR. BOROWITZ:  I just wanted to bring up another kind of lymphoma that I didn't hear mentioned and to just raise the issue of how much of a parallel we should draw between adults and children, and that is the lymphoproliferative disorders that arise in the post-transplant setting or in immunodeficiency disease.
	My own bias is that whatever you call them histologically, they are more alike than they are different, and I think that that is a group of tumors that we should also include in the discussion because they are different, on the one hand, from Burkitt's lymphoma, and on the other hand, from typical large B-cell lymphomas.
	DR. MURPHY:  It is hard to tell when they are lymphomas.
	DR. BOROWITZ:  That is certainly a reasonable point, and it is not always clear when they are lymphomas, although they have outcomes that are often similar.
	DR. PRZEPIORKA:  Other questions?  Dr. Hutchison, what about the histiocytic diseases, are they are adult diseases we should be looking for that could be used to tip off when to look for the pediatric histiocytic diseases?
	DR. HUTCHISON:  You know, it is hard to say because they are all so rare.  The main "malignant histiocytosis" that was thought to be fairly common in children is actually anaplastic large cell lymphoma now, and there are several different kinds of histiocytic proliferations in malignancies, you know, viral-associated hemophagocytic syndromes, there are histiocytic lymphomas which are not anaplastic large cell lymphoma, but they are exceedingly rare, they are less than 1 percent probably.  It is very hard to know what do with those, I think.
	I mean the Histiocyte Society exists partly to determine what to do with these, but we don't see them very often, and almost all of the results are anecdotal, to my knowledge.
Questions to the Committee
	DR. PRZEPIORKA:  Let's move on to the questions then, for lymphoma No. III.  What general principles could be used to relate lymphomas in adults to lymphomas in children?
	Dr. Murphy, would you like to take a recapitulation, if you will, of your previous recommendation?
	DR. MURPHY:  I think the general principles are the ones that underlie the REAL classification, and the WHO that followed it, which is it is a combination of criteria that define entities.  It's immunophenotype, it's morphology, it's cytogenetics, it is sometimes clinical features, and those are the ways to subclassify them.
	I think we are all in the general agreement that the common ones seen in children are not common in adults, although they occur rarely and vice versa, and so I think we have to fall back on the most modern paradigms for their classification and use those rather than come up with something entirely new, but what would it be, I have no idea.
	I mean we have got to, just as was pointed out here, use these criteria.
	DR. PRZEPIORKA:  Dr. Smith.
	DR. SMITH:  So, there is Burkitt's, there is lymphoblastic, and there is diffuse large, and there is anaplastic, and those four, if there were an adult indication for one of those four, then, it would warrant studying in children, and follicular and the other classifications that don't occur in children, would not necessarily warrant a pediatric evaluation.
	DR. MURPHY:  I have to agree with that.
	DR. PRZEPIORKA:  And Hodgkin's?
	DR. MURPHY:  Hodgkin's is the same.
	DR. PRZEPIORKA:  We have kind of answered No. 2 with the exception perhaps of unspecified lymphomas.  If I could get some clarification on unspecified lymphomas?
	DR. HIRSCHFELD:  We were trying to come up with kind of a hybrid schema, so this meant lymphomas which weren't mentioned previously.
	DR. PRZEPIORKA:  No. 3.  Are there pediatric lymphomas that have an adult counterpart that is not commonly classified as an adult lymphoma?
	DR. MURPHY:  Not that I know.
	DR. PRZEPIORKA:  I don't know of any adult diseases that would molecularly match a pediatric lymphoma, so I think that would be no.
	Any other discussion?  Did we answer all of your questions, Dr. Hirschfeld and Dr. Pazdur?
	DR. HIRSCHFELD:  I think so, thank you.
	DR. PRZEPIORKA:  Dr. Arceci.
Summary Comments
Robert J. Arceci, M.D., Ph.D.
	DR. ARCECI:  I have been doing this sort of as we have been going.
	[Slide.]
	Just to give you a feeling for how sometimes you don't think what you think is real, may not be real.  Don't take this next slide as an anti-evolutionary slide, but I think it brings up a point, that sometimes what we see is not what we actually get, so forget the first two frames here.
	[Slide.]
	This is an old cartoon, but this is the turtle walking in.  He walks in and an alligator walks out, this guy says, "Evolution is a fact, so you know it is true," and then, of course, the alligator spits out the turtle, so maybe it wasn't quite--what you see is not what is behind the scenes, and keep that in mind as we go through this stuff.
