Table of Contents Purpose of This PDQ Summary General Information Cellular Classification and Prognostic Variables
Treatment Option Overview Untreated Childhood Acute Lymphoblastic Leukemia Childhood Acute Lymphoblastic Leukemia in Remission Postinduction Treatment for Childhood Acute Lymphoblastic Leukemia Subgroups Recurrent Childhood Acute Lymphoblastic Leukemia Get More Information From NCI Changes to this Summary (09/05/2008) More Information
Purpose of This PDQ Summary
This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the treatment of childhood acute lymphoblastic leukemia (ALL). This summary is reviewed regularly and updated as necessary by the PDQ Pediatric Treatment Editorial Board.
Information about the following is included in this summary:
- Incidence and risk factors.
- Cellular classification.
- Prognostic variables.
- Treatment options.
- Treatment considerations for certain ALL childhood subgroups.
This summary is intended as a resource to inform and assist clinicians and other health professionals who care for pediatric cancer patients. It does not provide formal guidelines or recommendations for making health care decisions.
Some of the reference citations in this summary are accompanied by a level-of-evidence designation. These designations are intended to help readers assess the strength of the evidence supporting the use of specific interventions or approaches. The PDQ Pediatric and Adult Treatment Editorial Boards use a formal evidence ranking system in developing their level-of-evidence designations. Based on the strength of the available evidence, treatment options are described as either “standard” or “under clinical evaluation.” These classifications should not be used as a basis for reimbursement determinations.
This summary is also available in a patient version, which is written in less-technical language, and in Spanish.
Back to Top General Information
The National Cancer Institute provides the PDQ pediatric cancer treatment information summaries as a public service to increase the availability of evidence-based cancer information to health professionals, patients, and the public.
Cancer in children and adolescents is rare. Children and adolescents with
cancer should be referred to medical centers that have a multidisciplinary team
of cancer specialists with experience treating the cancers that occur during
childhood and adolescence. This multidisciplinary team approach incorporates the skills
of the primary care physician, pediatric surgical subspecialists, radiation
oncologists, pediatric medical oncologists/hematologists, rehabilitation
specialists, pediatric nurse specialists, social workers, and others to ensure that children receive treatment, supportive care, and rehabilitation
that will achieve optimal survival and quality of life. (Refer to the PDQ Supportive Care summaries for specific information about supportive care for children and adolescents with cancer.)
Guidelines for
pediatric cancer centers and their role in the treatment of pediatric patients
with cancer have been outlined by the American Academy of Pediatrics.[1] Since
treatment of children with acute lymphoblastic leukemia (ALL) entails many potential complications and
requires intensive supportive care (e.g., transfusions; management of infectious
complications; and emotional, financial, and developmental support), this
treatment is best coordinated by pediatric oncologists and performed in cancer
centers or hospitals with all of the necessary pediatric supportive care
facilities. Specialized care is essential for all children with ALL, including
those for whom specific clinical and laboratory features might confer a
favorable prognosis. It is equally important that the
clinical centers and the specialists directing the patient’s care maintain
contact with the referring physician in the community. Strong lines of
communication optimize any urgent or interim care required when the child is at
home.
In recent decades, dramatic improvements in survival have been achieved in children and adolescents with cancer. Childhood and adolescent cancer survivors require close follow-up because cancer therapy side effects may persist or develop months or years after treatment. (Refer to the PDQ Late Effects of Treatment for Childhood Cancer summary for specific information about the incidence, type, and monitoring of late effects in childhood and adolescent cancer survivors.)
ALL is the most common cancer diagnosed in children and represents 23% of cancer
diagnoses among children younger than 15 years. ALL occurs at an
annual rate of approximately 30 to 40 per million.[2] There are approximately 2,400
children and adolescents younger than 20 years diagnosed with ALL each
year in the United States,[3] and there has been a gradual increase in the incidence of ALL in the past 25 years.[4,5] A sharp peak in ALL incidence is observed among
children aged 2 to 3 years (>80 per million per year), with rates decreasing
to 20 per million for ages 8 to 10 years. The incidence of ALL among children
aged 2 to 3 years is approximately fourfold greater than that for infants and
is nearly tenfold greater than that for adolescents who are 19 years old. For
unexplained reasons, the incidence of ALL is substantially higher in white
children than in black children, with a nearly threefold higher incidence from age 2
to 3 years in white children compared with black children.[3] The incidence of ALL appears to be highest in Hispanic children (43 per million).[6]
There are few identified factors associated with an increased risk of ALL.[3] The
primary accepted nongenetic risk factors for ALL are prenatal exposure to
x-rays and postnatal exposure to high doses of radiation (e.g., therapeutic
radiation as previously used for conditions such as tinea capitis and thymus
enlargement).[7] Children with Down syndrome have increased risk of
developing both ALL [8] and acute myeloid leukemia (AML),[9] with a cumulative risk of
developing leukemia of approximately 2.1% by age 5 years and 2.7% by age 30
years.[10] Approximately one-half to two-thirds of the cases of acute leukemia in children
with Down syndrome are ALL. Patients with ALL and Down syndrome have a lower incidence of both favorable and unfavorable cytogenetic findings and a lower incidence of T-cell phenotype.[8,10-13] While the vast majority of cases of AML in children with Down syndrome occur before the age of 4 years (median age, 1 year),[10,13] ALL in children with Down syndrome has an age distribution similar to that of ALL in non–Down syndrome children, with a median age of 3 to 4 years.[10,13] Outcome in Down syndrome children with ALL has generally been reported as poorer than that of non–Down syndrome children.[11,12,14] The lower event-free survival and overall survival in children with Down syndrome appear to be related to higher rates of treatment-related mortality, especially during induction therapy,[12,13] and to the absence of favorable biological features.[13,11] Increased occurrence of ALL is also associated
with certain genetic conditions, including neurofibromatosis,[15] Shwachman
syndrome,[16,17] Bloom syndrome,[18] and ataxia telangiectasia.[19]
Many cases of ALL that develop in children have a prenatal origin. Evidence in support of this comes from the observation that the immunoglobulin or T-cell receptor antigen rearrangements that are unique to each patient’s leukemia cells can be detected in blood samples obtained at birth.[20,21] Similarly, there are data to support that patients with ALL characterized by specific chromosomal abnormalities had blood cells carrying the abnormalities at the time of birth.[20-22] Genetic studies of identical twins with concordant leukemia further support the prenatal origin of some leukemias.[23]
Among children with ALL, more than 95% attain remission and 75% to 85% survive free of leukemia recurrence at least 5 years from
diagnosis with current treatments that incorporate systemic therapy (e.g.,
combination chemotherapy) and specific central nervous system preventive
therapy (i.e., intrathecal chemotherapy with or without cranial
radiation).[2,3,24-32]
Despite the treatment advances noted in childhood ALL, numerous important
biologic and therapeutic questions remain to be answered to achieve
the goal of curing every child with ALL. The systematic investigation of these
issues requires large clinical trials, and the opportunity to participate in
these trials is offered to most patients/families. Clinical trials for
children and adolescents with ALL are generally designed to compare potentially
better therapy with therapy that is currently accepted as standard. Much of
the progress made in identifying curative therapies for childhood ALL and other
childhood cancers has been achieved through investigator-driven discovery, tested in carefully randomized, controlled clinical trials.[33,34]
Information about ongoing clinical trials is available from the NCI
Web site.
References
-
Guidelines for the pediatric cancer center and role of such centers in diagnosis and treatment. American Academy of Pediatrics Section Statement Section on Hematology/Oncology. Pediatrics 99 (1): 139-41, 1997.
[PUBMED Abstract]
-
Ries LA, Kosary CL, Hankey BF, et al., eds.: SEER Cancer Statistics Review, 1973-1996. Bethesda, Md: National Cancer Institute, 1999. Also available online. Last accessed April 19, 2007.
-
Smith MA, Ries LA, Gurney JG, et al.: Leukemia. In: Ries LA, Smith MA, Gurney JG, et al., eds.: Cancer incidence and survival among children and adolescents: United States SEER Program 1975-1995. Bethesda, Md: National Cancer Institute, SEER Program, 1999. NIH Pub.No. 99-4649., pp 17-34. Also available online. Last accessed April 19, 2007.
-
Xie Y, Davies SM, Xiang Y, et al.: Trends in leukemia incidence and survival in the United States (1973-1998). Cancer 97 (9): 2229-35, 2003.
[PUBMED Abstract]
-
Shah A, Coleman MP: Increasing incidence of childhood leukaemia: a controversy re-examined. Br J Cancer 97 (7): 1009-12, 2007.
[PUBMED Abstract]
-
McNeil DE, Coté TR, Clegg L, et al.: SEER update of incidence and trends in pediatric malignancies: acute lymphoblastic leukemia. Med Pediatr Oncol 39 (6): 554-7; discussion 552-3, 2002.
[PUBMED Abstract]
-
Ross JA, Davies SM, Potter JD, et al.: Epidemiology of childhood leukemia, with a focus on infants. Epidemiol Rev 16 (2): 243-72, 1994.
[PUBMED Abstract]
-
Whitlock JA: Down syndrome and acute lymphoblastic leukaemia. Br J Haematol 135 (5): 595-602, 2006.
[PUBMED Abstract]
-
Hasle H: Pattern of malignant disorders in individuals with Down's syndrome. Lancet Oncol 2 (7): 429-36, 2001.
[PUBMED Abstract]
-
Hasle H, Clemmensen IH, Mikkelsen M: Risks of leukaemia and solid tumours in individuals with Down's syndrome. Lancet 355 (9199): 165-9, 2000.
[PUBMED Abstract]
-
Bassal M, La MK, Whitlock JA, et al.: Lymphoblast biology and outcome among children with Down syndrome and ALL treated on CCG-1952. Pediatr Blood Cancer 44 (1): 21-8, 2005.
[PUBMED Abstract]
-
Chessells JM, Harrison G, Richards SM, et al.: Down's syndrome and acute lymphoblastic leukaemia: clinical features and response to treatment. Arch Dis Child 85 (4): 321-5, 2001.
[PUBMED Abstract]
-
Zeller B, Gustafsson G, Forestier E, et al.: Acute leukaemia in children with Down syndrome: a population-based Nordic study. Br J Haematol 128 (6): 797-804, 2005.
[PUBMED Abstract]
-
Whitlock JA, Sather HN, Gaynon P, et al.: Clinical characteristics and outcome of children with Down syndrome and acute lymphoblastic leukemia: a Children's Cancer Group study. Blood 106 (13): 4043-9, 2005.
[PUBMED Abstract]
-
Stiller CA, Chessells JM, Fitchett M: Neurofibromatosis and childhood leukaemia/lymphoma: a population-based UKCCSG study. Br J Cancer 70 (5): 969-72, 1994.
[PUBMED Abstract]
-
Strevens MJ, Lilleyman JS, Williams RB: Shwachman's syndrome and acute lymphoblastic leukaemia. Br Med J 2 (6129): 18, 1978.
[PUBMED Abstract]
-
Woods WG, Roloff JS, Lukens JN, et al.: The occurrence of leukemia in patients with the Shwachman syndrome. J Pediatr 99 (3): 425-8, 1981.
[PUBMED Abstract]
-
Passarge E: Bloom's syndrome: the German experience. Ann Genet 34 (3-4): 179-97, 1991.
[PUBMED Abstract]
-
Taylor AM, Metcalfe JA, Thick J, et al.: Leukemia and lymphoma in ataxia telangiectasia. Blood 87 (2): 423-38, 1996.
[PUBMED Abstract]
-
Yagi T, Hibi S, Tabata Y, et al.: Detection of clonotypic IGH and TCR rearrangements in the neonatal blood spots of infants and children with B-cell precursor acute lymphoblastic leukemia. Blood 96 (1): 264-8, 2000.
[PUBMED Abstract]
-
Taub JW, Konrad MA, Ge Y, et al.: High frequency of leukemic clones in newborn screening blood samples of children with B-precursor acute lymphoblastic leukemia. Blood 99 (8): 2992-6, 2002.
[PUBMED Abstract]
-
Greaves MF, Wiemels J: Origins of chromosome translocations in childhood leukaemia. Nat Rev Cancer 3 (9): 639-49, 2003.
[PUBMED Abstract]
-
Greaves MF, Maia AT, Wiemels JL, et al.: Leukemia in twins: lessons in natural history. Blood 102 (7): 2321-33, 2003.
[PUBMED Abstract]
-
Pui CH, Relling MV, Downing JR: Acute lymphoblastic leukemia. N Engl J Med 350 (15): 1535-48, 2004.
[PUBMED Abstract]
-
Pui CH, Evans WE: Treatment of acute lymphoblastic leukemia. N Engl J Med 354 (2): 166-78, 2006.
[PUBMED Abstract]
-
Gaynon PS, Trigg ME, Heerema NA, et al.: Children's Cancer Group trials in childhood acute lymphoblastic leukemia: 1983-1995. Leukemia 14 (12): 2223-33, 2000.
[PUBMED Abstract]
-
Schrappe M, Reiter A, Ludwig WD, et al.: Improved outcome in childhood acute lymphoblastic leukemia despite reduced use of anthracyclines and cranial radiotherapy: results of trial ALL-BFM 90. German-Austrian-Swiss ALL-BFM Study Group. Blood 95 (11): 3310-22, 2000.
[PUBMED Abstract]
-
Harms DO, Janka-Schaub GE: Co-operative study group for childhood acute lymphoblastic leukemia (COALL): long-term follow-up of trials 82, 85, 89 and 92. Leukemia 14 (12): 2234-9, 2000.
[PUBMED Abstract]
-
Maloney KW, Shuster JJ, Murphy S, et al.: Long-term results of treatment studies for childhood acute lymphoblastic leukemia: Pediatric Oncology Group studies from 1986-1994. Leukemia 14 (12): 2276-85, 2000.
[PUBMED Abstract]
-
Pui CH, Sandlund JT, Pei D, et al.: Improved outcome for children with acute lymphoblastic leukemia: results of Total Therapy Study XIIIB at St Jude Children's Research Hospital. Blood 104 (9): 2690-6, 2004.
[PUBMED Abstract]
-
Mitchell CD, Richards SM, Kinsey SE, et al.: Benefit of dexamethasone compared with prednisolone for childhood acute lymphoblastic leukaemia: results of the UK Medical Research Council ALL97 randomized trial. Br J Haematol 129 (6): 734-45, 2005.
[PUBMED Abstract]
-
Moghrabi A, Levy DE, Asselin B, et al.: Results of the Dana-Farber Cancer Institute ALL Consortium Protocol 95-01 for children with acute lymphoblastic leukemia. Blood 109 (3): 896-904, 2007.
[PUBMED Abstract]
-
Progress against childhood cancer: the Pediatric Oncology Group experience. Pediatrics 89 (4 Pt 1): 597-600, 1992.
[PUBMED Abstract]
-
Bleyer WA: The U.S. pediatric cancer clinical trials programmes: international implications and the way forward. Eur J Cancer 33 (9): 1439-47, 1997.
[PUBMED Abstract]
Back to Top Cellular Classification and Prognostic Variables
Children with acute lymphoblastic leukemia (ALL) are usually treated according
to risk groups defined by both clinical and laboratory features. The intensity
of treatment required for favorable outcome varies substantially among subsets
of children with ALL. Risk-based treatment assignment is utilized in children
with ALL so that those children who have a very good outcome with modest
therapy can be spared more intensive and toxic treatment, while a more
aggressive, thus more toxic, therapeutic approach can be provided for
patients who have a lower probability of long-term survival.[1,2]
Risk-based treatment assignment requires the availability of prognostic factors
that reliably predict outcome. For children with ALL, a number of clinical and
laboratory features have demonstrated prognostic value, some of which are
described below. The factors described are grouped into the following
categories: clinical and laboratory features at diagnosis; leukemic cell characteristics at diagnosis; and response to initial
treatment. As in any discussion of prognostic factors, the relative order of significance and the interrelationship of
the variables are often treatment dependent and require multivariate analysis
to determine which factors operate independently as prognostic variables.[3,4]
Because prognostic factors are treatment dependent, improvements in therapy may
diminish or abrogate the significance of any of these presumed prognostic
factors. For example, a report from the Children’s Cancer Group (CCG) showed
that the adverse prognostic significance of slow early response disappears when
these patients receive intensified postinduction chemotherapy.[5]
Outcome in Down syndrome children with ALL has generally been reported as poorer than that of non–Down syndrome children.[6-8] The lower event-free survival (EFS) and overall survival (OS) of children with Down syndrome appear to be related to higher rates of treatment-related mortality, especially during induction therapy,[7,8] and to the absence of favorable biological features.[6,8]
Overt testicular involvement at the time of diagnosis occurs in approximately 2% of males. In early ALL trials, testicular involvement at diagnosis was an adverse prognostic factor. With more aggressive initial therapy, however, the prognostic significance of initial testicular involvement is unclear.[9] The European Organization for Research and Treatment of Cancer (EORTC) reported no adverse prognostic significance for overt testicular involvement at diagnosis.[10] The role of radiation therapy for testicular involvement is also unclear. A study from St. Jude Children's Research Hospital suggests that a good outcome can be achieved with aggressive conventional chemotherapy without radiation.[9] The Children's Oncology Group (COG) has also adopted this strategy.
A subset of the prognostic factors discussed below is used for the initial
stratification of children with ALL for treatment assignment, and at the end of
this section there are brief descriptions of the prognostic groupings currently
applied to clinical trials in the United States.
Clinical and Laboratory Features at Diagnosis
-
Age at diagnosis
Age at diagnosis has strong prognostic significance,
reflecting the different underlying biology of ALL in different age groups.[11] Young children (aged 1–9 years) have a better disease-free survival than older children, adolescents, or infants.[1,12,13] The improved prognosis in younger children is at least partly explained by the more frequent occurrence of favorable cytogenetic features in the leukemic blasts including hyperdiploidy with 51 or more chromosomes, or the t(12;21) (TEL-AML1 translocation).[11,14] Multiple retrospective studies have suggested that adolescents aged 16 to 21 years have a better outcome when treated on pediatric versus adult protocols.[15-17] (For more information about adolescents with ALL, see the Postinduction Treatment for Childhood Acute Lymphoblastic Leukemia Subgroups section of this summary.)
Infants with ALL have a particularly high risk of treatment failure. Treatment failure is most common in infants younger than 3 months and in those with a poor response to a prednisone prophase.[18-25] Infants with ALL can be divided into two subgroups on the basis of the presence or absence of MLL gene rearrangements.[26] Approximately 80% of infants with ALL have an MLL gene rearrangement.[21,26,27] An MLL gene rearrangement is most common in infants younger than 6 months; from 6 months to 1 year, the incidence of MLL rearrangements decreases.[28] Infants with leukemia and MLL gene rearrangements have very high white blood cell (WBC) counts, increased incidence of central nervous system (CNS) involvement, and a poor outcome.[28] Blasts from infants with MLL gene rearrangements are typically CD10/cALLa negative and express high levels of FLT3.[29] Conversely, infants whose leukemia has a germline (nonrearranged) MLL gene frequently present with CD10/cALLa-positive precursor B-cell immunophenotype. These infants have a significantly better outcome than infants with ALL and MLL gene rearrangements.[21,30,31]
-
WBC count at diagnosis
Higher WBC counts at diagnosis represent an increased risk of treatment failure in patients with precursor B-cell ALL. A
WBC count of 50,000/µL is generally used as an operational cut point between
better and poorer prognosis,[1] although the relationship between WBC count and
prognosis is a continuous rather than a step function.[13,32] Elevated WBC
count is often associated with other high-risk prognostic factors, including
unfavorable chromosomal translocations such as t(4;11) and t(9;22) (see below).
-
CNS status at diagnosis
CNS status at diagnosis has prognostic significance. Patients who have a nontraumatic diagnostic lumbar puncture may be placed into one of three categories according to the number of WBC/µL and the presence/absence of blasts on cytospin:
-
CNS1: Cerebrospinal fluid (CSF) that is cytospin negative for blasts regardless of WBC count.
-
CNS2: CSF with fewer than 5 WBC/µL and cytospin positive for blasts.
-
CNS3 (CNS disease): CSF with 5 or more WBC/µL and cytospin positive for blasts.
