Minutes of the
Leukemia, Lymphoma, and Myeloma Progress Review Group
Advisory Committee to the Director
Teleconference

May 24, 2001

The teleconference of the Advisory Committee to the Director, National Cancer Institute, was convened on May 24, 2001, at 2:00 p.m. EST at the National Institutes of Health, Building 31, Conference Room 11A03.

Advisory Committee members participating in the teleconference:
Alan S. Rabson, M.D., Deputy Director, National Cancer Institute (Chair)
Martin D. Abeloff, Johns Hopkins Oncology Center (Board of Scientific Counselors)
Frederick R. Appelbaum, M.D., Fred Hutchison Cancer Research Center (Board of Scientific Advisors)
Waun Ki Hong, M.D., University of Texas M.D. Anderson Cancer Center (Board of Scientific Advisors)
Michael Katz, International Myeloma Foundation (Director's Consumer Liaison Group)

Ex Officio members participating:
Marvin Kalt, Ph.D., National Cancer Institute

Executive Secretary:

Susan J. Waldrop, National Cancer Institute

Other participants:

Kenneth C. Anderson, M.D., Dana-Farber Cancer Institute (Co-Chair, Leukemia, Lymphoma, and Myeloma Progress Review Group)
Clara Bloomfield, M.D., Ohio State University (Co-Chair, Leukemia, Lymphoma, and Myeloma Progress Review Group)
Kevin Callahan, National Cancer Institute
Riccardo Dalla-Favera, M.D., Columbia University (Co-Chair, Leukemia, Lymphoma, and Myeloma Progress Review Group)
Norma Davis, National Cancer Institute
Scott Jenkins, The Blue Sheet
Chitra Mohla, National Cancer Institute
Cherie Nichols, M.B.A., National Cancer Institute
Wyndham Wilson, M.D., Ph.D., National Cancer Institute (Executive Director, Leukemia, Lymphoma, and Myeloma Progress Review Group)
Shari Wohlert, National Cancer Institute

The purpose of the teleconference was to present to the Advisory Committee to the Director (ACD) for discussion and acceptance the draft report of the Leukemia, Lymphoma, and Myeloma Progress Review Group. The ACD must formally accept the report to enable NCI to develop an implementation plan based on the report's recommendations.

In the absence of NCI Director Dr. Richard Klausner, the meeting was chaired by NCI Deputy Director Dr. Alan Rabson. Ms. Waldrop noted that the meeting was open to the public and that the meeting summary would be posted on NCI's public Web site. She stated for the record that ACD members had been determined to have no conflicts of interest with respect to the matters under discussion at this meeting.

Dr. Bloomfield noted that this PRG was the first to focus on three sets of heterogeneous diseases. Although leukemia, lymphoma, and myeloma (LLM) are generally considered to be relatively rare diseases, taken together they constitute the fourth most common form of cancer. Every year, about 100,000 new cases occur and more than 60,000 people die of these diseases. Because the pathogenesis and pathophysiology of LLM are better understood than is the case for most other types of cancer, these diseases afford an opportunity to develop therapeutic approaches that will not only benefit LLM patients but will also translate to other malignancies. The recent early clinical success of STI-571-the first drug designed to target the causative molecular pathway of a malignancy, specifically chronic myelogenous leukemia-is an example of the extent to which outcomes have improved for LLM patients in recent decades.

Dr. Bloomfield expressed her thanks to Kevin Callahan and Cherie Nichols in particular for their help in the development of the LLM PRG report. She noted that this report differed somewhat from other PRG reports in that the group reached consensus on 10 overarching research priorities that, if supported, would have the greatest impact on prevention, diagnosis, treatment, and care of patients with these diseases. Dr. Dalla-Favera outlined these priorities, as follows, and briefly described the rationale for each.

Etiology

• Understand the interaction among genotype, immune function, infectious agents, environmental toxins, and lifestyle factors that can lead to hematopoietic malignancy. The etiology of LLM is not well understood and prior epidemiological research has focused on a single or limited group of hematological cancers and precursor conditions. Case-control and cohort investigations are needed.

Pathobiology

• Identify the basic mechanisms responsible for genome instability, chromosome translocations, and other mutations in hematological malignancies. Reducing the incidence of LLM will require a better understanding of (1) how various types of DNA damage occur in hematopoietic cells, (2) the impact of genetic factors on susceptibility to DNA damage, (3) repair capacity and other types of cellular responses to DNA damage, and (4) the role of environment in the broadest sense.
• Define the relationship between the development of hematologic malignancies and the host biological environment. The stromal microenvironment and the overall host environment are critical determinants of tumor initiation, progression, migration, and response to therapy. A major effort is needed to study the complex problem of tumor-host interactions in hematological malignancies.
• Provide molecular characterization of hematological malignancies, including the characterization of global patterns of genetic and epigenetic alternations and RNA and protein expression, as well as the validation of the molecular targets necessary for the survival, proliferation, and evolution of hematological malignancies. Rapid migration to a molecular definition of cancer will have a dramatic impact on diagnosis and treatment. The PRG recommends the expansion of several current NCI initiatives to promote the application of novel technologies to each of the hematological cancers.
• Further develop research on stem cells, both multi lineage and single lineage. Because understanding of how specific outcomes are determined at a molecular level in different types of normal blood cell precursors is limited, it is not currently possible to anticipate how specific molecular changes produce disease. Such information is essential to designing curative, nontoxic therapies.