	[Slide.]
	So, these are some of the notes I took down.  Hematologic malignancies in terms of Pediatric Rule, commonalities leading to the invocation of this Pediatric Rule.  Sorry about the George Bush spelling there, I didn't have time to spell it correctly.
	Defining usage.  I think we all agreed that defining the usage of this Pediatric Rule could be used when you had common target expression, that is, markers.  We didn't talk about tumor antigens, but I think we are going to have to discuss it in terms of vaccine development in the future, so I think just the expression of a shared antigen is worthwhile talking about.
	Common functional targets, that is, Sharon said chimeric proteins that are functionally related to the maintenance of the malignant phenotype.
	We didn't talk about shared host factors very extensively, but I think it is something that we might consider in terms of, let's say, a host has a specific enzyme defect that would make them more predisposed to efficacy of a drug or metabolism of a drug, so it is something that we maybe think about.
	Then, I think, as Charlie would say, demonstrated activity in adults with the, quote "same" cancer.  We will have to define that.
	[Slide.]
	Reasons for exclusivity.  Unique tumor biology may be infant AML, JMML, possibly CLL.  There are examples we all talked about, and I didn't want to enumerate all those, but I think that you are going to find some that, if there is an adult indication, it is just not going to work, and you may find some in pediatrics, like JMML, we may find a drug there that works that is not going to have relevance to it, AML.
	Distinctive patient clinical characteristics.  Kids with Down's syndrome, kids with inherited predisposition, the elderly.  Maybe if a drug is developed in the elderly, maybe it is going to be unique to that group.  Infants is another possibility.  So, there are going to be reasons why, I think, they can be excluded.
	Yes, Sharon.
	DR. MURPHY:  Just semantics, but since we are at an FDA hearing, don't you want to change the terminology and say "reasons for waivers" instead of "reasons for exclusivity?"
	DR. ARCECI:  Waivers would be fine.
	DR. MURPHY:  Because exclusivity refers to the freedom from generic competition.
	DR. ARCECI:  Okay.
	DR. MURPHY:  But I think you are talking about these things being where you would issue waivers, right?
	DR. ARCECI:  Yes.  Waivers is cool.
	Any others?  Waivers, basically, I think this is what we were talking about.
	[Slide.]
	There are some caveats, which I thought were pretty interesting.  One thing I think that David brought up particularly, which I would totally agree with biologically is that expression does not always translate to function, so if you express a translocation, it doesn't really mean that it is going to be a relevant target and do you have to prove that the protein is present or that it is relevant.
	I think that if your drug is designed to inhibit a function, you have got to prove that a protein is being made, and that may not always be the case in all pediatric or adult tumors.
	There may be cross-tumor commonalities, and Steven brought this up, and I think it is a fascinating idea, that is, if there is like a track in lung cancer, and a track in neuroblastoma, or other brain tumors, there are going to be some lesions, c-kit mutations and gastronomas, AML, there may be some things in solid tumors that we should be broad-minded about in terms of targeting, in terms of pediatric trials, and that should be, I would say, sufficient to say you should do it in pediatrics.
	Host factors, we have talked about a little bit.  There are going to be unique characteristics in pediatrics that you just going to not be able to use it in certain groups of patients.
	What I would say here is this group here is what Dr. Beckwith would always talk about, moral equivalency, and that is--and I think, Charlie, you brought this up, and Don--if it looks the same, behaves sort of the same, call it the same.  So, all those AMLs, all those AOLs that you don't have a specific translocation for, but if it smells right, it probably is right, and should we be treating those patients similarly and also not giving a waiver under those circumstances.
	I think that is not a bad way to do it - until we can split out more effectively, why not lump them.  This is what Beckwith used to always talk about in terms of if you can't make up your mind about a tumor specimen, if it looks aggressive, and it looks like this, it probably is a bad tumor.  So, whether it has a certain marker or not is irrelevant.
	The issue of danger of waiting for a drug's approval before starting studies, I think that this is an important issue in that the ability to start early is going to be really important for pediatric trial development, and we are going to miss out on good studies if we don't do that, like vitamin R that Charlie talked about.
	[Slide.]
	So, some issues in terms of the ethics that were brought up.  When should pediatric studies with new agents be initiated?  I don't think we have an absolute answer on this at this point.