Children with ALL who present with CNS disease at diagnosis (i.e., CNS3) are at a higher risk of treatment failure (both within the CNS and systemically) compared with patients not meeting the criteria for CNS disease at diagnosis. Patients with CNS2 status at diagnosis may be at increased risk of CNS relapse,[33] though this observation may not apply for all treatment regimens.[34] Any increased risk associated with CNS2 status on overall outcome may be overcome by more intensive intrathecal therapy.[35,36] A traumatic lumbar puncture (≥10 erythrocytes/µl) that includes blasts at diagnosis appears to be associated with increased risk of CNS relapse and indicates an overall poorer outcome.[36,37] High leukemia cell expression of the gene for interleukin-15 (IL-15) is associated with an increased likelihood of CNS3 status at diagnosis and also may predict for a higher rate of CNS relapse in patients who present with CNS1 status at diagnosis.[38]
-
Gender
In some studies, the prognosis for girls with ALL is slightly better than it is for
boys with ALL.[39-41] One reason for the better prognosis for girls is the
occurrence of testicular relapses among boys, but boys also appear to be at
increased risk of bone marrow and CNS relapse for reasons that are not well
understood.[39-41] However, in clinical trials with high 5-year EFS rates (>80%), male gender is not an adverse risk factor.[42,43]
-
Race
Survival rates in black and Hispanic children with ALL have been somewhat lower than
the rates in white children with ALL.[44] This difference may be therapy-dependent; a report from St. Jude Children's Research Hospital found no difference in outcome by racial groups.[45] Asian children with ALL fare slightly better than white children.[46] The reason for better outcome
in white and Asian children compared with black and Hispanic children is not known, but it cannot be
completely explained based on known prognostic factors.[46]
Leukemic Cell Characteristics
-
Morphology
In the past, ALL lymphoblasts were classified using
the French-American-British (FAB) criteria as having L1 morphology, L2
morphology, or L3 morphology.[47] Because of the lack of independent prognostic
significance and the subjective nature of this classification system, it is no
longer used in the United States. Most cases of ALL that show L3 morphology express surface immunoglobulin and have a C-MYC gene translocation identical to the findings for Burkitt lymphoma (e.g., t[8;14]). Patients with this specific, rare form of leukemia (mature B-cell or Burkitt leukemia) should be treated according to protocols for Burkitt lymphoma. (Refer to the PDQ summary on Childhood Non-Hodgkin Lymphoma Treatment for
more information on the treatment of B-cell ALL and Burkitt lymphoma.)
-
Immunophenotype
-
Precursor B-cell ALL: Precursor B-cell ALL, defined by the expression
of cytoplasmic CD79a, CD19, HLA-DR, and other B-cell–associated antigens, represents
80% to 85% of childhood ALL. Approximately 80% of precursor B-cell ALL expresses CD10 (cALLa). Absence of CD10 is associated with MLL gene rearrangements, particularly t(4;11), and a poor outcome.[18,48] It is not clear whether CD10-negativity has any independent prognostic significance in the absence of MLL gene rearrangements.[48,49]
-
Immunologic subtypes of precursor B-cell ALL: There are three major subtypes of precursor B-cell ALL:
- Pro-B ALL-CD10 negative and no surface or cytoplasmic immunoglobulin.
- Common precursor B-cell ALL-CD10 positive and no surface or cytoplasmic immunoglobulin.
- Pre-B ALL-presence of
cytoplasmic immunoglobulin.
Approximately three-quarters of patients with precursor B-cell ALL have the common precursor B-cell immunophenotype and have the best prognosis. Approximately 5% of patients have the pro-B immunophenotype. Pro-B is the most common immunophenotype seen in young infants and is often associated with a t(4;11) translocation. The leukemic cells of patients
with pre-B ALL contain cytoplasmic immunoglobulin (cIg), an intermediate stage
of B-cell differentiation, and 25% of patients with pre-B ALL have
the t(1;19) translocation (see below).[50] Approximately 3% of patients have transitional pre-B ALL with expression of surface immunoglobulin heavy chain without light chain, C-MYC gene involvement, or L3 morphology. Patients with this phenotype respond well to therapy used for precursor B-cell ALL.[51] Approximately 2% of patients
present with mature B-cell leukemia (surface Ig expression, generally with FAB L3
morphology and C-MYC gene translocation), also called Burkitt leukemia. This leukemia is a systemic
manifestation of Burkitt and Burkitt-like non-Hodgkin lymphoma and its
treatment is completely different from that for precursor B-cell ALL. Rare cases of mature B-cell leukemia that lack surface Ig but
have L3 morphology with C-MYC gene translocations should also be treated as Burkitt leukemia.[52] (Refer to the PDQ
summary on Childhood Non-Hodgkin's Lymphoma Treatment for more information on the
treatment of children with B-cell ALL and Burkitt lymphoma.)
-
Precursor T-cell ALL: T-cell ALL is defined by the leukemic cell expression of the
T-cell–associated antigens (cytoplasmic CD3, with CD7 plus CD2 or CD5) and is frequently associated
with a constellation of clinical features, including male gender, older age,
leukocytosis, and mediastinal mass.[50,53,54] With appropriately intensive
therapy, children with T-cell ALL have an outcome similar to that of
children with B-lineage ALL.[50,53,55] Neither the presence of a mediastinal mass at diagnosis nor the rate of resolution when receiving treatment have prognostic significance.[55,56]
Cytogenetic abnormalities common in B-lineage ALL (e.g., hyperdiploidy) are
rare in T-cell ALL.[57] Multiple other chromosomal translocations have been identified in T-cell ALL, with many involving transcription factors (e.g., TAL1, LMO1 and LMO2, LYL1, TLX1/HOX11, and TLX3/HOX11L2) and resulting in aberrant expression of these transcription factors in leukemia cells.[58] These translocations are often not apparent by karyotype, but are identified using more sensitive screening techniques, such as fluorescence in situ hybridization (FISH) or polymerase chain reaction (PCR).[58] High expression of TLX1/HOX11 resulting from translocations involving this gene occurs in 5% to 10% of pediatric T-cell ALL cases,[59-61] and is associated with more favorable outcome in both adults and children with T-cell ALL.[59,61-64] Overexpression of TLX3/HOX11L2 resulting from the t(5;14)(q35;q32) translocation occurs in approximately 20% of pediatric T-cell ALL cases [60,61,65] and appears to be associated with increased risk of treatment failure,[59,60,62,65] though not in all studies.[61] NOTCH1 mutations occur in approximately 50% of T-cell ALL cases, but the prognostic significance is unclear.[66,67] In the context of ALL Berlin-Frankfurt-Munster (BFM) 2000 therapy, NOTCH1 mutations appear to be associated with a favorable prognosis.[67] Another report, however, observed an unfavorable prognosis for the presence of NOTCH1 mutations in a cohort of children and adults with T-cell ALL, with the negative prognostic effect being most pronounced in adults.[68]
-
Myeloid antigen expression: Up to one-third of childhood ALL cases have leukemia
cells that express myeloid-associated surface antigens. Myeloid-associated antigen expression
appears to be associated with specific ALL subgroups, notably those with MLL
gene rearrangements and those with the TEL-AML1 gene rearrangement.[69] No independent adverse prognostic significance exists for
myeloid-surface antigen expression.[69,70]
-
Cytogenetics
-
Chromosome number
-
Hyperdiploidy: Hyperdiploidy (>50 chromosomes per cell or a DNA index >1.16) is
the presence of additional copies of whole chromosomes and occurs in 20% to 25%
of cases of precursor B-cell ALL but very rarely in cases of T-cell ALL.
Hyperdiploidy can be evaluated by measuring the DNA content of cells (DNA
index) or by karyotyping. Interphase FISH may detect hidden hyperdiploidy in cases either with a normal karyotype or in which cytogenetic analysis was unevaluable.[71] Hyperdiploidy generally occurs in cases with
favorable prognostic factors (patients aged 1–9 years with a low WBC count) and is itself
associated with favorable prognosis.[12,72,73] Outcome of children with hyperdiploidy, however, is heterogeneous and depends on age, sex, and specific trisomies.[11,74] Hyperdiploid leukemia cells are
particularly susceptible to undergoing apoptosis [75] and accumulate methotrexate and high levels of its active polyglutamate metabolites,[76] which may explain the
favorable outcome commonly observed for these cases. Certain patients with hyperdiploid ALL and more than 64 chromosomes may have a hypodiploid clone that has doubled. These cases may be interpretable based on the pattern of gains and losses of specific chromosomes. These patients have an unfavorable outcome.[77]
-
Trisomies: In the treatment approaches utilized by both the former Pediatric Oncology
Group (POG) and the former CCG, extra copies of certain
chromosomes appear to be specifically associated with favorable prognosis among
hyperdiploid ALL cases. Patients with triple trisomies (4, 10, and 17) have been shown to have an improved outcome as demonstrated by both POG and CCG analyses of National Cancer Institute (NCI) standard-risk but not high-risk ALL.[74,78-81] A United Kingdom Medical Research Council study showed that trisomies 4 and 18 were independent favorable prognostic indicators among hyperdiploid ALL cases.[74]
-
Hypodiploidy: A significant trend is observed for a progressively worse outcome with a decreasing chromosome number. Cases with 24 to 28 chromosomes (near haploidy) have the worst outcome.[82,83]
-
Chromosomal translocations
Recurring chromosomal translocations can be detected in a substantial
number of cases of childhood ALL, and some of these translocations, as
described below, have prognostic significance.
TEL-AML1 (t[12;21] cryptic translocation): Fusion of the TEL (ETV6) gene on
chromosome 12 to the AML1 (CBFA2) gene on chromosome 21 can be detected in 20%
to 25% of cases of B-precursor ALL but is rarely observed in T-cell
ALL.[84] Children with the t(12;21) cryptic translocation resulting in the
TEL-AML1 fusion are generally aged 2 to 9 years and have an excellent outcome.[11,84-87] Hispanic children with ALL have a lower incidence of t(12;21) compared with white children.[88] Reports indicate favorable EFS and OS in children with the TEL-AML1 fusion, however, this favorable prognosis may be modified by factors such as slow response to treatment, NCI risk category, and treatment regimen.[89-93] In one study of the treatment of newly diagnosed children with ALL, multivariate analysis of prognostic factors found age and leukocyte count, but not TEL-AML1, to be independent prognostic factors.[89] Patients with TEL-AML1 fusion seem to have a better outcome after relapse than do other patients; however, because of small numbers, the difference is not statistically significant.[94] Some relapses in patients with t(12;21) may represent a new independent second hit in a persistent preleukemic clone (with the first hit being the TEL-AML1 translocation).[95]
The Philadelphia chromosome t(9;22) is present in approximately 3% of children with
ALL and confers an unfavorable prognosis, especially when it is
associated with either a high WBC count or slow early response to initial
therapy.[73,96-100] Philadelphia-positive ALL is more common in older patients
with precursor B-cell ALL and high WBC count.
Rearrangements involving the MLL (11q23) gene occur in approximately 8% of
childhood ALL cases and are generally associated with an increased risk of treatment failure.[75] The t(4;11) is the most common translocation involving
the MLL gene in children with ALL and occurs in approximately 2% of cases.[101]
Patients with t(4;11) are usually infants with high WBC counts; they are more likely than other children with ALL to have CNS disease and to
have a poor response to initial therapy.[102] While both infants and adults
with the t(4;11) are at high risk of treatment failure, children with the
t(4;11) appear to have a better outcome than either infants or adults.[73,102,103] Irrespective of the type of 11q23 abnormality, infants with leukemia cells that have 11q23 abnormalities have a worse treatment outcome than older patients whose leukemia cells have an 11q23 abnormality.[24,28] Of interest, the t(11;19)
occurs in approximately 1% of cases and occurs in both early B-lineage
and T-cell ALL.[104] Outcome for infants with t(11;19) is poor, but outcome
appears relatively favorable in children with T-cell ALL and the t(11;19) translocation.[24,104]
The t(1;19) translocation occurs in 5% to 6% of childhood ALL, and involves
fusion of the E2A gene on chromosome 19 to the PBX1 gene on chromosome
1.[105,106] The t(1;19) may occur as either a balanced translocation or as an
unbalanced translocation and is primarily associated with pre-B ALL
(cytoplasmic immunoglobulin positive). Black children are more likely than white children to have pre-B ALL with the t(1;19).[45] Its presence was initially associated
with inferior outcome in the context of antimetabolite-based therapy.[105]
Studies have shown that the poorer prognosis associated with t(1;19) can be
largely overcome by more intensive therapy.[107,108]
Some studies suggested that cases with a balanced translocation t(1;19) had a worse outcome than did those with an unbalanced translocation der(19)t(1;19),[106] but this finding has not been observed consistently.[109]
-
Other chromosomal abnormalities
Intrachromosomal amplification of the chromosome 21 (iAMP21) with multiple extra copies of the RUNX1 (AML1) gene occurs in fewer than 5% of precursor B-cell ALL cases and has been associated with poor outcome.[71,110,111]
Early Response to Treatment
The rapidity with which leukemia cells are eliminated following onset of
treatment is also associated with outcome. Because treatment response is influenced by the drug sensitivity of leukemic cells and host pharmacodynamics and pharmacogenomics,[112] this measure has strong prognostic significance. Various ways of evaluating the
leukemia cell response to treatment have been utilized, including:
-
Day 7 and day 14 bone marrow responses:
Patients who have a rapid reduction
in the leukemia cells to less than 5% in their bone marrow within 7 or 14 days following
initiation of multiagent chemotherapy have a more favorable prognosis than do
patients who have slower clearance of leukemia cells from the bone
marrow.[73,113,114] Morphologic response to treatment continues to be used in new COG ALL trials to stratify patients into prognostic categories for
treatment assignment.
-
Peripheral blood response to steroid prophase:
Patients with a reduction in
peripheral blast count to less than 1,000/µL after a 7-day induction prophase
with prednisone and one dose of intrathecal methotrexate (a good prednisone
response) have a more favorable prognosis than do patients whose peripheral blast
counts remain above 1,000/µL (a poor prednisone response).[20,97,115] Treatment
stratification for protocols of the German BFM clinical trials group is partially based
on early response to the 7-day prednisone prophase (administered immediately prior to the initiation of multiagent remission induction). Patients whose
blast counts are less than 1,000/µL at diagnosis have a slightly better
outcome compared with other patients with a good prednisone response.[116]
-
Peripheral blood response to multiagent induction therapy:
Patients with
persistent circulating leukemia cells at 7 to 10 days after the initiation of
multiagent chemotherapy are at increased risk of relapse compared with patients
who have clearance of peripheral blasts within 1 week of therapy
initiation.[117,118] Rate of clearance of peripheral blasts has been found to be
of prognostic significance in both T-cell and B-lineage ALL.[119]
-
Minimal residual disease after induction therapy:
Patients in clinical remission after induction
therapy may have minimal residual disease (MRD), (i.e., leukemia cells in the blood or bone marrow) [120] that can only
be detected by highly sensitive techniques such as PCR
or specialized flow cytometry. Numerous groups have reported that patients with higher levels of MRD have a poorer prognosis than those who have lower levels of MRD.[121-130] Even for patients with the TEL-AML1 translocation, a population with generally favorable outcomes, higher levels of MRD at the end of induction therapy appear to be associated with higher risk of subsequent relapse.[92,93] Measuring MRD in the peripheral blood of patients with T-cell ALL has been studied and demonstrates a high concordance with MRD measurements using bone marrow.[120]
No study to date has shown that decreasing therapeutic intensity for patients with early low-level MRD or without MRD can maintain efficacy while decreasing morbidity. Likewise, no study to date has shown that increasing therapeutic intensity in patients with early high-level MRD improves outcome. Clinical trials of three major United States pediatric ALL groups (Dana-Farber Cancer Institute [DFCI], St. Jude Children's Research Hospital, and COG) use MRD measurements to determine post-induction treatment. Therapeutic adjustments based on MRD determinations in ALL should only be utilized in clinical trials.
Prognostic Groups
[Note: This subsection does not discuss infants as a prognostic group. For information about infants with acute lymphoblastic leukemia, refer to the Postinduction Treatment for Childhood Acute Lymphoblastic Leukemia Subgroups section of this summary.]
Former CCG studies made an initial risk assignment of patients older than 1 year as standard risk or high risk
based on the NCI consensus age and WBC criteria, regardless of phenotype.[1] The standard-risk category
included patients aged 1 to 9 years who had a WBC count at diagnosis less
than 50,000/µL. The remaining patients were classified as high risk.
Final treatment assignment for CCG protocols was based on the early response to
therapy (day 7 or day 14 bone marrow response) with slow early responders
in either risk group receiving augmented post-induction therapy.
Former POG studies defined the low-risk group based on the NCI consensus age and WBC
criteria and required the absence of adverse
translocations, absence of CNS disease and testicular disease, and the presence
of either the TEL-AML1 translocation or trisomy of chromosomes 4 and 10. The
high-risk group required the absence of favorable translocations and the
presence of CNS or testicular leukemia, or the presence of MLL gene
rearrangement, or unfavorable age and WBC count.[131] The standard-risk
category included patients not meeting the criteria for inclusion in any of the
other risk group categories.
In POG studies, patients with T-cell ALL were treated on different protocols than patients with precursor B-cell ALL.
The very high-risk category for CCG and POG was defined by one of the
following factors taking precedence over all other considerations: presence of the
t(9;22), M3 marrow on day 29 or M2 or M3 marrow on day 43, or hypodiploidy (DNA
index <0.95).[132]
Historically, the BFM group in Germany categorized risk groups differently than POG or CCG. Age and initial WBC count were not considered when assigning risk groups. Patients with an absolute blast count of 1,000/μL or greater at the end of a 7-day prednisone prophase (prednisone poor responders) were considered to be high risk. Prednisone good responders (those with absolute blast count <1,000/μL at the end of the prophase) were classified as either standard risk or moderate risk depending on whether their estimated leukemic cell mass estimate was relatively low (standard risk) or high (moderate risk). All patients with T-cell phenotype, mediastinal mass, or CNS involvement were considered moderate risk, and all patients with the t(9;22) were considered high risk.[13]
Since 2000, risk stratification on BFM protocols has been based almost solely on treatment response criteria. In addition to prednisone prophase response, treatment response is assessed via MRD measurements at two timepoints: 5 weeks and 12 weeks after initiation of therapy. Patients who are MRD negative at both timepoints are classified as standard risk, those who have low MRD (<10-3) at week 12 are considered moderate risk, and those with high MRD (≥10-3) at week 12 are high risk. Patients with a poor response to the prednisone prophase are also considered high risk, regardless of subsequent MRD. Phenotype, leukemic cell mass estimate, also known as BFM risk factor (BFM-RF), and CNS status at diagnosis do not factor into the current risk classification schema. However, patients with either the t(9;22) or the t(4;11) are considered high risk, regardless of early response measures.
Prognostic groups under clinical evaluation
A large, retrospective analysis of CCG and POG data led to the development of a new classification system for the COG.[133] Based on this analysis, patients with precursor B-cell ALL are initially assigned to a standard-risk or high-risk group based on age and initial WBC count (aged 1–9.99 years, and <50,000 WBC/µL is considered standard risk). All children with T-cell phenotype are considered high risk regardless of age and initial WBC count. Early treatment response (assessed by day 7 or day 14 marrow morphology and end-induction MRD assessment) and cytogenetics are subsequently used to modify initial risk-group classification. NCI standard-risk patients with rapid morphologic response (day 14 M1 marrow) and MRD less than 0.1% and an M1 marrow on day 29 are assigned to one of two groups based on cytogenetics. Patients with either t(12;21) or trisomies of chromosomes 4, 10, and 17 are considered "standard risk-low" while patients with neither of these two cytogenetics abnormalities are considered "standard risk-average." Standard-risk patients with either slow morphologic response (either day 7 or day 14 M1 marrow) and/or MRD more than 0.1% on day 29 are assigned to a third group (standard risk-high) and receive a more intensive postinduction treatment. High-risk patients with precursor B-cell ALL are divided into rapid-responder (rapid morphologic response and low MRD) or slow-responder groups. Patients are classified as very high risk if they have any of the following features (regardless of initial risk group): t(9;22), hypodiploidy less than 44 chromosomes, MLL translocation with a slow early morphologic response, M3 marrow on day 29 or M2 marrow and/or MRD greater than 1% at days 29 and 43.
The DFCI ALL Consortium is also testing a new risk classification system for patients with precursor B-cell ALL. All patients are initially classified as either standard risk or high risk based upon age, presenting leukocyte count, and the presence or absence of CNS disease. At the completion of a five-drug remission induction regimen (4 weeks from diagnosis), the level of MRD is determined. Patients with high MRD (≥0.1%) are classified as very high risk and receive a more intensive postremission consolidation. Patients with low MRD (<0.1%) continue to receive treatment based on their initial risk-group classification. The goal of this new classification schema is to determine whether intensification of therapy will improve the outcome of patients with high MRD at the end of remission induction. Patients with T-cell ALL are treated as high risk, regardless of MRD status. All patients with MLL translocations or hypodiploidy (<45 chromosomes) are classified as very high risk, regardless of MRD status or phenotype. Patients with the Philadelphia chromosome are treated as high risk, but receive an allogeneic stem cell transplant in first remission.
At St. Jude Children's Research Hospital, risk classification is based mainly on MRD level (assessed by flow cytometry) after 6 weeks of remission induction therapy as follows: low risk (<0.01%), standard risk (0.01% to <1%), and high risk (≥1%).
References
-
Smith M, Arthur D, Camitta B, et al.: Uniform approach to risk classification and treatment assignment for children with acute lymphoblastic leukemia. J Clin Oncol 14 (1): 18-24, 1996.
[PUBMED Abstract]
-
Carroll WL, Bhojwani D, Min DJ, et al.: Pediatric acute lymphoblastic leukemia. Hematology (Am Soc Hematol Educ Program) : 102-31, 2003.
[PUBMED Abstract]
-
Pui CH, Evans WE: Treatment of acute lymphoblastic leukemia. N Engl J Med 354 (2): 166-78, 2006.
[PUBMED Abstract]
-
Pullen J, Shuster JJ, Link M, et al.: Significance of commonly used prognostic factors differs for children with T cell acute lymphocytic leukemia (ALL), as compared to those with B-precursor ALL. A Pediatric Oncology Group (POG) study. Leukemia 13 (11): 1696-707, 1999.