Drug Development and Therapeutics

• Develop the required resources to translate "lead" structures and molecules into effective therapeutic agents. Hasten the translation of candidate validated targets to lead compounds and subsequent clinical trials and support the development of orphan therapeutic agents and diagnostics, including FDA approval. Target discovery, validation, and clinical translation for hematological diseases will form an important basis for future drug development in all cancer types. Consequently, NCI needs to magnify its efforts to offset the cost of drug development for relatively rare cancers.
• Foster partnerships between NCI and academia, advocates, cooperative groups, FDA, and industry to expedite drug development and availability of therapies. As lead agency for implementing the National Cancer Program, NCI should form a working group of equal partners to enhance cooperation and efficiency in developing new cancer treatments.

Education, Communication, and Survivorship Research

• Determine how to provide accurate, timely, and tailored information to patients to improve medical decision-making, access to clinical trials, quality of care during active treatment and follow-up, and quality of life. Effective health communication narrows the gap between discovery and applications and reduces health disparities. However, much of the available information on communicating with patients does not address the specific circumstances of those affected by hematological cancers.
• Develop education and training programs for certification of physicians and centers for diagnosis, treatment, and clinical trials in hematologic malignancies. Certification will lead to significant improvement in the treatment of hematological cancers through optimization of treatment approaches and channeling of patients to specialized physicians and centers where state-of-the-art treatments may be investigated and applied.
• Identify and target individuals and populations at high risk for adverse long-term outcomes to define the biological basis of identified associations and facilitate the design and testing of intervention and prevention strategies. Patient populations at high risk for adverse outcomes of LLM treatment have not been identified. Long-term outcomes research on these diseases has often been characterized by small sample sizes, lack of heterogeneity in study populations, and potential selection bias. However, identification of high-risk individuals and populations is essential to the rational development and testing of intervention and prevention strategies.

Dr. Wilson described the rationale for the Cancer Translational Research Allied Consortium (C-TRAC), a new initiative proposed by the PRG to serve as a model for the rapid development of new therapies for many kinds of cancers. Although hematological malignancies are a model for the discovery and development of targeted therapies, the therapeutic translation of potential targets lags far behind knowledge of the molecular basis of hematological malignancies. Even after the discovery and validation of a target, it takes 5-10 years to bring a new drug to trial, and financial barriers often prolong or prevent translation of new drugs to the clinical setting. C-TRAC is proposed as a possible solution to these concerns and as a new paradigm for the study and treatment of all types of cancer.

The goal of C-TRAC is to shorten drug development time from 5-10 years to 2 years through a novel alliance among academia, industry, government, and patients. The initiative would encompass the spectrum of drug discovery and development: identifying, validating, and credentialing targets; discovery and preclinical testing of agents; and scale-up and testing of promising agents in clinical trials. C-TRAC grants would be disease-based, and separate platforms would provide cross-cutting infrastructures for tumor banks, animal model repositories, advanced technology centers, high-throughput screening, drug synthesis and scale-up, and animal toxicology and pharmacokinetics. The structure of the initiative would be multi-institutional, with governance through a national leadership group and governing board.

Ms. Waldrop thanked the PRG co-chairs and executive director for their work and for their thoughtful consideration of the problem of timely therapeutic translation of new knowledge. The PRG's recommendation that efforts to expedite such translation be a high priority and its analysis of both the opportunities that exist and the barriers that need to be overcome is extremely useful to NCI. Ms. Waldrop noted for the record that specific implementation activities, such as consideration of initiative mechanisms and structure, are NCI's responsibility.

Dr. Appelbaum said he hoped that a message could be conveyed to participants in the PRG that the Board of Scientific Advisors gives considerable weight to PRG recommendations and generally approves initiatives that are proposed in response to such recommendations. He suggested that the letter of thanks sent to PRG participants should make reference to the importance PRG reports have in subsequent NCI funding decisions. He further suggested that department heads at the institutions of the younger PRG participants should be notified of these individuals' role in the PRG.

ACD members expressed enthusiasm for the report and unanimously accepted it for transmittal to NCI for consideration and development of an implementation plan. Ms. Waldrop thanked the PRG co-chairs and executive director and the ACD members for their work. She noted that the report will be made available on the NCI Web site as soon as possible, and that NCI staff will begin immediately to identify funding mechanisms for implementing the PRG's recommendations. A follow-up meeting will be held with the PRG to further discuss both the recommendations and the proposed implementation strategy.

The teleconference was adjourned at 3:00 p.m. EST.