	When is the right time to do simultaneous development of a new agent in pediatric and in medical oncology?  I think it can go either way, but I think that we are going to grapple with this question a little bit more in terms of dose finding and when we should be able to start. What kind of information do we need as pediatric oncologists to start a trial?  I don't think we have answered that.
	Endpoints that would satisfy the Pediatric Rule.  We touched on this, but would a study in pediatrics, looking at a surrogate marker, be sufficient to say that a company, for instance, had satisfied the Pediatric Rule, or should it be an efficacy study, or an activity study, and we really didn't answer that question, although we sort of brushed by it a little bit.  I think it is important because it really matters.
	I suspect that a surrogate trial, you can prove proof of principle much more easily and in fewer patients than it would take for an activity or clinical trial, so there is a price tag that is associated with that, as well, but what are the endpoints that we want.
	My gut feeling would be that if we are going to use a new drug in kids, we should have some potential benefit to justify its use.
	Down here, it goes along with these three things.  McIntyre, the ethicist up in Boston, talks about whose justice and what rationality.  So, whose sort of value system are we going to use when we ask kids to participate in these new agent trials?  I think we have to be very careful.  It should obviously be from their perspective in the end, and not necessarily our or the company's or CTEP's or anybody else's perspective.
	So, I think this ties into this right here, and is very important stuff that Susan brought up.
	[Slide.]
	Then, a couple of last issues.   How will priorities be established?  I really didn't hear a very clear demonstration of this.  I mean we have COG, we have CTEP, a bunch of Cooperative Groups in adults, medical oncology, but is unclear if we have five new agents to test in the subtype of AML, which ones are going to be done, and maybe that should go through strategy groups, through the Cooperative Groups, but maybe not always.  I think that is up for discussion right now.
	Who and which group should be involved?  This is something that Susan has asked extensively about, and so who should be sitting at the table to make these decisions.
	The other issue is how should studies be defined, do they all have to have clinical benefit, and I touched on this just a little while ago.
	[Slide.]
	Now, how should new agents be co-developed?  Should we be doing an MRC model in certain instances, that is, we sit down, Charlie, and we write a trial on AML together, and the pediatric oncologists do it in their centers, and the adult oncologists do it in their centers, and then we share the data, or should we, in fact, do separate trials in pediatrics and in adults, and I think, Frank, in terms of some of the Phase I work, you have to in order to know what you are dosing and what you are doing, and then just do your separate trials, and then be obligated to sit down and share that data afterwards.
	So, I don't think we have a clear idea how this should be done, but I think keeping it open is going to be important.
	How will constructive competitive be enhanced by this?  I think one of the things I saw that I feared a little bit in this is that there is now a mechanism of COG with industry, and I am sort of totally committed to COG, too, but I think we have to think about this.  Joe Simone would kill us if we didn't talk about it.
	If you have COG and CTEP deciding on how all new drugs are going to be developed in the U.S. or North America, I think we are doing ourselves and kids a disservice, and I think we want to enhance a little bit more competition, whether that is through consortia or whatever.
	This should be a very dynamic and competitive environment to do that, and we really didn't touch on that, but I think it impacts on drug companies tremendously in terms of how they approach people, who they approach, who is on the short list, who is the long list, which institutions can get the job done, and I don't think we have decided on that, and I don't think by making a list and having it all go through one group is necessarily the only way to do it.
	Lastly, we didn't touch on this, but who should be supporting this?  The Pediatric Rule applies to industry in a way, but we are talking about diseases that are very rare in applying these drugs.
	We want those new drugs, but it is assuming that all these new drugs are coming from pharmaceutical companies in a sense, and that may not necessarily be true.  I would only argue, and I not necessarily a Democrat, I am far to the left of that, but I think that government may think about planning or anticipating a way to support such pediatric clinical trials without necessarily asking pharmaceutical companies to do that.  That may be another mechanism by which to develop these things.
	[Slide.]
	Two last slides.  In terms of how we do this across subtypes, so a marker like ras or BCL-2 that is common amongst all subtypes, I think in this sense, we would just lump and test a trial, and then decide on which ones respond and which ones didn't.  That is one model to develop these kinds of trials.
	Another model is the targeted trial, and this is just a de-acetylation, a hidac inhibitor and demethylator, so if you had a trial designated to respond or to work on core binding factor or leukemias, then, could you hook up with the international community, and I am no sure how the drug companies would look upon that, or the adult groups and target 8;21 and inverted 16 AML, and do your trial in that group solely, and I think we would have to hook up with larger groups in order to effectively do that or else we are not going to have enough patients necessarily to see a difference.  You could do that in the post-remission or, in fact, upfront.