[PUBMED Abstract]
-
Nachman JB, Sather HN, Sensel MG, et al.: Augmented post-induction therapy for children with high-risk acute lymphoblastic leukemia and a slow response to initial therapy. N Engl J Med 338 (23): 1663-71, 1998.
[PUBMED Abstract]
-
Bassal M, La MK, Whitlock JA, et al.: Lymphoblast biology and outcome among children with Down syndrome and ALL treated on CCG-1952. Pediatr Blood Cancer 44 (1): 21-8, 2005.
[PUBMED Abstract]
-
Chessells JM, Harrison G, Richards SM, et al.: Down's syndrome and acute lymphoblastic leukaemia: clinical features and response to treatment. Arch Dis Child 85 (4): 321-5, 2001.
[PUBMED Abstract]
-
Zeller B, Gustafsson G, Forestier E, et al.: Acute leukaemia in children with Down syndrome: a population-based Nordic study. Br J Haematol 128 (6): 797-804, 2005.
[PUBMED Abstract]
-
Hijiya N, Liu W, Sandlund JT, et al.: Overt testicular disease at diagnosis of childhood acute lymphoblastic leukemia: lack of therapeutic role of local irradiation. Leukemia 19 (8): 1399-403, 2005.
[PUBMED Abstract]
-
Sirvent N, Suciu S, Bertrand Y, et al.: Overt testicular disease (OTD) at diagnosis is not associated with a poor prognosis in childhood acute lymphoblastic leukemia: results of the EORTC CLG Study 58881. Pediatr Blood Cancer 49 (3): 344-8, 2007.
[PUBMED Abstract]
-
Möricke A, Zimmermann M, Reiter A, et al.: Prognostic impact of age in children and adolescents with acute lymphoblastic leukemia: data from the trials ALL-BFM 86, 90, and 95. Klin Padiatr 217 (6): 310-20, 2005 Nov-Dec.
[PUBMED Abstract]
-
Trueworthy R, Shuster J, Look T, et al.: Ploidy of lymphoblasts is the strongest predictor of treatment outcome in B-progenitor cell acute lymphoblastic leukemia of childhood: a Pediatric Oncology Group study. J Clin Oncol 10 (4): 606-13, 1992.
[PUBMED Abstract]
-
Schrappe M, Reiter A, Ludwig WD, et al.: Improved outcome in childhood acute lymphoblastic leukemia despite reduced use of anthracyclines and cranial radiotherapy: results of trial ALL-BFM 90. German-Austrian-Swiss ALL-BFM Study Group. Blood 95 (11): 3310-22, 2000.
[PUBMED Abstract]
-
Forestier E, Schmiegelow K; on behalf of the Nordic Society of Paediatric Haematology and Oncology NOPHO.: The incidence peaks of the childhood acute leukemias reflect specific cytogenetic aberrations. J Pediatr Hematol Oncol 28 (8): 486-95, 2006.
[PUBMED Abstract]
-
de Bont JM, Holt B, Dekker AW, et al.: Significant difference in outcome for adolescents with acute lymphoblastic leukemia treated on pediatric vs adult protocols in the Netherlands. Leukemia 18 (12): 2032-5, 2004.
[PUBMED Abstract]
-
Boissel N, Auclerc MF, Lhéritier V, et al.: Should adolescents with acute lymphoblastic leukemia be treated as old children or young adults? Comparison of the French FRALLE-93 and LALA-94 trials. J Clin Oncol 21 (5): 774-80, 2003.
[PUBMED Abstract]
-
Nachman J: Clinical characteristics, biologic features and outcome for young adult patients with acute lymphoblastic leukaemia. Br J Haematol 130 (2): 166-73, 2005.
[PUBMED Abstract]
-
Reaman GH, Sposto R, Sensel MG, et al.: Treatment outcome and prognostic factors for infants with acute lymphoblastic leukemia treated on two consecutive trials of the Children's Cancer Group. J Clin Oncol 17 (2): 445-55, 1999.
[PUBMED Abstract]
-
Kosaka Y, Koh K, Kinukawa N, et al.: Infant acute lymphoblastic leukemia with MLL gene rearrangements: outcome following intensive chemotherapy and hematopoietic stem cell transplantation. Blood 104 (12): 3527-34, 2004.
[PUBMED Abstract]
-
Dördelmann M, Reiter A, Borkhardt A, et al.: Prednisone response is the strongest predictor of treatment outcome in infant acute lymphoblastic leukemia. Blood 94 (4): 1209-17, 1999.
[PUBMED Abstract]
-
Pieters R, Schrappe M, De Lorenzo P, et al.: A treatment protocol for infants younger than 1 year with acute lymphoblastic leukaemia (Interfant-99): an observational study and a multicentre randomised trial. Lancet 370 (9583): 240-50, 2007.
[PUBMED Abstract]
-
Biondi A, Cimino G, Pieters R, et al.: Biological and therapeutic aspects of infant leukemia. Blood 96 (1): 24-33, 2000.
[PUBMED Abstract]
-
Chessells JM, Harrison CJ, Watson SL, et al.: Treatment of infants with lymphoblastic leukaemia: results of the UK Infant Protocols 1987-1999. Br J Haematol 117 (2): 306-14, 2002.
[PUBMED Abstract]
-
Pui CH, Chessells JM, Camitta B, et al.: Clinical heterogeneity in childhood acute lymphoblastic leukemia with 11q23 rearrangements. Leukemia 17 (4): 700-6, 2003.
[PUBMED Abstract]
-
Biondi A, Rizzari C, Valsecchi MG, et al.: Role of treatment intensification in infants with acute lymphoblastic leukemia: results of two consecutive AIEOP studies. Haematologica 91 (4): 534-7, 2006.
[PUBMED Abstract]
-
Isoyama K, Eguchi M, Hibi S, et al.: Risk-directed treatment of infant acute lymphoblastic leukaemia based on early assessment of MLL gene status: results of the Japan Infant Leukaemia Study (MLL96). Br J Haematol 118 (4): 999-1010, 2002.
[PUBMED Abstract]
-
Rubnitz JE, Link MP, Shuster JJ, et al.: Frequency and prognostic significance of HRX rearrangements in infant acute lymphoblastic leukemia: a Pediatric Oncology Group study. Blood 84 (2): 570-3, 1994.
[PUBMED Abstract]
-
Pui CH, Gaynon PS, Boyett JM, et al.: Outcome of treatment in childhood acute lymphoblastic leukaemia with rearrangements of the 11q23 chromosomal region. Lancet 359 (9321): 1909-15, 2002.
[PUBMED Abstract]
-
Armstrong SA, Staunton JE, Silverman LB, et al.: MLL translocations specify a distinct gene expression profile that distinguishes a unique leukemia. Nat Genet 30 (1): 41-7, 2002.
[PUBMED Abstract]
-
Nagayama J, Tomizawa D, Koh K, et al.: Infants with acute lymphoblastic leukemia and a germline MLL gene are highly curable with use of chemotherapy alone: results from the Japan Infant Leukemia Study Group. Blood 107 (12): 4663-5, 2006.
[PUBMED Abstract]
-
Hilden JM, Dinndorf PA, Meerbaum SO, et al.: Analysis of prognostic factors of acute lymphoblastic leukemia in infants: report on CCG 1953 from the Children's Oncology Group. Blood 108 (2): 441-51, 2006.
[PUBMED Abstract]
-
Chessells JM, Bailey C, Richards SM: Intensification of treatment and survival in all children with lymphoblastic leukaemia: results of UK Medical Research Council trial UKALL X. Medical Research Council Working Party on Childhood Leukaemia. Lancet 345 (8943): 143-8, 1995.
[PUBMED Abstract]
-
Mahmoud HH, Rivera GK, Hancock ML, et al.: Low leukocyte counts with blast cells in cerebrospinal fluid of children with newly diagnosed acute lymphoblastic leukemia. N Engl J Med 329 (5): 314-9, 1993.
[PUBMED Abstract]
-
Gilchrist GS, Tubergen DG, Sather HN, et al.: Low numbers of CSF blasts at diagnosis do not predict for the development of CNS leukemia in children with intermediate-risk acute lymphoblastic leukemia: a Childrens Cancer Group report. J Clin Oncol 12 (12): 2594-600, 1994.
[PUBMED Abstract]
-
Pui CH, Mahmoud HH, Rivera GK, et al.: Early intensification of intrathecal chemotherapy virtually eliminates central nervous system relapse in children with acute lymphoblastic leukemia. Blood 92 (2): 411-5, 1998.
[PUBMED Abstract]
-
Bürger B, Zimmermann M, Mann G, et al.: Diagnostic cerebrospinal fluid examination in children with acute lymphoblastic leukemia: significance of low leukocyte counts with blasts or traumatic lumbar puncture. J Clin Oncol 21 (2): 184-8, 2003.
[PUBMED Abstract]
-
Gajjar A, Harrison PL, Sandlund JT, et al.: Traumatic lumbar puncture at diagnosis adversely affects outcome in childhood acute lymphoblastic leukemia. Blood 96 (10): 3381-4, 2000.
[PUBMED Abstract]
-
Cario G, Izraeli S, Teichert A, et al.: High interleukin-15 expression characterizes childhood acute lymphoblastic leukemia with involvement of the CNS. J Clin Oncol 25 (30): 4813-20, 2007.
[PUBMED Abstract]
-
Pui CH, Boyett JM, Relling MV, et al.: Sex differences in prognosis for children with acute lymphoblastic leukemia. J Clin Oncol 17 (3): 818-24, 1999.
[PUBMED Abstract]
-
Shuster JJ, Wacker P, Pullen J, et al.: Prognostic significance of sex in childhood B-precursor acute lymphoblastic leukemia: a Pediatric Oncology Group Study. J Clin Oncol 16 (8): 2854-63, 1998.
[PUBMED Abstract]
-
Chessells JM, Richards SM, Bailey CC, et al.: Gender and treatment outcome in childhood lymphoblastic leukaemia: report from the MRC UKALL trials. Br J Haematol 89 (2): 364-72, 1995.
[PUBMED Abstract]
-
Silverman LB, Gelber RD, Dalton VK, et al.: Improved outcome for children with acute lymphoblastic leukemia: results of Dana-Farber Consortium Protocol 91-01. Blood 97 (5): 1211-8, 2001.
[PUBMED Abstract]
-
Pui CH, Sandlund JT, Pei D, et al.: Improved outcome for children with acute lymphoblastic leukemia: results of Total Therapy Study XIIIB at St Jude Children's Research Hospital. Blood 104 (9): 2690-6, 2004.
[PUBMED Abstract]
-
Bhatia S: Influence of race and socioeconomic status on outcome of children treated for childhood acute lymphoblastic leukemia. Curr Opin Pediatr 16 (1): 9-14, 2004.
[PUBMED Abstract]
-
Pui CH, Sandlund JT, Pei D, et al.: Results of therapy for acute lymphoblastic leukemia in black and white children. JAMA 290 (15): 2001-7, 2003.
[PUBMED Abstract]
-
Kadan-Lottick NS, Ness KK, Bhatia S, et al.: Survival variability by race and ethnicity in childhood acute lymphoblastic leukemia. JAMA 290 (15): 2008-14, 2003.
[PUBMED Abstract]
-
Bennett JM, Catovsky D, Daniel MT, et al.: The morphological classification of acute lymphoblastic leukaemia: concordance among observers and clinical correlations. Br J Haematol 47 (4): 553-61, 1981.
[PUBMED Abstract]
-
Möricke A, Ratei R, Ludwig WD, et al.: Prognostic factors in CD10 negative precursor b-cell acute lymphoblastic leukemia in children: data from three consecutive trials ALL-BFM 86, 90, and 95. [Abstract] Blood 104 (11): A-1957, 540a, 2004.
-
Consolini R, Legitimo A, Rondelli R, et al.: Clinical relevance of CD10 expression in childhood ALL. The Italian Association for Pediatric Hematology and Oncology (AIEOP). Haematologica 83 (11): 967-73, 1998.
[PUBMED Abstract]
-
Pui CH: Childhood leukemias. N Engl J Med 332 (24): 1618-30, 1995.
[PUBMED Abstract]
-
Koehler M, Behm FG, Shuster J, et al.: Transitional pre-B-cell acute lymphoblastic leukemia of childhood is associated with favorable prognostic clinical features and an excellent outcome: a Pediatric Oncology Group study. Leukemia 7 (12): 2064-8, 1993.
[PUBMED Abstract]
-
Navid F, Mosijczuk AD, Head DR, et al.: Acute lymphoblastic leukemia with the (8;14)(q24;q32) translocation and FAB L3 morphology associated with a B-precursor immunophenotype: the Pediatric Oncology Group experience. Leukemia 13 (1): 135-41, 1999.
[PUBMED Abstract]
-
Uckun FM, Sensel MG, Sun L, et al.: Biology and treatment of childhood T-lineage acute lymphoblastic leukemia. Blood 91 (3): 735-46, 1998.
[PUBMED Abstract]
-
Nathan PC, Maze R, Spiegler B, et al.: CNS-directed therapy in young children with T-lineage acute lymphoblastic leukemia: High-dose methotrexate versus cranial irradiation. Pediatr Blood Cancer 42 (1): 24-9, 2004.
[PUBMED Abstract]
-
Goldberg JM, Silverman LB, Levy DE, et al.: Childhood T-cell acute lymphoblastic leukemia: the Dana-Farber Cancer Institute acute lymphoblastic leukemia consortium experience. J Clin Oncol 21 (19): 3616-22, 2003.
[PUBMED Abstract]
-
Attarbaschi A, Mann G, Dworzak M, et al.: Mediastinal mass in childhood T-cell acute lymphoblastic leukemia: significance and therapy response. Med Pediatr Oncol 39 (6): 558-65, 2002.
[PUBMED Abstract]
-
Schneider NR, Carroll AJ, Shuster JJ, et al.: New recurring cytogenetic abnormalities and association of blast cell karyotypes with prognosis in childhood T-cell acute lymphoblastic leukemia: a pediatric oncology group report of 343 cases. Blood 96 (7): 2543-9, 2000.
[PUBMED Abstract]
-
Armstrong SA, Look AT: Molecular genetics of acute lymphoblastic leukemia. J Clin Oncol 23 (26): 6306-15, 2005.
[PUBMED Abstract]
-
Bergeron J, Clappier E, Radford I, et al.: Prognostic and oncogenic relevance of TLX1/HOX11 expression level in T-ALLs. Blood 110 (7): 2324-30, 2007.
[PUBMED Abstract]
-
van Grotel M, Meijerink JP, Beverloo HB, et al.: The outcome of molecular-cytogenetic subgroups in pediatric T-cell acute lymphoblastic leukemia: a retrospective study of patients treated according to DCOG or COALL protocols. Haematologica 91 (9): 1212-21, 2006.
[PUBMED Abstract]
-
Cavé H, Suciu S, Preudhomme C, et al.: Clinical significance of HOX11L2 expression linked to t(5;14)(q35;q32), of HOX11 expression, and of SIL-TAL fusion in childhood T-cell malignancies: results of EORTC studies 58881 and 58951. Blood 103 (2): 442-50, 2004.
[PUBMED Abstract]
-
Baak U, Gökbuget N, Orawa H, et al.: Thymic adult T-cell acute lymphoblastic leukemia stratified in standard- and high-risk group by aberrant HOX11L2 expression: experience of the German multicenter ALL study group. Leukemia 22 (6): 1154-60, 2008.
[PUBMED Abstract]
-
Ferrando AA, Neuberg DS, Dodge RK, et al.: Prognostic importance of TLX1 (HOX11) oncogene expression in adults with T-cell acute lymphoblastic leukaemia. Lancet 363 (9408): 535-6, 2004.
[PUBMED Abstract]
-
Kees UR, Heerema NA, Kumar R, et al.: Expression of HOX11 in childhood T-lineage acute lymphoblastic leukaemia can occur in the absence of cytogenetic aberration at 10q24: a study from the Children's Cancer Group (CCG). Leukemia 17 (5): 887-93, 2003.
[PUBMED Abstract]
-
Ballerini P, Blaise A, Busson-Le Coniat M, et al.: HOX11L2 expression defines a clinical subtype of pediatric T-ALL associated with poor prognosis. Blood 100 (3): 991-7, 2002.
[PUBMED Abstract]
-
Weng AP, Ferrando AA, Lee W, et al.: Activating mutations of NOTCH1 in human T cell acute lymphoblastic leukemia. Science 306 (5694): 269-71, 2004.
[PUBMED Abstract]
-
Breit S, Stanulla M, Flohr T, et al.: Activating NOTCH1 mutations predict favorable early treatment response and long-term outcome in childhood precursor T-cell lymphoblastic leukemia. Blood 108 (4): 1151-7, 2006.
[PUBMED Abstract]
-
Zhu YM, Zhao WL, Fu JF, et al.: NOTCH1 mutations in T-cell acute lymphoblastic leukemia: prognostic significance and implication in multifactorial leukemogenesis. Clin Cancer Res 12 (10): 3043-9, 2006.
[PUBMED Abstract]
-
Pui CH, Rubnitz JE, Hancock ML, et al.: Reappraisal of the clinical and biologic significance of myeloid-associated antigen expression in childhood acute lymphoblastic leukemia. J Clin Oncol 16 (12): 3768-73, 1998.
[PUBMED Abstract]
-
Uckun FM, Sather HN, Gaynon PS, et al.: Clinical features and treatment outcome of children with myeloid antigen positive acute lymphoblastic leukemia: a report from the Children's Cancer Group. Blood 90 (1): 28-35, 1997.
[PUBMED Abstract]
-
Harrison CJ, Moorman AV, Barber KE, et al.: Interphase molecular cytogenetic screening for chromosomal abnormalities of prognostic significance in childhood acute lymphoblastic leukaemia: a UK Cancer Cytogenetics Group Study. Br J Haematol 129 (4): 520-30, 2005.
[PUBMED Abstract]
-
Raimondi SC, Pui CH, Hancock ML, et al.: Heterogeneity of hyperdiploid (51-67) childhood acute lymphoblastic leukemia. Leukemia 10 (2): 213-24, 1996.
[PUBMED Abstract]
-
Hann I, Vora A, Harrison G, et al.: Determinants of outcome after intensified therapy of childhood lymphoblastic leukaemia: results from Medical Research Council United Kingdom acute lymphoblastic leukaemia XI protocol. Br J Haematol 113 (1): 103-14, 2001.
[PUBMED Abstract]
-
Moorman AV, Richards SM, Martineau M, et al.: Outcome heterogeneity in childhood high-hyperdiploid acute lymphoblastic leukemia. Blood 102 (8): 2756-62, 2003.
[PUBMED Abstract]
-
Pui CH, Evans WE: Acute lymphoblastic leukemia. N Engl J Med 339 (9): 605-15, 1998.
[PUBMED Abstract]
-
Synold TW, Relling MV, Boyett JM, et al.: Blast cell methotrexate-polyglutamate accumulation in vivo differs by lineage, ploidy, and methotrexate dose in acute lymphoblastic leukemia. J Clin Invest 94 (5): 1996-2001, 1994.
[PUBMED Abstract]
-
Charrin C, Thomas X, Ffrench M, et al.: A report from the LALA-94 and LALA-SA groups on hypodiploidy with 30 to 39 chromosomes and near-triploidy: 2 possible expressions of a sole entity conferring poor prognosis in adult acute lymphoblastic leukemia (ALL). Blood 104 (8): 2444-51, 2004.
[PUBMED Abstract]
-
Harris MB, Shuster JJ, Carroll A, et al.: Trisomy of leukemic cell chromosomes 4 and 10 identifies children with B-progenitor cell acute lymphoblastic leukemia with a very low risk of treatment failure: a Pediatric Oncology Group study. Blood 79 (12): 3316-24, 1992.
[PUBMED Abstract]
-
Heerema NA, Sather HN, Sensel MG, et al.: Prognostic impact of trisomies of chromosomes 10, 17, and 5 among children with acute lymphoblastic leukemia and high hyperdiploidy (> 50 chromosomes). J Clin Oncol 18 (9): 1876-87, 2000.
[PUBMED Abstract]
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Sutcliffe MJ, Shuster JJ, Sather HN, et al.: High concordance from independent studies by the Children's Cancer Group (CCG) and Pediatric Oncology Group (POG) associating favorable prognosis with combined trisomies 4, 10, and 17 in children with NCI Standard-Risk B-precursor Acute Lymphoblastic Leukemia: a Children's Oncology Group (COG) initiative. Leukemia 19 (5): 734-40, 2005.
[PUBMED Abstract]
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Pui CH, Sallan S, Relling MV, et al.: International Childhood Acute Lymphoblastic Leukemia Workshop: Sausalito, CA, 30 November-1 December 2000. Leukemia 15 (5): 707-15, 2001.
[PUBMED Abstract]
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Pui CH, Carroll AJ, Raimondi SC, et al.: Clinical presentation, karyotypic characterization, and treatment outcome of childhood acute lymphoblastic leukemia with a near-haploid or hypodiploid less than 45 line. Blood 75 (5): 1170-7, 1990.
[PUBMED Abstract]
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Nachman JB, Heerema NA, Sather H, et al.: Outcome of treatment in children with hypodiploid acute lymphoblastic leukemia. Blood 110 (4): 1112-5, 2007.
[PUBMED Abstract]
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McLean TW, Ringold S, Neuberg D, et al.: TEL/AML-1 dimerizes and is associated with a favorable outcome in childhood acute lymphoblastic leukemia. Blood 88 (11): 4252-8, 1996.
[PUBMED Abstract]
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Borkhardt A, Cazzaniga G, Viehmann S, et al.: Incidence and clinical relevance of TEL/AML1 fusion genes in children with acute lymphoblastic leukemia enrolled in the German and Italian multicenter therapy trials. Associazione Italiana Ematologia Oncologia Pediatrica and the Berlin-Frankfurt-Münster Study Group. Blood 90 (2): 571-7, 1997.
[PUBMED Abstract]
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Uckun FM, Pallisgaard N, Hokland P, et al.: Expression of TEL-AML1 fusion transcripts and response to induction therapy in standard risk acute lymphoblastic leukemia. Leuk Lymphoma 42 (1-2): 41-56, 2001.
[PUBMED Abstract]
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Kanerva J, Saarinen-Pihkala UM, Niini T, et al.: Favorable outcome in 20-year follow-up of children with very-low-risk ALL and minimal standard therapy, with special reference to TEL-AML1 fusion. Pediatr Blood Cancer 42 (1): 30-5, 2004.
[PUBMED Abstract]
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Aldrich MC, Zhang L, Wiemels JL, et al.: Cytogenetics of Hispanic and White children with acute lymphoblastic leukemia in California. Cancer Epidemiol Biomarkers Prev 15 (3): 578-81, 2006.
[PUBMED Abstract]
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Loh ML, Goldwasser MA, Silverman LB, et al.: Prospective analysis of TEL/AML1-positive patients treated on Dana-Farber Cancer Institute Consortium Protocol 95-01. Blood 107 (11): 4508-13, 2006.
[PUBMED Abstract]
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Rubnitz J, Wichlan D, Devidas M, et al.: Prospective analysis of TEL and MLL gene rearrangements in childhood acute lymphoblastic leukemia: a Children's Oncology Group study. [Abstract] Blood 108 (11): A-218, 68a, 2006.
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Borowitz MJ, Devidas M, Bowman WP, et al.: Prognostic significance of minimal residual disease (MRD) in childhood B-precursor ALL and its relation to other risk factors: a Children's Oncology Group (COG) study. [Abstract] Blood 108 (11): A-219, 68a, 2006.
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de Haas V, Oosten L, Dee R, et al.: Minimal residual disease studies are beneficial in the follow-up of TEL/AML1 patients with B-precursor acute lymphoblastic leukaemia. Br J Haematol 111 (4): 1080-6, 2000.
[PUBMED Abstract]
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Madzo J, Zuna J, Muzíková K, et al.: Slower molecular response to treatment predicts poor outcome in patients with TEL/AML1 positive acute lymphoblastic leukemia: prospective real-time quantitative reverse transcriptase-polymerase chain reaction study. Cancer 97 (1): 105-13, 2003.
[PUBMED Abstract]
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Seeger K, Stackelberg AV, Taube T, et al.: Relapse of TEL-AML1--positive acute lymphoblastic leukemia in childhood: a matched-pair analysis. J Clin Oncol 19 (13): 3188-93, 2001.
[PUBMED Abstract]
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Zuna J, Ford AM, Peham M, et al.: TEL deletion analysis supports a novel view of relapse in childhood acute lymphoblastic leukemia. Clin Cancer Res 10 (16): 5355-60, 2004.
[PUBMED Abstract]
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Aricò M, Valsecchi MG, Camitta B, et al.: Outcome of treatment in children with Philadelphia chromosome-positive acute lymphoblastic leukemia. N Engl J Med 342 (14): 998-1006, 2000.
[PUBMED Abstract]
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Schrappe M, Aricò M, Harbott J, et al.: Philadelphia chromosome-positive (Ph+) childhood acute lymphoblastic leukemia: good initial steroid response allows early prediction of a favorable treatment outcome. Blood 92 (8): 2730-41, 1998.
[PUBMED Abstract]
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Ribeiro RC, Broniscer A, Rivera GK, et al.: Philadelphia chromosome-positive acute lymphoblastic leukemia in children: durable responses to chemotherapy associated with low initial white blood cell counts. Leukemia 11 (9): 1493-6, 1997.
[PUBMED Abstract]
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Heerema NA, Harbott J, Galimberti S, et al.: Secondary cytogenetic aberrations in childhood Philadelphia chromosome positive acute lymphoblastic leukemia are nonrandom and may be associated with outcome. Leukemia 18 (4): 693-702, 2004.
[PUBMED Abstract]
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Jones LK, Saha V: Philadelphia positive acute lymphoblastic leukaemia of childhood. Br J Haematol 130 (4): 489-500, 2005.
[PUBMED Abstract]
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Rubnitz JE, Look AT: Molecular genetics of childhood leukemias. J Pediatr Hematol Oncol 20 (1): 1-11, 1998 Jan-Feb.
[PUBMED Abstract]
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Pui CH, Frankel LS, Carroll AJ, et al.: Clinical characteristics and treatment outcome of childhood acute lymphoblastic leukemia with the t(4;11)(q21;q23): a collaborative study of 40 cases. Blood 77 (3): 440-7, 1991.
[PUBMED Abstract]
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Johansson B, Moorman AV, Haas OA, et al.: Hematologic malignancies with t(4;11)(q21;q23)--a cytogenetic, morphologic, immunophenotypic and clinical study of 183 cases. European 11q23 Workshop participants. Leukemia 12 (5): 779-87, 1998.
[PUBMED Abstract]
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Rubnitz JE, Camitta BM, Mahmoud H, et al.: Childhood acute lymphoblastic leukemia with the MLL-ENL fusion and t(11;19)(q23;p13.3) translocation. J Clin Oncol 17 (1): 191-6, 1999.
[PUBMED Abstract]
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Crist WM, Carroll AJ, Shuster JJ, et al.: Poor prognosis of children with pre-B acute lymphoblastic leukemia is associated with the t(1;19)(q23;p13): a Pediatric Oncology Group study. Blood 76 (1): 117-22, 1990.
[PUBMED Abstract]
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Hunger SP: Chromosomal translocations involving the E2A gene in acute lymphoblastic leukemia: clinical features and molecular pathogenesis. Blood 87 (4): 1211-24, 1996.
[PUBMED Abstract]
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Uckun FM, Sensel MG, Sather HN, et al.: Clinical significance of translocation t(1;19) in childhood acute lymphoblastic leukemia in the context of contemporary therapies: a report from the Children's Cancer Group. J Clin Oncol 16 (2): 527-35, 1998.
[PUBMED Abstract]
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Raimondi SC, Behm FG, Roberson PK, et al.: Cytogenetics of pre-B-cell acute lymphoblastic leukemia with emphasis on prognostic implications of the t(1;19). J Clin Oncol 8 (8): 1380-8, 1990.
[PUBMED Abstract]
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Pui CH, Raimondi SC, Hancock ML, et al.: Immunologic, cytogenetic, and clinical characterization of childhood acute lymphoblastic leukemia with the t(1;19) (q23; p13) or its derivative. J Clin Oncol 12 (12): 2601-6, 1994.
[PUBMED Abstract]
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Robinson HM, Broadfield ZJ, Cheung KL, et al.: Amplification of AML1 in acute lymphoblastic leukemia is associated with a poor outcome. Leukemia 17 (11): 2249-50, 2003.
[PUBMED Abstract]
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Moorman AV, Richards SM, Robinson HM, et al.: Prognosis of children with acute lymphoblastic leukemia (ALL) and intrachromosomal amplification of chromosome 21 (iAMP21). Blood 109 (6): 2327-30, 2007.
[PUBMED Abstract]
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Relling MV, Dervieux T: Pharmacogenetics and cancer therapy. Nat Rev Cancer 1 (2): 99-108, 2001.
[PUBMED Abstract]
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Gaynon PS, Desai AA, Bostrom BC, et al.: Early response to therapy and outcome in childhood acute lymphoblastic leukemia: a review. Cancer 80 (9): 1717-26, 1997.
[PUBMED Abstract]
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Steinherz PG, Gaynon PS, Breneman JC, et al.: Cytoreduction and prognosis in acute lymphoblastic leukemia--the importance of early marrow response: report from the Childrens Cancer Group. J Clin Oncol 14 (2): 389-98, 1996.
[PUBMED Abstract]
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Aricò M, Basso G, Mandelli F, et al.: Good steroid response in vivo predicts a favorable outcome in children with T-cell acute lymphoblastic leukemia. The Associazione Italiana Ematologia Oncologia Pediatrica (AIEOP). Cancer 75 (7): 1684-93, 1995.
[PUBMED Abstract]
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Lauten M, Stanulla M, Zimmermann M, et al.: Clinical outcome of patients with childhood acute lymphoblastic leukaemia and an initial leukaemic blood blast count of less than 1000 per microliter. Klin Padiatr 213 (4): 169-74, 2001 Jul-Aug.
[PUBMED Abstract]
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Gajjar A, Ribeiro R, Hancock ML, et al.: Persistence of circulating blasts after 1 week of multiagent chemotherapy confers a poor prognosis in childhood acute lymphoblastic leukemia. Blood 86 (4): 1292-5, 1995.
[PUBMED Abstract]
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Rautonen J, Hovi L, Siimes MA: Slow disappearance of peripheral blast cells: an independent risk factor indicating poor prognosis in children with acute lymphoblastic leukemia. Blood 71 (4): 989-91, 1988.
[PUBMED Abstract]
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Griffin TC, Shuster JJ, Buchanan GR, et al.: Slow disappearance of peripheral blood blasts is an adverse prognostic factor in childhood T cell acute lymphoblastic leukemia: a Pediatric Oncology Group study. Leukemia 14 (5): 792-5, 2000.
[PUBMED Abstract]
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Coustan-Smith E, Sancho J, Hancock ML, et al.: Use of peripheral blood instead of bone marrow to monitor residual disease in children with acute lymphoblastic leukemia. Blood 100 (7): 2399-402, 2002.
[PUBMED Abstract]
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Zhou J, Goldwasser MA, Li A, et al.: Quantitative analysis of minimal residual disease predicts relapse in children with B-lineage acute lymphoblastic leukemia in DFCI ALL Consortium Protocol 95-01. Blood 110 (5): 1607-11, 2007.
[PUBMED Abstract]
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Dibenedetto SP, Lo Nigro L, Mayer SP, et al.: Detectable molecular residual disease at the beginning of maintenance therapy indicates poor outcome in children with T-cell acute lymphoblastic leukemia. Blood 90 (3): 1226-32, 1997.
[PUBMED Abstract]
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van Dongen JJ, Seriu T, Panzer-Grümayer ER, et al.: Prognostic value of minimal residual disease in acute lymphoblastic leukaemia in childhood. Lancet 352 (9142): 1731-8, 1998.
[PUBMED Abstract]
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Panzer-Grümayer ER, Schneider M, Panzer S, et al.: Rapid molecular response during early induction chemotherapy predicts a good outcome in childhood acute lymphoblastic leukemia. Blood 95 (3): 790-4, 2000.
[PUBMED Abstract]
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Coustan-Smith E, Sancho J, Hancock ML, et al.: Clinical importance of minimal residual disease in childhood acute lymphoblastic leukemia. Blood 96 (8): 2691-6, 2000.
[PUBMED Abstract]
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Nyvold C, Madsen HO, Ryder LP, et al.: Precise quantification of minimal residual disease at day 29 allows identification of children with acute lymphoblastic leukemia and an excellent outcome. Blood 99 (4): 1253-8, 2002.
[PUBMED Abstract]
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Dworzak MN, Fröschl G, Printz D, et al.: Prognostic significance and modalities of flow cytometric minimal residual disease detection in childhood acute lymphoblastic leukemia. Blood 99 (6): 1952-8, 2002.
[PUBMED Abstract]
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Willemse MJ, Seriu T, Hettinger K, et al.: Detection of minimal residual disease identifies differences in treatment response between T-ALL and precursor B-ALL. Blood 99 (12): 4386-93, 2002.
[PUBMED Abstract]
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Gameiro P, Moreira I, Yetgin S, et al.: Polymerase chain reaction (PCR)- and reverse transcription PCR-based minimal residual disease detection in long-term follow-up of childhood acute lymphoblastic leukaemia. Br J Haematol 119 (3): 685-96, 2002.
[PUBMED Abstract]
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Björklund E, Mazur J, Söderhäll S, et al.: Flow cytometric follow-up of minimal residual disease in bone marrow gives prognostic information in children with acute lymphoblastic leukemia. Leukemia 17 (1): 138-48, 2003.
[PUBMED Abstract]
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Shuster JJ, Camitta BM, Pullen J, et al.: Identification of newly diagnosed children with acute lymphocytic leukemia at high risk for relapse. Cancer Research, Therapy and Control 9(1-2): 101-107, 1999.
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Heerema NA, Nachman JB, Sather HN, et al.: Hypodiploidy with less than 45 chromosomes confers adverse risk in childhood acute lymphoblastic leukemia: a report from the children's cancer group. Blood 94 (12): 4036-45, 1999.
[PUBMED Abstract]
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Schultz KR, Pullen DJ, Sather HN, et al.: Risk- and response-based classification of childhood B-precursor acute lymphoblastic leukemia: a combined analysis of prognostic markers from the Pediatric Oncology Group (POG) and Children's Cancer Group (CCG). Blood 109 (3): 926-35, 2007.
[PUBMED Abstract]
Back to Top Treatment Option Overview
Risk-based treatment assignment is an important therapeutic strategy utilized for
children with acute lymphoblastic leukemia (ALL). This approach allows
children who historically have a very good outcome to be treated with modest therapy and to be
spared more intensive and toxic treatment, while allowing children with a
historically lower probability of long-term survival to receive more intensive
therapy that may increase their chance of cure. As discussed in the Cellular
Classification and Prognostic Variables section of this summary, a number of
clinical and laboratory features have demonstrated prognostic value. A subset
of the known prognostic factors (e.g., age, white blood cell [WBC] count at
diagnosis, presence of specific cytogenetic abnormalities) are used for the
initial stratification of children with ALL into treatment groups with varying
degrees of risk of treatment failure. Event-free survival (EFS) rates exceed 80% in
children meeting good-risk criteria for age and WBC count; in
children meeting high-risk criteria, EFS rates are approximately 70%.[1-4] Application of biological factors (e.g., specific chromosomal
translocations and hypodiploidy) can identify patient groups with expected outcome survival
rates ranging from less than 40% to more than 95%.[5,6]
Nationwide clinical trials are generally available for children with ALL, with
specific protocols designed for children at standard (low) risk of treatment
failure and for children at higher risk of treatment failure. Clinical trials
for children with ALL are generally designed to compare therapy that is
currently accepted as standard for a particular risk group with a potentially
better treatment approach that may improve survival outcome and/or diminish
toxicities associated with the standard treatment regimen. Many of the
improvements in therapy that have led to increased survival rates in children
with ALL have been made through nationwide clinical trials,[7,8] and it is
appropriate for children and adolescents with ALL to be offered participation
in a clinical trial. In addition, treatment planning by a multidisciplinary
team of pediatric cancer specialists with experience and expertise in treating
leukemias of childhood is required to determine and implement optimum
treatment. This treatment is best accomplished in a center with specialized expertise in pediatric cancer.[9]
Older children and adolescents (≥10 years) and infants (<12 months) have a less favorable outcome
than children aged 1 to 9 years at diagnosis, and more aggressive treatments are generally employed for these patients.[10] Increasing evidence demonstrates a significant advantage for adolescents with ALL being treated on pediatric-based treatment protocols.[11] A report from France of 15- to 20-year-old patients diagnosed between 1993 and 1999 showed superior outcome in patients treated on a pediatric trial (67% 5-year EFS) compared with patients treated on an adult trial (41% 5-year EFS).[12] The reason for these differences is not known, though possible explanations include treatment setting (i.e., site experience in treating ALL), adherence to protocol therapy, and components of protocol therapy itself.
Successful treatment of children with ALL requires the control of systemic
disease (e.g., marrow, liver and spleen, lymph nodes) as well as the prevention or treatment of extramedullary disease, particularly in the central nervous
system (CNS). Only 3% of patients have detectable CNS involvement by
conventional criteria at diagnosis (≥5 WBC/μL with lymphoblast cells present).
Unless specific therapy is directed toward the CNS, however, 50% to 70% or more of children will eventually develop overt CNS
leukemia. Therefore, all children with ALL should receive systemic combination
chemotherapy together with some form of CNS prophylaxis. At present, most groups treat patients
with documented CNS leukemia at diagnosis (>5 WBC/μl with blasts; CNS3), and those with T-cell phenotype and high WBC count at diagnosis, with intrathecal therapy and subsequent cranial radiation.
Treatment for children with ALL is divided into stages: remission induction,
consolidation or intensification, and maintenance (continuation) therapy, with
CNS sanctuary therapy generally provided in each stage. An intensification
phase of therapy following remission induction is used for all patients. The
intensity of both induction therapy and postinduction therapy is determined by
the clinical and biologic prognostic factors utilized for risk-based treatment
assignment and some type of early response assessment. This assessment may include day 7 and/or day 14 marrow blast percentage, day 8 peripheral blood blast count, and minimal residual disease determinations in bone marrow and/or peripheral blood during or at the end of induction.[5,13-15] The duration of therapy for children with ALL
ranges between 2 and 3 years.
Overt testicular involvement at the time of diagnosis occurs in approximately 2% of males. In early ALL trials, testicular involvement at diagnosis was an adverse prognostic factor. With more aggressive initial therapy, however, the prognostic significance of initial testicular involvement is unclear.[16,17] The role of radiation therapy for testicular involvement is also unclear. A study from St. Jude Children's Research Hospital suggests that a good outcome can be achieved with aggressive conventional chemotherapy without radiation.[16] The Children's Oncology Group has also adopted this strategy.
Subgroups of patients who have a poor prognosis with current standard therapy
may require different treatment. For example, infants with ALL are at higher risk for treatment failure, with the
poorest prognosis for those with MLL gene rearrangements.[18-21] These children
are generally treated with regimens designed specifically for infants.[21-24] Current regimens for infants employ intensified treatment approaches and may
offer improved disease control compared with previous less intensive
approaches, but long-term outcome and toxicity are unknown.[23-26] Certain
children (older than 1 year) with ALL may have a less than 50% likelihood
of long-term remission with current therapy (e.g., t[9;22] Philadelphia
chromosome-positive ALL, hypodiploid patients, and those with initial induction failure). For these
patients, allogeneic bone marrow transplantation from ahuman leukocyte antigen ( HLA)-matched sibling should be considered during first remission.[27-32]
HLA-matched sibling
donor transplant, however, has not been proven to be of benefit in patients defined as
high-risk solely by WBC count, gender, and age.[33,34]
Since myelosuppression and generalized immunosuppression are an anticipated
consequence of both leukemia and its treatment with chemotherapy, patients must be closely monitored during treatment. Adequate
facilities must be immediately available both for hematologic support and for
the treatment of infectious and other complications throughout all phases of leukemia
treatment. Approximately 1% of patients die during induction therapy and another 1% to 3% die during first remission from treatment-related complications.[35]
References
-
Gaynon PS, Trigg ME, Heerema NA, et al.: Children's Cancer Group trials in childhood acute lymphoblastic leukemia: 1983-1995. Leukemia 14 (12): 2223-33, 2000.
[PUBMED Abstract]
-
Schrappe M, Reiter A, Zimmermann M, et al.: Long-term results of four consecutive trials in childhood ALL performed by the ALL-BFM study group from 1981 to 1995. Berlin-Frankfurt-Münster. Leukemia 14 (12): 2205-22, 2000.
[PUBMED Abstract]
-
Silverman LB, Declerck L, Gelber RD, et al.: Results of Dana-Farber Cancer Institute Consortium protocols for children with newly diagnosed acute lymphoblastic leukemia (1981-1995). Leukemia 14 (12): 2247-56, 2000.
[PUBMED Abstract]
-
Pui CH, Sandlund JT, Pei D, et al.: Improved outcome for children with acute lymphoblastic leukemia: results of Total Therapy Study XIIIB at St Jude Children's Research Hospital. Blood 104 (9): 2690-6, 2004.
[PUBMED Abstract]
-
Pui CH, Evans WE: Treatment of acute lymphoblastic leukemia. N Engl J Med 354 (2): 166-78, 2006.
[PUBMED Abstract]
-
Chauvenet AR, Martin PL, Devidas M, et al.: Antimetabolite therapy for lesser-risk B-lineage acute lymphoblastic leukemia of childhood: a report from Children's Oncology Group Study P9201. Blood 110 (4): 1105-11, 2007.
[PUBMED Abstract]
-
Progress against childhood cancer: the Pediatric Oncology Group experience. Pediatrics 89 (4 Pt 1): 597-600, 1992.
[PUBMED Abstract]
-
Bleyer WA: The U.S. pediatric cancer clinical trials programmes: international implications and the way forward. Eur J Cancer 33 (9): 1439-47, 1997.