	So, a couple different models to develop those trials, I think are worth continuing to think about.  They were brought up throughout the discussion today.
	[Slide.]
	Those were just some summary thoughts on this whole thing, and we may actually finish early, it depends on your discussion.
	DR. PRZEPIORKA:  I think the overall message here is that there is quite a laundry list of diseases in adults with counterparts in children for which you could invoke the Pediatric Rule, but the pediatric oncologists would like to also raise your awareness about whether or not there is truly a need to do so, and hope that they could some input into deciding whether or not there is truly a need to do so on individual diseases.
	Does anyone else have other comments or questions?  That was an excellent, excellent summary.
	DR. REYNOLDS:  I think one point that Steve Hirschfeld made earlier, that I would just like to remind everyone of, is that what we have seen also is that there is a paucity of laboratory models for which to prioritize the drugs, and I think that we should see some commitment from all of us towards trying to get such models, because they will allow us to see whether or not there is a response that can be then predictive of what is going to happen in the clinic, and certainly if they had models for that, as Steve suggested, would take a lot of this discussion and make it very simple, because if there was a response on that model, then, you would clearly want to study that drug.
	DR. HIRSCHFELD:  Or perhaps maybe we might believe negatives a little more strongly, and particularly if there were multiple models in, let's say, two out of three of the preclinical models or three out of three in some matrix could give you that type of information.
	DR. REYNOLDS:  Exactly.  The negative data might even be more valuable in terms of trying to guide people in terms of applying waivers.
	DR. PRZEPIORKA:  Dr. Weiner.
	DR. WEINER:  I am sorry, I need to run out, and wanted to thank you for this absolutely wonderful summary.  Besides the ethical issues, I think the other thing that presses on us is family community, in general, is the need for transparency, which I understand is quite a current term these days according to William Safire, the need for transparency about the prioritization decision-making process.  It has got to be open, and it has got to include all of the relevant parties, and it has to have a level playing field, as Dr. Pazdur said.
	So, thank you.
	DR. PRZEPIORKA:  Dr. Arceci.
	DR. ARCECI:  Pat, I think the one exception to the preclinical models is probably going to be in immunological or vaccine development trials.  I may be wrong on this, but it seems like the ability to generate vaccines in preclinical models is probably easier than in humans.
	That doesn't mean that an approach can't be tried, but it may be one area where a response in an animal may be very unpredictive, I am not sure yet.  I hope it is going to be right, but it seems like it is harder in humans.
	DR. REYNOLDS:  I agree with you.  I just think that what we need to do is to make a concerted effort to try and develop at least some models, and I don't see why that can't be done and done jointly between NIH, FDA, and industry to try and find some of these models.  Even if we do it in a few diseases or one disease, at least we will have a starting point, and even if we only do it for cytotoxics, it would be a starting point.
	DR. PRZEPIORKA:  Dr. Hirschfeld.
	DR. HIRSCHFELD:  I want to begin by thanking Dr. Arceci for his very eloquent summation, and I wanted to comment that the advice that we got today, and will continue to solicit and continue to receive, should be viewed as, in essence, triggers, and not necessarily absolutes, and what you have helped us is to refine our examination in making determinations when particular disease categories come about, and it doesn't mean that every time such a disease comes about, that automatically, the Pediatric Rule will be invoked, but what it does do is give us a framework to begin to look, and we hope to have a continuing dialogue, so that when disease indications are presented, that we not only have an opportunity to ask the question should the Pediatric Rule be triggered, but we would have some basis for saying yes, we have discussed this publicly, there is scientific evidence to support it, and we would now, in each case, make a determination, and in every case, the sponsor always has the option of applying for a waiver and stating why there should not be.
	I feel comfortable that between all these checks and balances, that the system should not be become overburdened with the need to establish priorities and that there would arise a circumstance where children with cancer would be viewed as a commodity for further commercialization of a product, but rather that what we would be doing is using the tools at hand to act as catalysts to obtain what we hope would be credible data in areas where these studies are needed.
	DR. PRZEPIORKA:  Other comments or questions?
	Hearing none, I will call the meeting adjourned.
	DR. HIRSCHFELD:  Thank you, everyone.
	DR. PRZEPIORKA:  Thank you.
	[Whereupon, at 3:30 p.m., the meeting adjourned.]
- - -