[PUBMED Abstract]
-
Guidelines for the pediatric cancer center and role of such centers in diagnosis and treatment. American Academy of Pediatrics Section Statement Section on Hematology/Oncology. Pediatrics 99 (1): 139-41, 1997.
[PUBMED Abstract]
-
Nachman J: Clinical characteristics, biologic features and outcome for young adult patients with acute lymphoblastic leukaemia. Br J Haematol 130 (2): 166-73, 2005.
[PUBMED Abstract]
-
Ramanujachar R, Richards S, Hann I, et al.: Adolescents with acute lymphoblastic leukaemia: emerging from the shadow of paediatric and adult treatment protocols. Pediatr Blood Cancer 47 (6): 748-56, 2006.
[PUBMED Abstract]
-
Boissel N, Auclerc MF, Lhéritier V, et al.: Should adolescents with acute lymphoblastic leukemia be treated as old children or young adults? Comparison of the French FRALLE-93 and LALA-94 trials. J Clin Oncol 21 (5): 774-80, 2003.
[PUBMED Abstract]
-
Szczepański T, Orfão A, van der Velden VH, et al.: Minimal residual disease in leukaemia patients. Lancet Oncol 2 (7): 409-17, 2001.
[PUBMED Abstract]
-
Gaynon PS, Desai AA, Bostrom BC, et al.: Early response to therapy and outcome in childhood acute lymphoblastic leukemia: a review. Cancer 80 (9): 1717-26, 1997.
[PUBMED Abstract]
-
Campana D: Determination of minimal residual disease in leukaemia patients. Br J Haematol 121 (6): 823-38, 2003.
[PUBMED Abstract]
-
Hijiya N, Liu W, Sandlund JT, et al.: Overt testicular disease at diagnosis of childhood acute lymphoblastic leukemia: lack of therapeutic role of local irradiation. Leukemia 19 (8): 1399-403, 2005.
[PUBMED Abstract]
-
Sirvent N, Suciu S, Bertrand Y, et al.: Overt testicular disease (OTD) at diagnosis is not associated with a poor prognosis in childhood acute lymphoblastic leukemia: results of the EORTC CLG Study 58881. Pediatr Blood Cancer 49 (3): 344-8, 2007.
[PUBMED Abstract]
-
Rubnitz JE, Link MP, Shuster JJ, et al.: Frequency and prognostic significance of HRX rearrangements in infant acute lymphoblastic leukemia: a Pediatric Oncology Group study. Blood 84 (2): 570-3, 1994.
[PUBMED Abstract]
-
Biondi A, Cimino G, Pieters R, et al.: Biological and therapeutic aspects of infant leukemia. Blood 96 (1): 24-33, 2000.
[PUBMED Abstract]
-
Pui CH, Gaynon PS, Boyett JM, et al.: Outcome of treatment in childhood acute lymphoblastic leukaemia with rearrangements of the 11q23 chromosomal region. Lancet 359 (9321): 1909-15, 2002.
[PUBMED Abstract]
-
Silverman LB, McLean TW, Gelber RD, et al.: Intensified therapy for infants with acute lymphoblastic leukemia: results from the Dana-Farber Cancer Institute Consortium. Cancer 80 (12): 2285-95, 1997.
[PUBMED Abstract]
-
Chessells JM, Harrison CJ, Watson SL, et al.: Treatment of infants with lymphoblastic leukaemia: results of the UK Infant Protocols 1987-1999. Br J Haematol 117 (2): 306-14, 2002.
[PUBMED Abstract]
-
Reaman GH, Sposto R, Sensel MG, et al.: Treatment outcome and prognostic factors for infants with acute lymphoblastic leukemia treated on two consecutive trials of the Children's Cancer Group. J Clin Oncol 17 (2): 445-55, 1999.
[PUBMED Abstract]
-
Pieters R, Schrappe M, De Lorenzo P, et al.: A treatment protocol for infants younger than 1 year with acute lymphoblastic leukaemia (Interfant-99): an observational study and a multicentre randomised trial. Lancet 370 (9583): 240-50, 2007.
[PUBMED Abstract]
-
Kosaka Y, Koh K, Kinukawa N, et al.: Infant acute lymphoblastic leukemia with MLL gene rearrangements: outcome following intensive chemotherapy and hematopoietic stem cell transplantation. Blood 104 (12): 3527-34, 2004.
[PUBMED Abstract]
-
Hilden JM, Dinndorf PA, Meerbaum SO, et al.: Analysis of prognostic factors of acute lymphoblastic leukemia in infants: report on CCG 1953 from the Children's Oncology Group. Blood 108 (2): 441-51, 2006.
[PUBMED Abstract]
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Snyder DS, Nademanee AP, O'Donnell MR, et al.: Long-term follow-up of 23 patients with Philadelphia chromosome-positive acute lymphoblastic leukemia treated with allogeneic bone marrow transplant in first complete remission. Leukemia 13 (12): 2053-8, 1999.
[PUBMED Abstract]
-
Aricò M, Valsecchi MG, Camitta B, et al.: Outcome of treatment in children with Philadelphia chromosome-positive acute lymphoblastic leukemia. N Engl J Med 342 (14): 998-1006, 2000.
[PUBMED Abstract]
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Mori T, Manabe A, Tsuchida M, et al.: Allogeneic bone marrow transplantation in first remission rescues children with Philadelphia chromosome-positive acute lymphoblastic leukemia: Tokyo Children's Cancer Study Group (TCCSG) studies L89-12 and L92-13. Med Pediatr Oncol 37 (5): 426-31, 2001.
[PUBMED Abstract]
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Appelbaum FR: Hematopoietic cell transplantation beyond first remission. Leukemia 16 (2): 157-9, 2002.
[PUBMED Abstract]
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Balduzzi A, Valsecchi MG, Uderzo C, et al.: Chemotherapy versus allogeneic transplantation for very-high-risk childhood acute lymphoblastic leukaemia in first complete remission: comparison by genetic randomisation in an international prospective study. Lancet 366 (9486): 635-42, 2005 Aug 20-26.
[PUBMED Abstract]
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Schrauder A, Reiter A, Gadner H, et al.: Superiority of allogeneic hematopoietic stem-cell transplantation compared with chemotherapy alone in high-risk childhood T-cell acute lymphoblastic leukemia: results from ALL-BFM 90 and 95. J Clin Oncol 24 (36): 5742-9, 2006.
[PUBMED Abstract]
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Ribera JM, Ortega JJ, Oriol A, et al.: Comparison of intensive chemotherapy, allogeneic, or autologous stem-cell transplantation as postremission treatment for children with very high risk acute lymphoblastic leukemia: PETHEMA ALL-93 Trial. J Clin Oncol 25 (1): 16-24, 2007.
[PUBMED Abstract]
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Hahn T, Wall D, Camitta B, et al.: The role of cytotoxic therapy with hematopoietic stem cell transplantation in the therapy of acute lymphoblastic leukemia in children: an evidence-based review. Biol Blood Marrow Transplant 11 (11): 823-61, 2005.
[PUBMED Abstract]
-
Christensen MS, Heyman M, Möttönen M, et al.: Treatment-related death in childhood acute lymphoblastic leukaemia in the Nordic countries: 1992-2001. Br J Haematol 131 (1): 50-8, 2005.
[PUBMED Abstract]
Back to Top Untreated Childhood Acute Lymphoblastic Leukemia
Induction Chemotherapy
Three-drug induction therapy using vincristine, prednisone/dexamethasone, plus
L-asparaginase in conjunction with intrathecal therapy (IT), results in complete
remission rates of greater than 95%.[1] For patients at high risk of
treatment failure, a more intense induction regimen (four or five agents) may result
in improved event-free survival (EFS),[2-4] and high-risk patients generally
receive induction therapy that includes an anthracycline (e.g., daunomycin) in
addition to vincristine, prednisone/dexamethasone, plus L-asparaginase. For
patients who are at standard risk or low risk of treatment failure, four-drug induction therapy does not appear necessary for
favorable outcome provided that adequate postremission intensification therapy
is administered.[2,5,6] Because of the likelihood of increased toxicity with four-drug induction therapy, Children's Oncology Group (COG) protocols for National Cancer Institute (NCI) standard-risk precursor B-cell ALL currently utilize dexamethasone,
vincristine, and L-asparaginase. Induction regimens using
four or more agents are reserved for higher risk patients.[2,5,7]
Many current regimens utilize dexamethasone instead of prednisone during remission induction and later phases of therapy. The Children's Cancer Group (CCG) conducted a randomized trial comparing dexamethasone and prednisone in standard-risk patients, and reported that dexamethasone was associated with a superior EFS.[8] Results from another randomized trial conducted by the United Kingdom Medical Research Council (MRC) demonstrated that dexamethasone was associated with a more favorable outcome than prednisolone in all patient subgroups.[9] In the MRC trial, patients who received dexamethasone had a significantly lower incidence of both central nervous system (CNS) and non-CNS relapses than patients who received prednisolone.[9] However, a third randomized trial (conducted in Japan) did not confirm a survival advantage with dexamethasone.[10] This discrepant result might have been due to the use of a higher dose of prednisolone during induction therapy, the use of a more intensive backbone chemotherapy regimen, and/or the smaller number of patients included in that trial.
While dexamethasone may be more effective than prednisone, data also suggest that dexamethasone may also be more toxic, especially in the context of more intensive induction regimens. Several reports indicate that dexamethasone may increase the frequency and severity of infections and/or other complications in patients receiving intensive (more than three drugs) induction regimens.[11,12] The Berlin-Frankfurt-Muenster (BFM) group observed increased mortality in adolescent patients who received dexamethasone instead of prednisone during a four-drug induction regimen. However, the MRC group did not observe any toxicity or mortality differences between dexamethasone and prednisone during a four-drug induction regimen.[3] Dexamethasone appears to have a greater suppressive effect on short-term linear growth than prednisone,[13] and has been associated with a higher risk of osteonecrosis, especially in adolescent patients.[14]
Several forms of L-asparaginase are available for use in the treatment of
children with ALL, with Eschericia coli (E. coli) L-asparaginase being most commonly used.
PEG-L-asparaginase is an alternative form of L-asparaginase in which the E. coli
enzyme is modified by the covalent attachment of polyethylene glycol.
PEG-L-asparaginase has a much longer serum half-life than native E. coli
L-asparaginase, allowing it to produce asparagine depletion with less frequent
administration.[15] A single intramuscular dose of PEG-L-asparaginase given in
conjunction with vincristine and prednisone during induction therapy appears to
have similar activity and toxicity as nine doses of intramuscular E. coli
L-asparaginase (three times a week for 3 weeks).[16] In a randomized comparison of PEG-L-asparaginase versus native E. coli asparaginase in which each agent was to be given over a 30-week period following achievement of remission, similar outcome and similar rates of asparaginase-related toxicities were observed for both groups of patients.[17]
In another randomized trial in which patients with standard-risk ALL were randomly assigned to receive PEG-L-asparaginase versus native E. coli asparaginase in induction and each of two delayed intensification courses, the use of PEG-L-asparaginase was associated with more rapid blast clearance and a lower incidence of neutralizing antibodies.[16] Current COG protocols use PEG-L-asparaginase during induction for all patients with ALL. Patients with an allergic reaction to PEG-L-asparaginase should be switched to Erwinia L-asparaginase. If Erwinia L-asparaginase is utilized, the shorter half-life of the Erwinia preparation requires more frequent administration and a higher dose. In two studies, patients randomly assigned to receive Erwinia L-asparaginase on the same schedule and dosage as E. coli L-asparaginase had a significantly worse EFS.[18,19]
More than 95% of children with newly diagnosed ALL will achieve a complete remission within the first 4
weeks of treatment. Of the 2% to 4% of patients who fail to achieve complete remission within the first 4 weeks, approximately half will experience a toxic death during the induction phase (usually due to infection) and the other half will have resistant disease (persistent morphologic leukemia).[19-21] Patients who require more than 4 weeks to achieve remission have a poor
prognosis and may benefit from an allogeneic stem cell transplant once complete remission is achieved.[22-24] Outcome is also less favorable for patients who demonstrate
more than 25% blasts in the bone marrow or persistent blasts in the peripheral
blood after 1 week of intensive multiagent induction therapy,[3,25,26] and protocols of
the former CCG-based treatment decisions on the day 7 bone marrow
response (for high-risk patients) or day 14 bone marrow response (for
standard-risk patients).[27]
Options under clinical evaluation for end-induction treatment assignment
The COG is evaluating a new end-induction classification system. Standard-risk patients (aged 1–9.99 years, <50,000 white blood cell count (WBC)/µL, precursor B-cell ALL) receive a three-drug induction regimen with dexamethasone, PEG-L-asparaginase, and vincristine. High-risk precursor B-cell ALL patients receive a four-drug induction regimen including daunomycin and are randomly assigned to receive either dexamethasone for 14 days or prednisone for 28 days. Patients with T-cell ALL receive a four-drug induction regimen with prednisone as the induction steroid. Patients with ALL undergo an evaluation on day 28 that includes a bone marrow biopsy/aspiration for morphology and minimal residual disease (MRD) determinations. On the basis of day 14 marrow morphology, day 28 marrow morphology, and day 28 MRD determination, ALL patients are classified as rapid responders, slow responders, very slow responders, or induction failures. Patients with t(9;22) and hypodiploidy with fewer than 44 chromosomes move to the very high-risk protocol at the end of induction therapy, regardless of response classification. Patients with MLL gene rearrangements who do not show a rapid response also move to the very high-risk treatment protocol. Patients with ALL and slow or rapid response to induction receive consolidation on the appropriate standard or high-risk precursor B-cell ALL or T-cell treatment protocol. Patients with very slow response to induction therapy receive an additional 2 weeks of induction therapy and then have a day 42 bone marrow evaluation for morphology and MRD. Patients with an M1 day 42 marrow and less than 0.1 MRD go onto consolidation therapy; all other patients are considered induction failures and move to the very high-risk treatment protocol.
Table 1. COG End-Induction Response Classification
Early Marrow Morphology
|
MRD Day 28
|
Marrow Morphology Day 28
|
COG Classification
|
Day 7
|
Day 14
|
|
|
|
M1 |
- |
<0.1% |
M1 |
Rapid response |
M2/M3 |
M1 |
<0.1% |
M1 |
Rapid response |
- |
M2/M3 |
<1.0% |
M1 |
Slow response |
Any |
Any |
0.1%–1.0% |
M1 |
Slow response |
Any |
Any |
>1.0% |
M1, M2 |
Very slow response; extended induction |
Any |
Any |
Any |
M2 |
Very slow response; extended induction |
Any |
Any |
Any |
M3 |
Induction failure |
The Dana-Farber Cancer Institute (DFCI) ALL Consortium is also testing a new risk classification system for patients with precursor B-cell ALL. All patients are initially risk classified as either standard risk or high risk based upon age, presenting leukocyte count, and presence or absence of CNS disease. At the completion of a five-drug remission induction regimen (4 weeks from diagnosis), the level of MRD is determined. Patients with high MRD (≥0.1%) are classified as very high risk and receive a more intensive postremission consolidation. Patients with low MRD (<0.1%) continue to receive treatment based on their initial risk group classification. The goal of this new classification schema is to determine whether intensification of therapy will improve the outcome of patients with high MRD at the end of remission induction. Patients with T-cell ALL are treated as high risk, regardless of MRD status. All patients with MLL translocations or hypodiploidy (<45 chromosomes) are classified as very high-risk, regardless of MRD status or phenotype. Patients with the Philadelphia chromosome are treated as high risk, but receive an allogeneic stem cell transplant in first remission.
Central Nervous System Therapy
The early institution of adequate CNS
therapy is critical for eliminating clinically evident CNS disease at diagnosis and for preventing CNS relapse in patients without overt CNS involvement at diagnosis. IT chemotherapy is usually started at the beginning of induction, intensified during consolidation (4–8 doses of IT given every 2–3 weeks), and often continued throughout maintenance. A current goal of ALL therapy
design is to achieve effective CNS therapy while minimizing
neurotoxicity. Every patient with ALL receives IT chemotherapy with
methotrexate alone or methotrexate with cytarabine plus hydrocortisone.[28] IT methotrexate may also
have a significant systemic effect that could result in a decrease in marrow
relapse rate.[29] Historically, significant control of bone marrow relapse did not occur
until CNS therapy was instituted. Conversely, the type and extent of
systemic intensification also appears to influence the efficacy of the CNS
therapy. Systemically administered drugs such as dexamethasone,
L-asparaginase, high-dose methotrexate, and high-dose cytarabine may provide some
degree of CNS protection. For example, in a CCG study of patients with
standard-risk ALL, oral dexamethasone decreased the CNS relapse rate by 50% compared with patients receiving oral prednisone (patients received IT methotrexate alone for
CNS prophylaxis).[8]
No clinical evidence of CNS involvement at diagnosis
IT chemotherapy may be the sole form of presymptomatic CNS therapy, or
it may be combined with systemic moderate-dose to high-dose infusions of methotrexate
with leucovorin rescue and/or cranial radiation (12–18 Gy).[30] The DFCI ALL Consortium 95-01 trial randomized lower risk patients to receive either 18 Gy of cranial irradiation with IT chemotherapy or more frequently dosed IT chemotherapy alone (no radiation therapy) and demonstrated no significant difference in EFS.[19] Appropriate
systemic therapy combined with IT chemotherapy resulted in CNS relapse rates of
less than 5% for children with standard-risk ALL.[5,20,31,32] The question of whether to use triple (methotrexate, prednisone, cytarabine) IT therapy or single (methotrexate) IT therapy in nonirradiated standard-risk patients was studied as a randomized question in the CCG-1952 clinical trial.[33] The results showed an isolated CNS relapse rate of 3.4 ± 1.0% for triple IT therapy and 5.9 ± 1.2% for single IT therapy (P = .004). There were, however, more bone marrow relapses in the group that received the triple IT therapy, leading to a worse overall survival (OS) in this group (90.3 ± 1.5%) compared with the single IT therapy group (94.4 ± 1.1%; P = .01). When the analysis was restricted to patients with precursor B-cell ALL and rapid early response (M1 marrow on day 14), there was no difference between triple and single IT therapy in CNS relapse rate, OS, or EFS.[33] Patients with blasts in the cerebrospinal fluid (CSF) but less than 5 WBC/µL (CNS2) are at increased risk of CNS relapse and may require more intensive IT chemotherapy (but not cranial radiation).[34,35] Data also suggest that a traumatic lumbar puncture with blasts at the time of diagnosis is associated with an increased risk of CNS relapse, however, with more intensive IT chemotherapy, the risk is abrogated.[35,36]
Approximately 5% to 20% of children with ALL receive cranial radiation as part of their CNS-directed therapy, even if they present without CNS involvement at diagnosis, including those with T-cell phenotype and subsets of patients with high-risk precursor B-cell ALL.[37,38] Whether some or all of these patients could be as effectively treated without radiation is controversial and is currently under investigation.[39]
Toxic effects of CNS-directed therapy for childhood ALL can be divided into
two broad groups. Acute/subacute toxicities include seizures, stroke, somnolence
syndrome, and ascending paralysis. Chronic and late toxicities include
meningiomas, leukoencephalopathy and a range of neurocognitive, behavioral, and
neuroendocrine disturbances.[40,41]
Long-term deleterious effects of cranial radiation, particularly at doses higher than 18 Gy, have been recognized
for years.[42] Children receiving these higher doses of cranial radiation are at
significant risk of neurocognitive and neuroendocrine sequelae.[43-47] Young children (i.e., younger than 4 years) are at increased risk of neurocognitive decline and other sequelae following cranial radiation.[48-50] Girls may be at a higher risk of radiation-induced neuropsychologic and neuroendocrine sequelae than boys.[49-51] In general, high-dose methotrexate should not be given following cranial radiation because of the increased risk of neurologic sequelae, including leukoencephalopathy. In addition, radiation has been associated with the development of second neoplasms (many of which are benign or of low malignant potential).[47,52] Attempts at reducing the adverse sequelae of cranial radiation have included lowering the dose and utilizing alternative fractionation schedules. Children receiving 18 Gy of cranial radiation may be at diminished risk of
neurologic toxicity compared with those receiving 24 Gy,[53] although
neurocognitive and neuroendocrine effects, as well as development of second malignant neoplasms have been noted at this lower
dose.[21,48,54] In the German BFM and DFCI ALL Consortium studies, many of the patients treated with cranial radiation receive a dose of only 12 Gy.[21] Longer follow-up is needed to determine whether 12 Gy will be associated with a lower incidence of neurologic sequelae. In a randomized trial, hyperfractionated radiation (at a dose of 18 Gy) did not decrease neurologic late effects when compared with conventionally fractionated radiation, although cognitive function for both groups was not significantly impaired.[55,56][Level of evidence: 1iiC]
The most common toxicity associated with IT chemotherapy alone is seizures. Approximately 5% to 10% of patients
with ALL treated with frequent doses of IT chemotherapy will have at least one seizure during therapy.[7] Patients with ALL
who develop seizures during the course of treatment and who receive anticonvulsant therapy should not receive phenobarbital or phenytoin as
anticonvulsant treatment, as these drugs may increase the clearance of some
chemotherapeutic drugs and adversely affect treatment outcome.[57] Valproic acid or gabapentin are alternative
anticonvulsants with less enzyme-inducing capabilities.[57] In general,
patients who receive IT chemotherapy without cranial radiation as CNS
therapy appear to have a low incidence of neurocognitive sequelae, and the
deficits that do develop represent relatively modest declines in a limited
number of domains of neuropsychological functioning.[58-60] This modest decline is especially seen in young children and girls.[61] Regimens that utilize a biweekly schedule of 12 doses of intravenous high-dose
methotrexate with leucovorin rescue and IT chemotherapy in the
off-week have been associated with excessive neurologic toxicity.[62] Controversy exists about whether patients who receive dexamethasone are at higher risk
for neurocognitive disturbances.[63]
Presymptomatic CNS therapy options under clinical evaluation
The following are examples of national and/or institutional clinical trials that are currently being conducted. Information about ongoing clinical trials is available from the NCI Web site.
- In the COG-AALL0232 study, patients with high-risk precursor B-cell ALL receive either IT methotrexate alone (rapid early responders) or IT methotrexate with cranial radiation (slow early responders). One goal of this study is to determine whether oral dexamethasone, high-dose methotrexate, or both agents will decrease the incidence of CNS relapse.
- In the COG-AALL0434 protocol for patients with T-cell ALL, low-risk T-cell patients will be treated without cranial radiation, and intermediate-risk T-cell patients will receive 12 Gy (instead of 18 Gy) cranial radiation. High-risk T-cell patients will continue to receive 18 Gy cranial radiation.
- A clinical trial at St. Jude Children's Research Hospital is testing whether intensive IT and systemic chemotherapy without radiation can be used for CNS prophylaxis in all patients regardless of initial CNS status.
-
DFCI ALL Consortium Protocol 05-01 is testing whether IT chemotherapy alone can replace cranial radiation in some high-risk patients. Approximately 20% of patients will receive cranial radiation, including B-lineage patients with high presenting leukocyte counts (≥100,000 μ/L), CNS3 disease at diagnosis, or high MRD levels at the end of remission induction, and all T-cell ALL patients. The remaining 80% of patients will receive triple IT chemotherapy, but no radiation. The goal of this treatment schema is to reduce neurotoxicity and other CNS late effects without compromising efficacy by limiting the number of patients exposed to radiation and by lowering the radiation dose (12 Gy instead of 18 Gy) to those still receiving radiation.
Clinically evident CNS involvement at diagnosis
Standard treatment for ALL patients with clinically evident CNS disease (>5 WBC/μL with blasts on cytospin; CNS3) at diagnosis includes IT chemotherapy and cranial radiation (usual dose: 18 Gy). Spinal radiation is no longer used.
Treatment options under clinical evaluation
The following is an example of a national and/or institutional clinical trial that is currently being conducted. Information about ongoing clinical trials is available from the NCI Web site.
- A clinical trial at St. Jude Children's Research Hospital is testing whether patients with clinically evident CNS disease at diagnosis can be treated with intensive IT and systemic chemotherapy without radiation.
Current Clinical Trials
Check for U.S. clinical trials from NCI's PDQ Cancer Clinical Trials Registry that are now accepting patients with untreated childhood acute lymphoblastic leukemia. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.
General information about clinical trials is also available from the NCI Web site.
References
-
Pui CH, Evans WE: Treatment of acute lymphoblastic leukemia. N Engl J Med 354 (2): 166-78, 2006.
[PUBMED Abstract]
-
Tubergen DG, Gilchrist GS, O'Brien RT, et al.: Improved outcome with delayed intensification for children with acute lymphoblastic leukemia and intermediate presenting features: a Childrens Cancer Group phase III trial. J Clin Oncol 11 (3): 527-37, 1993.
[PUBMED Abstract]
-
Gaynon PS, Steinherz PG, Bleyer WA, et al.: Improved therapy for children with acute lymphoblastic leukemia and unfavorable presenting features: a follow-up report of the Childrens Cancer Group Study CCG-106. J Clin Oncol 11 (11): 2234-42, 1993.
[PUBMED Abstract]
-
LeClerc JM, Billett AL, Gelber RD, et al.: Treatment of childhood acute lymphoblastic leukemia: results of Dana-Farber ALL Consortium Protocol 87-01. J Clin Oncol 20 (1): 237-46, 2002.
[PUBMED Abstract]
-
Veerman AJ, Hählen K, Kamps WA, et al.: High cure rate with a moderately intensive treatment regimen in non-high-risk childhood acute lymphoblastic leukemia. Results of protocol ALL VI from the Dutch Childhood Leukemia Study Group. J Clin Oncol 14 (3): 911-8, 1996.
[PUBMED Abstract]
-
Chauvenet AR, Martin PL, Devidas M, et al.: Antimetabolite therapy for lesser-risk B-lineage acute lymphoblastic leukemia of childhood: a report from Children's Oncology Group Study P9201. Blood 110 (4): 1105-11, 2007.
[PUBMED Abstract]
-
Mahoney DH Jr, Shuster J, Nitschke R, et al.: Intermediate-dose intravenous methotrexate with intravenous mercaptopurine is superior to repetitive low-dose oral methotrexate with intravenous mercaptopurine for children with lower-risk B-lineage acute lymphoblastic leukemia: a Pediatric Oncology Group phase III trial. J Clin Oncol 16 (1): 246-54, 1998.
[PUBMED Abstract]
-
Bostrom BC, Sensel MR, Sather HN, et al.: Dexamethasone versus prednisone and daily oral versus weekly intravenous mercaptopurine for patients with standard-risk acute lymphoblastic leukemia: a report from the Children's Cancer Group. Blood 101 (10): 3809-17, 2003.
[PUBMED Abstract]
-
Mitchell CD, Richards SM, Kinsey SE, et al.: Benefit of dexamethasone compared with prednisolone for childhood acute lymphoblastic leukaemia: results of the UK Medical Research Council ALL97 randomized trial. Br J Haematol 129 (6): 734-45, 2005.
[PUBMED Abstract]
-
Igarashi S, Manabe A, Ohara A, et al.: No advantage of dexamethasone over prednisolone for the outcome of standard- and intermediate-risk childhood acute lymphoblastic leukemia in the Tokyo Children's Cancer Study Group L95-14 protocol. J Clin Oncol 23 (27): 6489-98, 2005.
[PUBMED Abstract]
-
Hurwitz CA, Silverman LB, Schorin MA, et al.: Substituting dexamethasone for prednisone complicates remission induction in children with acute lymphoblastic leukemia. Cancer 88 (8): 1964-9, 2000.
[PUBMED Abstract]
-
Belgaumi AF, Al-Bakrah M, Al-Mahr M, et al.: Dexamethasone-associated toxicity during induction chemotherapy for childhood acute lymphoblastic leukemia is augmented by concurrent use of daunomycin. Cancer 97 (11): 2898-903, 2003.
[PUBMED Abstract]
-
Ahmed SF, Tucker P, Mushtaq T, et al.: Short-term effects on linear growth and bone turnover in children randomized to receive prednisolone or dexamethasone. Clin Endocrinol (Oxf) 57 (2): 185-91, 2002.
[PUBMED Abstract]
-
Mattano LA Jr, Sather HN, Trigg ME, et al.: Osteonecrosis as a complication of treating acute lymphoblastic leukemia in children: a report from the Children's Cancer Group. J Clin Oncol 18 (18): 3262-72, 2000.
[PUBMED Abstract]
-
Asselin BL, Whitin JC, Coppola DJ, et al.: Comparative pharmacokinetic studies of three asparaginase preparations. J Clin Oncol 11 (9): 1780-6, 1993.
[PUBMED Abstract]
-
Avramis VI, Sencer S, Periclou AP, et al.: A randomized comparison of native Escherichia coli asparaginase and polyethylene glycol conjugated asparaginase for treatment of children with newly diagnosed standard-risk acute lymphoblastic leukemia: a Children's Cancer Group study. Blood 99 (6): 1986-94, 2002.
[PUBMED Abstract]
-
Silverman LB, Gelber RD, Dalton VK, et al.: Improved outcome for children with acute lymphoblastic leukemia: results of Dana-Farber Consortium Protocol 91-01. Blood 97 (5): 1211-8, 2001.
[PUBMED Abstract]
-
Duval M, Suciu S, Ferster A, et al.: Comparison of Escherichia coli-asparaginase with Erwinia-asparaginase in the treatment of childhood lymphoid malignancies: results of a randomized European Organisation for Research and Treatment of Cancer-Children's Leukemia Group phase 3 trial. Blood 99 (8): 2734-9, 2002.
[PUBMED Abstract]
-
Moghrabi A, Levy DE, Asselin B, et al.: Results of the Dana-Farber Cancer Institute ALL Consortium Protocol 95-01 for children with acute lymphoblastic leukemia. Blood 109 (3): 896-904, 2007.
[PUBMED Abstract]
-
Pui CH, Sandlund JT, Pei D, et al.: Improved outcome for children with acute lymphoblastic leukemia: results of Total Therapy Study XIIIB at St Jude Children's Research Hospital. Blood 104 (9): 2690-6, 2004.
[PUBMED Abstract]
-
Schrappe M, Reiter A, Ludwig WD, et al.: Improved outcome in childhood acute lymphoblastic leukemia despite reduced use of anthracyclines and cranial radiotherapy: results of trial ALL-BFM 90. German-Austrian-Swiss ALL-BFM Study Group. Blood 95 (11): 3310-22, 2000.
[PUBMED Abstract]
-
Balduzzi A, Valsecchi MG, Uderzo C, et al.: Chemotherapy versus allogeneic transplantation for very-high-risk childhood acute lymphoblastic leukaemia in first complete remission: comparison by genetic randomisation in an international prospective study. Lancet 366 (9486): 635-42, 2005 Aug 20-26.
[PUBMED Abstract]
-
Silverman LB, Gelber RD, Young ML, et al.: Induction failure in acute lymphoblastic leukemia of childhood. Cancer 85 (6): 1395-404, 1999.
[PUBMED Abstract]
-
Ogden AK, Pollock BH, Bernstein ML, et al.: Intermediate-dose methotrexate and intravenous 6-mercaptopurine chemotherapy for children with acute lymphoblastic leukemia who did not respond to initial induction therapy. J Pediatr Hematol Oncol 24 (3): 182-7, 2002 Mar-Apr.
[PUBMED Abstract]
-
Gajjar A, Ribeiro R, Hancock ML, et al.: Persistence of circulating blasts after 1 week of multiagent chemotherapy confers a poor prognosis in childhood acute lymphoblastic leukemia. Blood 86 (4): 1292-5, 1995.
[PUBMED Abstract]
-
Steinherz PG, Gaynon PS, Breneman JC, et al.: Cytoreduction and prognosis in acute lymphoblastic leukemia--the importance of early marrow response: report from the Childrens Cancer Group. J Clin Oncol 14 (2): 389-98, 1996.
[PUBMED Abstract]
-
Nachman JB, Sather HN, Sensel MG, et al.: Augmented post-induction therapy for children with high-risk acute lymphoblastic leukemia and a slow response to initial therapy. N Engl J Med 338 (23): 1663-71, 1998.
[PUBMED Abstract]
-
Pullen J, Boyett J, Shuster J, et al.: Extended triple intrathecal chemotherapy trial for prevention of CNS relapse in good-risk and poor-risk patients with B-progenitor acute lymphoblastic leukemia: a Pediatric Oncology Group study. J Clin Oncol 11 (5): 839-49, 1993.
[PUBMED Abstract]
-
Thyss A, Suciu S, Bertrand Y, et al.: Systemic effect of intrathecal methotrexate during the initial phase of treatment of childhood acute lymphoblastic leukemia. The European Organization for Research and Treatment of Cancer Children's Leukemia Cooperative Group. J Clin Oncol 15 (5): 1824-30, 1997.
[PUBMED Abstract]
-
Clarke M, Gaynon P, Hann I, et al.: CNS-directed therapy for childhood acute lymphoblastic leukemia: Childhood ALL Collaborative Group overview of 43 randomized trials. J Clin Oncol 21 (9): 1798-809, 2003.
[PUBMED Abstract]
-
Tubergen DG, Gilchrist GS, O'Brien RT, et al.: Prevention of CNS disease in intermediate-risk acute lymphoblastic leukemia: comparison of cranial radiation and intrathecal methotrexate and the importance of systemic therapy: a Childrens Cancer Group report. J Clin Oncol 11 (3): 520-6, 1993.
[PUBMED Abstract]
-
Conter V, Aricò M, Valsecchi MG, et al.: Extended intrathecal methotrexate may replace cranial irradiation for prevention of CNS relapse in children with intermediate-risk acute lymphoblastic leukemia treated with Berlin-Frankfurt-Münster-based intensive chemotherapy. The Associazione Italiana di Ematologia ed Oncologia Pediatrica. J Clin Oncol 13 (10): 2497-502, 1995.
[PUBMED Abstract]
-
Matloub Y, Lindemulder S, Gaynon PS, et al.: Intrathecal triple therapy decreases central nervous system relapse but fails to improve event-free survival when compared with intrathecal methotrexate: results of the Children's Cancer Group (CCG) 1952 study for standard-risk acute lymphoblastic leukemia, reported by the Children's Oncology Group. Blood 108 (4): 1165-73, 2006.
[PUBMED Abstract]
-
Mahmoud HH, Rivera GK, Hancock ML, et al.: Low leukocyte counts with blast cells in cerebrospinal fluid of children with newly diagnosed acute lymphoblastic leukemia. N Engl J Med 329 (5): 314-9, 1993.
[PUBMED Abstract]
-
Bürger B, Zimmermann M, Mann G, et al.: Diagnostic cerebrospinal fluid examination in children with acute lymphoblastic leukemia: significance of low leukocyte counts with blasts or traumatic lumbar puncture. J Clin Oncol 21 (2): 184-8, 2003.
[PUBMED Abstract]
-
Gajjar A, Harrison PL, Sandlund JT, et al.: Traumatic lumbar puncture at diagnosis adversely affects outcome in childhood acute lymphoblastic leukemia. Blood 96 (10): 3381-4, 2000.
[PUBMED Abstract]
-
Schrappe M, Reiter A, Riehm H: Prophylaxis and treatment of neoplastic meningeosis in childhood acute lymphoblastic leukemia. J Neurooncol 38 (2-3): 159-65, 1998 Jun-Jul.
[PUBMED Abstract]
-
Laver JH, Barredo JC, Amylon M, et al.: Effects of cranial radiation in children with high risk T cell acute lymphoblastic leukemia: a Pediatric Oncology Group report. Leukemia 14 (3): 369-73, 2000.
[PUBMED Abstract]
-
Nathan PC, Maze R, Spiegler B, et al.: CNS-directed therapy in young children with T-lineage acute lymphoblastic leukemia: High-dose methotrexate versus cranial irradiation. Pediatr Blood Cancer 42 (1): 24-9, 2004.
[PUBMED Abstract]
-
Moore IM, Espy KA, Kaufmann P, et al.: Cognitive consequences and central nervous system injury following treatment for childhood leukemia. Semin Oncol Nurs 16 (4): 279-90; discussion 291-9, 2000.
[PUBMED Abstract]
-
Goshen Y, Stark B, Kornreich L, et al.: High incidence of meningioma in cranial irradiated survivors of childhood acute lymphoblastic leukemia. Pediatr Blood Cancer 49 (3): 294-7, 2007.
[PUBMED Abstract]
-
Eiser C, Tillmann V: Learning difficulties in children treated for acute lymphoblastic leukaemia (ALL). Pediatr Rehabil 4 (3): 105-18, 2001 Jul-Sep.
[PUBMED Abstract]
-
Stubberfield TG, Byrne GC, Jones TW: Growth and growth hormone secretion after treatment for acute lymphoblastic leukemia in childhood. 18-Gy versus 24-Gy cranial irradiation. J Pediatr Hematol Oncol 17 (2): 167-71, 1995.
[PUBMED Abstract]
-
Rowland JH, Glidewell OJ, Sibley RF, et al.: Effects of different forms of central nervous system prophylaxis on neuropsychologic function in childhood leukemia. J Clin Oncol 2 (12): 1327-35, 1984.
[PUBMED Abstract]
-
Halberg FE, Kramer JH, Moore IM, et al.: Prophylactic cranial irradiation dose effects on late cognitive function in children treated for acute lymphoblastic leukemia. Int J Radiat Oncol Biol Phys 22 (1): 13-6, 1992.
[PUBMED Abstract]
-
Hill JM, Kornblith AB, Jones D, et al.: A comparative study of the long term psychosocial functioning of childhood acute lymphoblastic leukemia survivors treated by intrathecal methotrexate with or without cranial radiation. Cancer 82 (1): 208-18, 1998.
[PUBMED Abstract]
-
Pui CH, Cheng C, Leung W, et al.: Extended follow-up of long-term survivors of childhood acute lymphoblastic leukemia. N Engl J Med 349 (7): 640-9, 2003.
[PUBMED Abstract]
-
Jankovic M, Brouwers P, Valsecchi MG, et al.: Association of 1800 cGy cranial irradiation with intellectual function in children with acute lymphoblastic leukaemia. ISPACC. International Study Group on Psychosocial Aspects of Childhood Cancer. Lancet 344 (8917): 224-7, 1994.
[PUBMED Abstract]
-
Sklar C, Mertens A, Walter A, et al.: Final height after treatment for childhood acute lymphoblastic leukemia: comparison of no cranial irradiation with 1800 and 2400 centigrays of cranial irradiation. J Pediatr 123 (1): 59-64, 1993.
[PUBMED Abstract]
-
Christie D, Leiper AD, Chessells JM, et al.: Intellectual performance after presymptomatic cranial radiotherapy for leukaemia: effects of age and sex. Arch Dis Child 73 (2): 136-40, 1995.
[PUBMED Abstract]
-
Waber DP, Tarbell NJ, Kahn CM, et al.: The relationship of sex and treatment modality to neuropsychologic outcome in childhood acute lymphoblastic leukemia. J Clin Oncol 10 (5): 810-7, 1992.
[PUBMED Abstract]
-
Löning L, Zimmermann M, Reiter A, et al.: Secondary neoplasms subsequent to Berlin-Frankfurt-Münster therapy of acute lymphoblastic leukemia in childhood: significantly lower risk without cranial radiotherapy. Blood 95 (9): 2770-5, 2000.
[PUBMED Abstract]
-
Waber DP, Shapiro BL, Carpentieri SC, et al.: Excellent therapeutic efficacy and minimal late neurotoxicity in children treated with 18 grays of cranial radiation therapy for high-risk acute lymphoblastic leukemia: a 7-year follow-up study of the Dana-Farber Cancer Institute Consortium Protocol 87-01. Cancer 92 (1): 15-22, 2001.
[PUBMED Abstract]
-
Hata M, Ogino I, Aida N, et al.: Prophylactic cranial irradiation of acute lymphoblastic leukemia in childhood: outcomes of late effects on pituitary function and growth in long-term survivors. Int J Cancer 96 (Suppl): 117-24, 2001.
[PUBMED Abstract]
-
Waber DP, Silverman LB, Catania L, et al.: Outcomes of a randomized trial of hyperfractionated cranial radiation therapy for treatment of high-risk acute lymphoblastic leukemia: therapeutic efficacy and neurotoxicity. J Clin Oncol 22 (13): 2701-7, 2004.
[PUBMED Abstract]
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Waber DP, Turek J, Catania L, et al.: Neuropsychological outcomes from a randomized trial of triple intrathecal chemotherapy compared with 18 Gy cranial radiation as CNS treatment in acute lymphoblastic leukemia: findings from Dana-Farber Cancer Institute ALL Consortium Protocol 95-01. J Clin Oncol 25 (31): 4914-21, 2007.
[PUBMED Abstract]
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Relling MV, Pui CH, Sandlund JT, et al.: Adverse effect of anticonvulsants on efficacy of chemotherapy for acute lymphoblastic leukaemia. Lancet 356 (9226): 285-90, 2000.
[PUBMED Abstract]
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Jansen NC, Kingma A, Schuitema A, et al.: Post-treatment intellectual functioning in children treated for acute lymphoblastic leukaemia (ALL) with chemotherapy-only: a prospective, sibling-controlled study. Eur J Cancer 42 (16): 2765-72, 2006.
[PUBMED Abstract]
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Espy KA, Moore IM, Kaufmann PM, et al.: Chemotherapeutic CNS prophylaxis and neuropsychologic change in children with acute lymphoblastic leukemia: a prospective study. J Pediatr Psychol 26 (1): 1-9, 2001 Jan-Feb.
[PUBMED Abstract]
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Copeland DR, Moore BD 3rd, Francis DJ, et al.: Neuropsychologic effects of chemotherapy on children with cancer: a longitudinal study. J Clin Oncol 14 (10): 2826-35, 1996.
[PUBMED Abstract]
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von der Weid N, Mosimann I, Hirt A, et al.: Intellectual outcome in children and adolescents with acute lymphoblastic leukaemia treated with chemotherapy alone: age- and sex-related differences. Eur J Cancer 39 (3): 359-65, 2003.
[PUBMED Abstract]
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Mahoney DH Jr, Shuster JJ, Nitschke R, et al.: Acute neurotoxicity in children with B-precursor acute lymphoid leukemia: an association with intermediate-dose intravenous methotrexate and intrathecal triple therapy--a Pediatric Oncology Group study. J Clin Oncol 16 (5): 1712-22, 1998.
[PUBMED Abstract]
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Waber DP, Carpentieri SC, Klar N, et al.: Cognitive sequelae in children treated for acute lymphoblastic leukemia with dexamethasone or prednisone. J Pediatr Hematol Oncol 22 (3): 206-13, 2000 May-Jun.
[PUBMED Abstract]
Back to Top Childhood Acute Lymphoblastic Leukemia in Remission
Consolidation/Intensification
Once remission has been achieved, systemic treatment in conjunction with
central nervous system (CNS) sanctuary therapy follows. The intensity of the
postinduction chemotherapy varies considerably, but all patients receive some
form of intensification following achievement of remission and before
beginning continuous maintenance therapy. Intensification may involve the
use of intermediate-dose or high-dose methotrexate,[1-4] the use of similar drugs
as those used to achieve remission,[2,5] the use of different drug combinations
with little known cross resistance to the induction therapy drug
combination,[2,6] the extended use of high-dose L-asparaginase,[7] or
combinations of the above.[2,8-10]
In children with standard-risk disease, there has been an attempt to limit
exposure to drugs, such as the anthracyclines and alkylating agents, that are
associated with an increased risk of late toxic effects.[3,11,12] For example,
regimens utilizing a limited number of courses of intermediate-dose or high-dose
methotrexate have been used with good results for treating children with
standard-risk acute lymphoblastic leukemia (ALL).[1,3,4,11] Extended use of high-dose asparaginase reduced patients' exposure to alkylating agents and anthracyclines.[7,13] Another treatment
approach for decreasing late effects of therapy utilizes anthracyclines and
alkylating agents but limits their cumulative dose to an amount not associated
with substantial long-term toxicity. An example of this approach is the use of
delayed intensification, in which patients receive an anthracycline-based
reinduction regimen and a cyclophosphamide-containing reconsolidation
regimen at approximately 3 months after remission is achieved. The use of
delayed intensification improves outcome for children with standard-risk ALL,
in comparison to that achieved without an intensification phase.[14-16] In a Children's Cancer Group (CCG) study, which included a three-drug induction and utilized prednisone as the corticosteroid throughout all treatment phases, two blocks of delayed intensification produced a small event-free survival (EFS) benefit compared with one block of delayed intensification in intermediate-risk patients.[17]
The benefit of two blocks of delayed intensification, however, may depend, in part, on the type of corticosteroid used (prednisone vs. dexamethasone). In a subsequent CCG study for standard-risk ALL in which dexamethasone was used instead of prednisone, two blocks of delayed intensification were not associated with a survival benefit in patients who were rapid early responders.[18]
In high-risk patients, a number of different approaches have been used with
comparable efficacy.[6,7,19-21] Treatment for high-risk patients generally
includes blocks of intensified therapy, such as the delayed intensification
blocks (reinduction/reconsolidation) used by the former CCG
and by the German Berlin-Frankfurt-Munster (BFM) group.[2,8,19] For high-risk
patients with slow early response to therapy (M3 marrow on day 7 of induction
therapy), augmented BFM therapy has been shown to improve outcome, particularly for younger patients.[22] The
augmented BFM regimen utilizes two courses of delayed intensification, while
also intensifying therapy with repeated courses of intravenous methotrexate
(without leucovorin rescue) given with vincristine and asparaginase as well as additional vincristine/L-asparaginase pulses during consolidation and delayed intensification phases. Similarly, in an Italian study, investigators showed that two applications of delayed intensification therapy (protocol II) significantly improved outcome for patients with a poor response to prednisone.[23]
The augmented BFM regimen has also been evaluated in children with high-risk ALL and a rapid response to induction therapy. For these children, augmented intensity during consolidation, interim maintenance, and delayed intensification resulted in a higher EFS rate than that achieved with standard-intensity treatment. Increased duration of intensive therapy was not beneficial, and a single application of delayed intensification was as effective as two applications. [24][Level of evidence: 1iiA] Of note, there is a significant incidence of avascular necrosis of bone in teenaged patients who receive the augmented BFM regimen.[25]
Maintenance
The backbone of maintenance therapy in most protocols includes daily oral
mercaptopurine and weekly oral methotrexate. If the patient has not had
cranial radiation, intrathecal chemotherapy for CNS sanctuary therapy is
continued during maintenance therapy. Clinical trials generally call for
giving oral mercaptopurine in the evening, which is supported by evidence that
this practice may improve EFS.[26] It is imperative to
carefully monitor children on maintenance therapy for both drug-related
toxicity and for compliance with the oral chemotherapy agents used during
maintenance therapy.[27] Treating physicians must also recognize that some patients may develop severe hematopoietic toxicity when
receiving conventional dosages of mercaptopurine because of an inherited
deficiency (homozygous mutant) of thiopurine S-methyltransferase, an enzyme that inactivates
mercaptopurine.[28,29] These patients are able to tolerate mercaptopurine only
if dosages much lower than those conventionally used are administered.[28,29]
Patients who are heterozygous for this mutant enzyme gene generally tolerate
mercaptopurine without serious toxicity, but they do require more frequent dose
reductions for hematopoietic toxicity than patients who are homozygous for the
normal allele.[28]
The use of continuous 6-thioguanine (6-TG) instead of 6-mercaptopurine (6-MP) during the maintenance phase is associated with an increased risk of hepatic complications, including veno-occlusive disease and portal hypertension.[30-33] Because of the risk of hepatic complications, 6-TG is no longer utilized in maintenance therapy in any protocol. It remains unknown if short term use of 6-TG can improve outcome without excessive toxicity.
Pulses of vincristine and corticosteroid are often added to the
standard maintenance backbone, although the benefit of these pulses within the context of intensive, multiagent regimens remains somewhat controversial. A CCG randomized trial demonstrated improved
outcome in patients receiving monthly vincristine/prednisone pulses,[34] and a
meta-analysis combining data from six clinical trials showed an EFS advantage for vincristine/prednisone pulses.[35] However, in a multicenter randomized trial in children with intermediate-risk ALL being treated on a BFM regimen, there was no benefit associated with the addition of six pulses of vincristine/dexamethasone during the continuation phase, although the pulses were administered less frequently than in other trials in which a benefit had been demonstrated.[36] When pulses are used during the maintenance phase, dexamethasone is
preferred over prednisone for younger patients based on data from a
CCG study, in which dexamethasone was compared to prednisone for children aged 1 to
9 years with lower-risk ALL.[14,37] On that trial, patients randomized to receive
dexamethasone had significantly fewer CNS relapses and a significantly better
EFS rate.[14,37] In a Medical Research Council trial comparing dexamethasone versus prednisolone during induction and maintenance therapies in both standard- and high-risk patients, the EFS and incidence of both CNS and non-CNS relapses improved with the use of dexamethasone.[38] The benefit of using dexamethasone in
adolescents requires further investigation because of the increased risk of steroid-induced osteonecrosis and a higher incidence of bone fractures in this age
group.[39,40]
Maintenance chemotherapy generally continues until 2 to 3 years of continuous
complete remission. Extending the duration of maintenance therapy to 5 years
does not improve outcome.[35]
Treatment options under clinical evaluation
The following are examples of national and/or institutional clinical trials that are currently being conducted. Information about ongoing clinical trials is available from the NCI Web site.
Risk-based treatment assignment is a key therapeutic strategy utilized for
children with ALL, and protocols are designed for specific patient populations
that have varying degrees of risk for treatment failure. The Cellular
Classification and Prognostic Variables section of this summary describes the
clinical and laboratory features used for the initial stratification of
children with ALL into risk-based treatment groups.
Children's Oncology Group (COG) protocols
COG studies for standard-risk ALL
The current COG standard-risk ALL study divides patients into rapid-responder and slow-responder subgroups. Rapid responders are assigned to two separate groups based on cytogenetics. Patients with triple trisomy (chromosomes 4, 10, and 17) or a TEL-AML1 translocation are considered low risk. These patients are randomly assigned to receive standard therapy (simple consolidation, interim maintenance, delayed intensification, and maintenance) with or without additional PEG-L-asparaginase during consolidation and interim maintenance. Patients with ALL and rapid response, who do not have triple trisomy or TEL-AML1 (classified as standard-risk average group), are randomly assigned to receive treatment in a 2 × 2 factorial design to evaluate various components of the hemiaugmented BFM regimen.
Standard-risk ALL patients with slow early response disease receive the fully augmented BFM regimen.
COG studies for high-risk ALL
In the COG trials, patients with ALL and rapid response to induction therapy receive hemiaugmented BFM, while patients with slow response receive the fully augmented BFM regimen. There are two randomized groups in the COG high-risk precursor B-cell ALL protocol (AALL032). During induction, patients are randomly assigned to receive either dexamethasone (14 days) or prednisone (28 days). All patients receive dexamethasone during delayed intensification (DI) and maintenance phases. During the first interim maintenance phase, patients receive either Capizzi methotrexate or high-dose methotrexate with leucovorin rescue as given in BFM protocols.
COG studies for children at very high risk of relapse
The COG is evaluating high-dose intermittent chemotherapy, including high doses of methotrexate, high-dose cytosine arabinoside, and ifosfamide in patients with t(9;22), patients with hypodiploid ALL with fewer than 44 chromosomes, and patients with MLL gene rearrangements and slow early response who attain remission. Patients with induction failure are also eligible for this trial. Patients with a matched sibling donor will receive a bone marrow transplant in first remission.
Other Protocols
- A study at St. Jude Children’s Research Hospital is testing intensified chemotherapy with antimetabolites and asparaginase including double-reinduction therapy to determine whether this regimen can increase overall survival and whether cranial radiation can be omitted in all patients.
-
The Dana-Farber Cancer Institute Consortium Protocol 05-01 is comparing the relative efficacy and toxicity of intravenous PEG-L-asparaginase with intramuscular E. coli asparaginase during postinduction consolidation for patients in all risk groups. The protocol is also testing whether an intensified consolidation improves the outcome for very high-risk patients (patients with high minimal residual disease at the end of remission induction, MLL gene rearrangements, or hypodiploidy <45 chromosomes).
Current Clinical Trials
Check for U.S. clinical trials from NCI's PDQ Cancer Clinical Trials Registry that are now accepting patients with childhood acute lymphoblastic leukemia in remission. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.
General information about clinical trials is also available from the NCI Web site.
References
-
Harris MB, Shuster JJ, Pullen DJ, et al.: Consolidation therapy with antimetabolite-based therapy in standard-risk acute lymphocytic leukemia of childhood: a Pediatric Oncology Group Study. J Clin Oncol 16 (8): 2840-7, 1998.
[PUBMED Abstract]
-
Schrappe M, Reiter A, Ludwig WD, et al.: Improved outcome in childhood acute lymphoblastic leukemia despite reduced use of anthracyclines and cranial radiotherapy: results of trial ALL-BFM 90. German-Austrian-Swiss ALL-BFM Study Group. Blood 95 (11): 3310-22, 2000.
[PUBMED Abstract]
-
Veerman AJ, Hählen K, Kamps WA, et al.: High cure rate with a moderately intensive treatment regimen in non-high-risk childhood acute lymphoblastic leukemia. Results of protocol ALL VI from the Dutch Childhood Leukemia Study Group. J Clin Oncol 14 (3): 911-8, 1996.
[PUBMED Abstract]
-
Mahoney DH Jr, Shuster JJ, Nitschke R, et al.: Intensification with intermediate-dose intravenous methotrexate is effective therapy for children with lower-risk B-precursor acute lymphoblastic leukemia: A Pediatric Oncology Group study. J Clin Oncol 18 (6): 1285-94, 2000.
[PUBMED Abstract]
-
Tubergen DG, Gilchrist GS, O'Brien RT, et al.: Improved outcome with delayed intensification for children with acute lymphoblastic leukemia and intermediate presenting features: a Childrens Cancer Group phase III trial. J Clin Oncol 11 (3): 527-37, 1993.
[PUBMED Abstract]
-
Richards S, Burrett J, Hann I, et al.: Improved survival with early intensification: combined results from the Medical Research Council childhood ALL randomised trials, UKALL X and UKALL XI. Medical Research Council Working Party on Childhood Leukaemia. Leukemia 12 (7): 1031-6, 1998.
[PUBMED Abstract]
-
Silverman LB, Gelber RD, Dalton VK, et al.: Improved outcome for children with acute lymphoblastic leukemia: results of Dana-Farber Consortium Protocol 91-01. Blood 97 (5): 1211-8, 2001.
[PUBMED Abstract]
-
Hann I, Vora A, Richards S, et al.: Benefit of intensified treatment for all children with acute lymphoblastic leukaemia: results from MRC UKALL XI and MRC ALL97 randomised trials. UK Medical Research Council's Working Party on Childhood Leukaemia. Leukemia 14 (3): 356-63, 2000.
[PUBMED Abstract]
-
Harris MB, Shuster JJ, Pullen J, et al.: Treatment of children with early pre-B and pre-B acute lymphocytic leukemia with antimetabolite-based intensification regimens: a Pediatric Oncology Group Study. Leukemia 14 (9): 1570-6, 2000.
[PUBMED Abstract]
-
Rizzari C, Valsecchi MG, Aricò M, et al.: Effect of protracted high-dose L-asparaginase given as a second exposure in a Berlin-Frankfurt-Münster-based treatment: results of the randomized 9102 intermediate-risk childhood acute lymphoblastic leukemia study--a report from the Associazione Italiana Ematologia Oncologia Pediatrica. J Clin Oncol 19 (5): 1297-303, 2001.
[PUBMED Abstract]
-
Chauvenet AR, Martin PL, Devidas M, et al.: Antimetabolite therapy for lesser-risk B-lineage acute lymphoblastic leukemia of childhood: a report from Children's Oncology Group Study P9201. Blood 110 (4): 1105-11, 2007.
[PUBMED Abstract]
-
Gustafsson G, Kreuger A, Clausen N, et al.: Intensified treatment of acute childhood lymphoblastic leukaemia has improved prognosis, especially in non-high-risk patients: the Nordic experience of 2648 patients diagnosed between 1981 and 1996. Nordic Society of Paediatric Haematology and Oncology (NOPHO) Acta Paediatr 87 (11): 1151-61, 1998.
[PUBMED Abstract]
-
Pession A, Valsecchi MG, Masera G, et al.: Long-term results of a randomized trial on extended use of high dose L-asparaginase for standard risk childhood acute lymphoblastic leukemia. J Clin Oncol 23 (28): 7161-7, 2005.
[PUBMED Abstract]
-
Gaynon PS, Trigg ME, Heerema NA, et al.: Children's Cancer Group trials in childhood acute lymphoblastic leukemia: 1983-1995. Leukemia 14 (12): 2223-33, 2000.
[PUBMED Abstract]
-
Riehm H, Gadner H, Henze G, et al.: Results and significance of six randomized trials in four consecutive ALL-BFM studies. Hamatol Bluttransfus 33: 439-50, 1990.
[PUBMED Abstract]
-
Hutchinson RJ, Gaynon PS, Sather H, et al.: Intensification of therapy for children with lower-risk acute lymphoblastic leukemia: long-term follow-up of patients treated on Children's Cancer Group Trial 1881. J Clin Oncol 21 (9): 1790-7, 2003.
[PUBMED Abstract]
-
Lange BJ, Bostrom BC, Cherlow JM, et al.: Double-delayed intensification improves event-free survival for children with intermediate-risk acute lymphoblastic leukemia: a report from the Children's Cancer Group. Blood 99 (3): 825-33, 2002.
[PUBMED Abstract]
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Matloub Y, Angiolillo A, Bostrom B, et al.: Double delayed intensification (DDI) is equivalent to single DI (SDI) in children with National Cancer Institute (NCI) standard-risk acute lymphoblastic leukemia (SR-ALL) treated on Children's Cancer Group (CCG) clinical trial 1991 (CCG-1991). [Abstract] Blood 108 (11): A-146, 2006.
-
Gaynon PS, Steinherz PG, Bleyer WA, et al.: Improved therapy for children with acute lymphoblastic leukemia and unfavorable presenting features: a follow-up report of the Childrens Cancer Group Study CCG-106. J Clin Oncol 11 (11): 2234-42, 1993.
[PUBMED Abstract]
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Pui CH, Mahmoud HH, Rivera GK, et al.: Early intensification of intrathecal chemotherapy virtually eliminates central nervous system relapse in children with acute lymphoblastic leukemia. Blood 92 (2): 411-5, 1998.
[PUBMED Abstract]
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Lauer SJ, Shuster JJ, Mahoney DH Jr, et al.: A comparison of early intensive methotrexate/mercaptopurine with early intensive alternating combination chemotherapy for high-risk B-precursor acute lymphoblastic leukemia: a Pediatric Oncology Group phase III randomized trial. Leukemia 15 (7): 1038-45, 2001.
[PUBMED Abstract]
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Nachman J, Sather HN, Gaynon PS, et al.: Augmented Berlin-Frankfurt-Munster therapy abrogates the adverse prognostic significance of slow early response to induction chemotherapy for children and adolescents with acute lymphoblastic leukemia and unfavorable presenting features: a report from the Children's Cancer Group. J Clin Oncol 15 (6): 2222-30, 1997.
[PUBMED Abstract]
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Aricò M, Valsecchi MG, Conter V, et al.: Improved outcome in high-risk childhood acute lymphoblastic leukemia defined by prednisone-poor response treated with double Berlin-Frankfurt-Muenster protocol II. Blood 100 (2): 420-6, 2002.
[PUBMED Abstract]
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Seibel NL, Steinherz PG, Sather HN, et al.: Early postinduction intensification therapy improves survival for children and adolescents with high-risk acute lymphoblastic leukemia: a report from the Children's Oncology Group. Blood 111 (5): 2548-55, 2008.
[PUBMED Abstract]
-
Mattano LA Jr, Sather HN, Trigg ME, et al.: Osteonecrosis as a complication of treating acute lymphoblastic leukemia in children: a report from the Children's Cancer Group. J Clin Oncol 18 (18): 3262-72, 2000.
[PUBMED Abstract]
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Schmiegelow K, Glomstein A, Kristinsson J, et al.: Impact of morning versus evening schedule for oral methotrexate and 6-mercaptopurine on relapse risk for children with acute lymphoblastic leukemia. Nordic Society for Pediatric Hematology and Oncology (NOPHO). J Pediatr Hematol Oncol 19 (2): 102-9, 1997 Mar-Apr.
[PUBMED Abstract]
-
Davies HA, Lilleyman JS: Compliance with oral chemotherapy in childhood lymphoblastic leukaemia. Cancer Treat Rev 21 (2): 93-103, 1995.
[PUBMED Abstract]
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Relling MV, Hancock ML, Rivera GK, et al.: Mercaptopurine therapy intolerance and heterozygosity at the thiopurine S-methyltransferase gene locus. J Natl Cancer Inst 91 (23): 2001-8, 1999.
[PUBMED Abstract]
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Andersen JB, Szumlanski C, Weinshilboum RM, et al.: Pharmacokinetics, dose adjustments, and 6-mercaptopurine/methotrexate drug interactions in two patients with thiopurine methyltransferase deficiency. Acta Paediatr 87 (1): 108-11, 1998.
[PUBMED Abstract]
-
Broxson EH, Dole M, Wong R, et al.: Portal hypertension develops in a subset of children with standard risk acute lymphoblastic leukemia treated with oral 6-thioguanine during maintenance therapy. Pediatr Blood Cancer 44 (3): 226-31, 2005.
[PUBMED Abstract]
-
De Bruyne R, Portmann B, Samyn M, et al.: Chronic liver disease related to 6-thioguanine in children with acute lymphoblastic leukaemia. J Hepatol 44 (2): 407-10, 2006.
[PUBMED Abstract]
-
Vora A, Mitchell CD, Lennard L, et al.: Toxicity and efficacy of 6-thioguanine versus 6-mercaptopurine in childhood lymphoblastic leukaemia: a randomised trial. Lancet 368 (9544): 1339-48, 2006.
[PUBMED Abstract]
-
Jacobs SS, Stork LC, Bostrom BC, et al.: Substitution of oral and intravenous thioguanine for mercaptopurine in a treatment regimen for children with standard risk acute lymphoblastic leukemia: a collaborative Children's Oncology Group/National Cancer Institute pilot trial (CCG-1942). Pediatr Blood Cancer 49 (3): 250-5, 2007.
[PUBMED Abstract]
-
Bleyer WA, Sather HN, Nickerson HJ, et al.: Monthly pulses of vincristine and prednisone prevent bone marrow and testicular relapse in low-risk childhood acute lymphoblastic leukemia: a report of the CCG-161 study by the Childrens Cancer Study Group. J Clin Oncol 9 (6): 1012-21, 1991.
[PUBMED Abstract]
-
Duration and intensity of maintenance chemotherapy in acute lymphoblastic leukaemia: overview of 42 trials involving 12 000 randomised children. Childhood ALL Collaborative Group. Lancet 347 (9018): 1783-8, 1996.
[PUBMED Abstract]
-
Conter V, Valsecchi MG, Silvestri D, et al.: Pulses of vincristine and dexamethasone in addition to intensive chemotherapy for children with intermediate-risk acute lymphoblastic leukaemia: a multicentre randomised trial. Lancet 369 (9556): 123-31, 2007.
[PUBMED Abstract]
-
Bostrom BC, Sensel MR, Sather HN, et al.: Dexamethasone versus prednisone and daily oral versus weekly intravenous mercaptopurine for patients with standard-risk acute lymphoblastic leukemia: a report from the Children's Cancer Group. Blood 101 (10): 3809-17, 2003.
[PUBMED Abstract]
-
Mitchell CD, Richards SM, Kinsey SE, et al.: Benefit of dexamethasone compared with prednisolone for childhood acute lymphoblastic leukaemia: results of the UK Medical Research Council ALL97 randomized trial. Br J Haematol 129 (6): 734-45, 2005.
[PUBMED Abstract]
-
Ojala AE, Lanning FP, Pääkkö E, et al.: Osteonecrosis in children treated for acute lymphoblastic leukemia: a magnetic resonance imaging study after treatment. Med Pediatr Oncol 29 (4): 260-5, 1997.
[PUBMED Abstract]
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Strauss AJ, Su JT, Dalton VM, et al.: Bony morbidity in children treated for acute lymphoblastic leukemia. J Clin Oncol 19 (12): 3066-72, 2001.
[PUBMED Abstract]
Back to Top Postinduction Treatment for Childhood Acute Lymphoblastic Leukemia Subgroups
T-cell Acute Lymphoblastic Leukemia
Historically, patients with T-cell acute lymphoblastic leukemia (ALL) have had a worse prognosis than children with precursor B-cell ALL. With current treatment regimens, outcomes for children with T-cell ALL are now approaching those achieved for children with precursor B-cell ALL. For example, the 5-year event-free survival (EFS) for children with T-cell ALL treated on the Dana-Farber Cancer Institute (DFCI) Consortium ALL protocols was 75% compared with 84% for children with precursor B-cell ALL.[1]
Protocols of the former Pediatric Oncology Group (POG) treated children with T-cell ALL distinctly from children with B-lineage ALL. The POG-9404 protocol for patients with T-cell ALL was designed to evaluate the role of high-dose methotrexate and the role of the cardioprotectant dexrazoxane. The multiagent chemotherapy backbone for this protocol was based on the DFCI 87-001 regimen. Results of an interim analysis of the POG protocol led investigators to conclude that the addition of high-dose methotrexate to the DFCI-based chemotherapy regimen results in significantly improved EFS, due in large measure to a decrease in the rate of central nervous system (CNS) relapse.[2] This POG study was the first clinical trial to provide convincing evidence that high-dose methotrexate can improve outcome for children with T-cell ALL. High-dose asparaginase and doxorubicin were also important components of this regimen.[1,2]
Protocols of the former Children’s Cancer Group (CCG) treated children with T-cell ALL on the same treatment regimens as children with precursor B-cell ALL, basing protocol and treatment assignment on the patients' clinical characteristics (e.g., age and white blood cell count [WBC]) and the disease response to initial therapy. Most children with T-cell ALL meet National Cancer Institute (NCI) high-risk criteria. Results from CCG-1961 showed that an augmented Berlin-Frankfurt-Munster (BFM) regimen with a single delayed intensification course produced the best results for patients with morphologic rapid response to initial induction therapy.[3] Almost 60% of events in this group, however, were isolated CNS relapses. Overall results from POG-9404 and CCG-1961 were similar, though POG-9404 used cranial radiation for every patient while CCG-1961 used cranial radiation only for patients with slow morphologic response.[4,2] Among children with NCI standard-risk T-cell ALL, the EFS for children treated on CCG-1952 and CCG-1991 studies was inferior to the EFS for children treated on the POG-9404 study.[5]
In the Children’s Oncology Group (COG), children with T-cell ALL are no longer treated on the same protocols as children with precursor B-cell ALL. All patients with T-cell ALL are considered high risk regardless of age and WBC count. Pilot studies from this group have demonstrated the feasibility of incorporating nelarabine (a nucleoside analog with demonstrated activity in patients with relapsed and refractory T-cell lymphoblastic disease) [6,7] in the context of a BFM backbone for patients with newly diagnosed T-cell ALL; efficacy will be evaluated in the current trial.[8]
Treatment options under clinical evaluation
The following is an example of a national and/or institutional clinical trial that is currently being conducted. Information about ongoing clinical trials is available from the NCI Web site.
- COG protocol AALL0434 is a phase III trial for patients aged 1 to 30 years with T-cell ALL utilizing a hemi-augmented BFM backbone. Patients are classified into one of three risk groups (low, intermediate, or high) based on NCI age/leukocyte criteria, CNS status at diagnosis, morphologic marrow response on days 15 and 29, and minimal residual disease (MRD) level at day 29. The objectives of the trial are 1) to determine the safety and efficacy of adding nelarabine to the augmented BFM regimen in high and intermediate risk patients, 2) to determine the relative safety and efficacy of high-dose versus Capizzi dose methotrexate during interim maintenance, and 3) to test the efficacy of treating low-risk T-cell ALL patients without cranial radiation.
Current Clinical Trials
Check for U.S. clinical trials from NCI's PDQ Cancer Clinical Trials Registry that are now accepting patients with T-cell childhood acute lymphoblastic leukemia. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.
General information about clinical trials is also available from the NCI Web site.
Infants With Acute Lymphoblastic Leukemia
Infant ALL is uncommon, representing approximately 2% to 4% of cases of childhood ALL.[9] Because of their distinctive biological characteristics and their high risk for
leukemia recurrence, infants with ALL are treated on protocols specifically
designed for this patient population. Despite intensification of therapy, long-term EFS rates from recent trials remain below 50%, and for those infants with MLL gene rearrangement the EFS rates continue to be in the 30% to 40% range.[10-13] Common therapeutic themes of the intensive chemotherapy regimens used to treat infants with ALL are the inclusion of postinduction intensification courses with high doses of cytarabine and methotrexate.[11,13,14]
Treating infants with and without MLL gene rearrangements with different treatment protocols has been evaluated in a Japanese study. A favorable outcome was obtained with antimetabolite-based therapy for MLL-germline (nonrearranged) patients, while outcome remained unfavorable, despite intensive chemotherapy, for infants with MLL gene rearrangements.[10] An additional study from Japan confirms the good outcome of infants without MLL gene rearrangements.[10] This raises the question whether infants with B-lineage immunophenotype and germline MLL configuration should be treated on the same protocols as similar patients older than 1 year, although infants without MLL gene rearrangements treated on the Interfant-99 also had favorable outcome (4-year EFS of 74%).[13]
The role of bone marrow transplantation in infants with MLL-rearranged ALL remains controversial. Case series have suggested that allogeneic transplants in first remission may be effective;[15-17] in a retrospective analysis of 256 patients initially treated between 1983 and 1995, however, no benefit was observed for any type of allogeneic stem cell transplant compared with intensive chemotherapy without transplant.[18] Similarly, in the Interfant-99 study after adjusting for waiting time to transplantation, high-risk patients who underwent hematopoietic stem cell transplantation had 4-year disease-free survival (DFS) rates that did not significantly differ from those of high-risk patients treated with chemotherapy alone.[13] A COG study of infants with ALL observed that patients with MLL gene rearrangements who underwent transplantation in first remission as per protocol had outcome inferior to a comparable group of infants who completed treatment with chemotherapy.[11]
Treatment options under clinical evaluation
The following is an example of a national and/or institutional clinical trial that is currently being conducted. Information about ongoing clinical trials is available from the NCI Web site.
- The Interfant-06 Study Group is conducting an international collaborative randomized trial (including sites in the United States) to test whether an ALL/AML hybrid regimen might improve outcomes for infants with MLL-rearranged ALL. The role of allogeneic transplantation in first remission is also being assessed in high-risk patients (defined as MLL-rearranged, younger than 6 months, and WBC >300,000 u/L).
Adolescent Patients with ALL
Older children and adolescents (10 years or older) with ALL more frequently present with adverse prognostic factors at diagnosis, including T-cell immunophenotype, and a lower incidence of favorable cytogenetic abnormalities.[19,20] These patients have a less favorable outcome than children aged 1 to 9 years at diagnosis, and more aggressive treatments are generally employed for them.[21] A study from France of 15- to 20-year-old patients diagnosed between 1993 and 1999, demonstrated superior outcome for patients treated on a pediatric trial (67%; 5-year EFS) compared with patients treated on an adult trial (41%; 5-year EFS).[22] Other studies have confirmed that older adolescent patients fare better on pediatric rather than adult regimens.[20,23,24] For instance, the DFCI ALL Consortium reported a 5-year EFS of 78% in adolescents aged 15 to 18 years.[23] The reason for this difference is not known, although possible explanations include treatment setting (i.e., site experience in treating ALL), adherence to protocol therapy, and the components of protocol therapy.[23] Adolescents with ALL appear to be at higher risk than younger children for developing therapy-related complications, including osteonecrosis, deep venous thromboses, and pancreatitis.[20,25-27] High body mass index is also a risk factor for osteonecrosis,[28] and may be associated with a higher relapse rate in older patients.[29]
Philadelphia Chromosome–Positive Acute Lymphoblastic Leukemia
Hematopoietic stem cell transplantation (HSCT) from a matched sibling donor is the treatment of choice for patients with Philadelphia chromosome–positive (Ph+) ALL.[30-32] In a retrospective, multigroup analysis of children and young adults with Ph+ ALL, HSCT from a matched sibling donor improved outcome compared with standard chemotherapy.[33] In this retrospective analysis, Ph+ ALL patients undergoing HSCT from an unrelated donor had a very poor outcome. More rigorous human leukocyte antigen (HLA) matching by molecular high-resolution typing, however, has significantly improved outcome for patients receiving matched unrelated donor transplants.[34] Patients with Ph+ ALL who show a rapid morphologic response to induction therapy have an improved outcome compared with patients who show a slow response.[35] Following MRD by reverse transcription polymerase chain reaction for the BCR-ABL fusion transcript may provide a means to predict which patients will benefit from allogeneic HSCT.[36,37]
Imatinib mesylate is a selective inhibitor of the BCR-ABL protein kinase. Phase I and II studies of single-agent imatinib in children and adults with relapsed or refractory Ph+ ALL have demonstrated relatively high response rates, although these responses tended to be of short duration.[38,39] Clinical trials in adults with Ph+ ALL have demonstrated the feasibility of administering imatinib mesylate in combination with multiagent chemotherapy.[40] Preliminary outcome for results also demonstrated higher rates of complete remission in adult Ph+ ALL patients receiving imatinib mesylate.[40] The COG AALL0031 study evaluated whether imatinib mesylate could be incorporated into an intensive chemotherapy regimen for children with Ph+ ALL. Patients received imatinib mesylate in conjuction with chemotherapy during postinduction therapy. Some children proceeded to allogeneic stem cell transplant after two cycles of consolidation chemotherapy with imatinib mesylate, while other patients received imatinib mesylate in combination with chemotherapy throughout all treatment phases. Continuous dosing of imatinib mesylate in combination with intensive chemotherapy blocks appeared to be feasible without any additional significant toxicities observed. Efficacy results from this trial are pending longer follow-up.[41]
Current Clinical Trials
Check for U.S. clinical trials from NCI's PDQ Cancer Clinical Trials Registry that are now accepting patients with Philadelphia chromosome positive childhood precursor acute lymphoblastic leukemia. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.
General information about clinical trials is also available from the NCI Web site.
References
-
Goldberg JM, Silverman LB, Levy DE, et al.: Childhood T-cell acute lymphoblastic leukemia: the Dana-Farber Cancer Institute acute lymphoblastic leukemia consortium experience. J Clin Oncol 21 (19): 3616-22, 2003.
[PUBMED Abstract]
-
Asselin B, Shuster J, Amylon M, et al.: Improved event-free survival (EFS) with high dose methotrexate (HDM) in T-cell lymphoblastic leukemia (T-ALL) and advanced lymphoblastic lymphoma (T-NHL): a Pediatric Oncology Group (POG) study. [Abstract] Proceedings of the American Society of Clinical Oncology A-1464, 2001.
-
Seibel NL, Asselin BL, Nachman JB, et al.: Treatment of high risk T-cell acute lymphoblastic leukemia (T-ALL): comparison of recent experience of the Children’s Cancer Group (CCG) and Pediatric Oncology Group (POG). [Abstract] Blood 104 (11): A-681, 2004.
-
Seibel NL, Steinherz P, Sather H, et al.: Early treatment intensification improves outcome in children and adolescents with acute lymphoblastic leukemia (ALL) presenting with unfavorable features who show a rapid early response (RER) to induction chemotherapy: a report of CCG-1961. [Abstract] Blood 102 (11): A-787, 2003.
-
Matloub Y, Asselin BL, Stork LC, et al.: Outcome of children with T-Cell acute lymphoblastic leukemia (T-ALL) and standard risk (SR) features: results of CCG-1952, CCG-1991 and POG 9404. [Abstract] Blood 104 (11): A-680, 195a, 2004.
-
Berg SL, Blaney SM, Devidas M, et al.: Phase II study of nelarabine (compound 506U78) in children and young adults with refractory T-cell malignancies: a report from the Children's Oncology Group. J Clin Oncol 23 (15): 3376-82, 2005.
[PUBMED Abstract]
-
Kurtzberg J, Ernst TJ, Keating MJ, et al.: Phase I study of 506U78 administered on a consecutive 5-day schedule in children and adults with refractory hematologic malignancies. J Clin Oncol 23 (15): 3396-403, 2005.
[PUBMED Abstract]
-
Dunsmore K, Devidas M, Borowitz MJ, et al.: Nelarabine can be safely incorporated into an intensive, multiagent chemotherapy regimen for the treatment of T-cell acute lymphocytic leukemia (ALL) in children: a report of the Children's Oncology Group (COG) AALL00P2 protocol for T-cell leukemia. [Abstract] Blood 108 (11): A-1864, 2006.
-
Silverman LB: Acute lymphoblastic leukemia in infancy. Pediatr Blood Cancer 49 (7 Suppl): 1070-3, 2007.
[PUBMED Abstract]
-
Tomizawa D, Koh K, Sato T, et al.: Outcome of risk-based therapy for infant acute lymphoblastic leukemia with or without an MLL gene rearrangement, with emphasis on late effects: a final report of two consecutive studies, MLL96 and MLL98, of the Japan Infant Leukemia Study Group. Leukemia 21 (11): 2258-63, 2007.
[PUBMED Abstract]
-
Hilden JM, Dinndorf PA, Meerbaum SO, et al.: Analysis of prognostic factors of acute lymphoblastic leukemia in infants: report on CCG 1953 from the Children's Oncology Group. Blood 108 (2): 441-51, 2006.
[PUBMED Abstract]
-
Biondi A, Rizzari C, Valsecchi MG, et al.: Role of treatment intensification in infants with acute lymphoblastic leukemia: results of two consecutive AIEOP studies. Haematologica 91 (4): 534-7, 2006.
[PUBMED Abstract]
-
Pieters R, Schrappe M, De Lorenzo P, et al.: A treatment protocol for infants younger than 1 year with acute lymphoblastic leukaemia (Interfant-99): an observational study and a multicentre randomised trial. Lancet 370 (9583): 240-50, 2007.
[PUBMED Abstract]
-
Silverman LB, McLean TW, Gelber RD, et al.: Intensified therapy for infants with acute lymphoblastic leukemia: results from the Dana-Farber Cancer Institute Consortium. Cancer 80 (12): 2285-95, 1997.
[PUBMED Abstract]
-
Sanders JE, Im HJ, Hoffmeister PA, et al.: Allogeneic hematopoietic cell transplantation for infants with acute lymphoblastic leukemia. Blood 105 (9): 3749-56, 2005.
[PUBMED Abstract]
-
Eapen M, Rubinstein P, Zhang MJ, et al.: Comparable long-term survival after unrelated and HLA-matched sibling donor hematopoietic stem cell transplantations for acute leukemia in children younger than 18 months. J Clin Oncol 24 (1): 145-51, 2006.
[PUBMED Abstract]
-
Jacobsohn DA, Hewlett B, Morgan E, et al.: Favorable outcome for infant acute lymphoblastic leukemia after hematopoietic stem cell transplantation. Biol Blood Marrow Transplant 11 (12): 999-1005, 2005.
[PUBMED Abstract]
-
Pui CH, Gaynon PS, Boyett JM, et al.: Outcome of treatment in childhood acute lymphoblastic leukaemia with rearrangements of the 11q23 chromosomal region. Lancet 359 (9321): 1909-15, 2002.
[PUBMED Abstract]
-
Möricke A, Zimmermann M, Reiter A, et al.: Prognostic impact of age in children and adolescents with acute lymphoblastic leukemia: data from the trials ALL-BFM 86, 90, and 95. Klin Padiatr 217 (6): 310-20, 2005 Nov-Dec.
[PUBMED Abstract]
-
Barry E, DeAngelo DJ, Neuberg D, et al.: Favorable outcome for adolescents with acute lymphoblastic leukemia treated on Dana-Farber Cancer Institute Acute Lymphoblastic Leukemia Consortium Protocols. J Clin Oncol 25 (7): 813-9, 2007.
[PUBMED Abstract]
-
Nachman J: Clinical characteristics, biologic features and outcome for young adult patients with acute lymphoblastic leukaemia. Br J Haematol 130 (2): 166-73, 2005.
[PUBMED Abstract]
-
Boissel N, Auclerc MF, Lhéritier V, et al.: Should adolescents with acute lymphoblastic leukemia be treated as old children or young adults? Comparison of the French FRALLE-93 and LALA-94 trials. J Clin Oncol 21 (5): 774-80, 2003.
[PUBMED Abstract]
-
Ramanujachar R, Richards S, Hann I, et al.: Adolescents with acute lymphoblastic leukaemia: emerging from the shadow of paediatric and adult treatment protocols. Pediatr Blood Cancer 47 (6): 748-56, 2006.
[PUBMED Abstract]
-
Ramanujachar R, Richards S, Hann I, et al.: Adolescents with acute lymphoblastic leukaemia: outcome on UK national paediatric (ALL97) and adult (UKALLXII/E2993) trials. Pediatr Blood Cancer 48 (3): 254-61, 2007.
[PUBMED Abstract]
-
Mattano LA Jr, Sather HN, Trigg ME, et al.: Osteonecrosis as a complication of treating acute lymphoblastic leukemia in children: a report from the Children's Cancer Group. J Clin Oncol 18 (18): 3262-72, 2000.
[PUBMED Abstract]
-
Strauss AJ, Su JT, Dalton VM, et al.: Bony morbidity in children treated for acute lymphoblastic leukemia. J Clin Oncol 19 (12): 3066-72, 2001.
[PUBMED Abstract]
-
Bürger B, Beier R, Zimmermann M, et al.: Osteonecrosis: a treatment related toxicity in childhood acute lymphoblastic leukemia (ALL)--experiences from trial ALL-BFM 95. Pediatr Blood Cancer 44 (3): 220-5, 2005.
[PUBMED Abstract]
-
Niinimäki RA, Harila-Saari AH, Jartti AE, et al.: High body mass index increases the risk for osteonecrosis in children with acute lymphoblastic leukemia. J Clin Oncol 25 (12): 1498-504, 2007.
[PUBMED Abstract]
-
Butturini AM, Dorey FJ, Lange BJ, et al.: Obesity and outcome in pediatric acute lymphoblastic leukemia. J Clin Oncol 25 (15): 2063-9, 2007.
[PUBMED Abstract]
-
Mori T, Manabe A, Tsuchida M, et al.: Allogeneic bone marrow transplantation in first remission rescues children with Philadelphia chromosome-positive acute lymphoblastic leukemia: Tokyo Children's Cancer Study Group (TCCSG) studies L89-12 and L92-13. Med Pediatr Oncol 37 (5): 426-31, 2001.
[PUBMED Abstract]
-
Dombret H, Gabert J, Boiron JM, et al.: Outcome of treatment in adults with Philadelphia chromosome-positive acute lymphoblastic leukemia--results of the prospective multicenter LALA-94 trial. Blood 100 (7): 2357-66, 2002.
[PUBMED Abstract]
-
Hahn T, Wall D, Camitta B, et al.: The role of cytotoxic therapy with hematopoietic stem cell transplantation in the therapy of acute lymphoblastic leukemia in children: an evidence-based review. Biol Blood Marrow Transplant 11 (11): 823-61, 2005.
[PUBMED Abstract]
-
Aricò M, Valsecchi MG, Camitta B, et al.: Outcome of treatment in children with Philadelphia chromosome-positive acute lymphoblastic leukemia. N Engl J Med 342 (14): 998-1006, 2000.
[PUBMED Abstract]
-
Locatelli F, Zecca M, Messina C, et al.: Improvement over time in outcome for children with acute lymphoblastic leukemia in second remission given hematopoietic stem cell transplantation from unrelated donors. Leukemia 16 (11): 2228-37, 2002.
[PUBMED Abstract]
-
Roy A, Bradburn M, Moorman AV, et al.: Early response to induction is predictive of survival in childhood Philadelphia chromosome positive acute lymphoblastic leukaemia: results of the Medical Research Council ALL 97 trial. Br J Haematol 129 (1): 35-44, 2005.
[PUBMED Abstract]
-
Cazzaniga G, Lanciotti M, Rossi V, et al.: Prospective molecular monitoring of BCR/ABL transcript in children with Ph+ acute lymphoblastic leukaemia unravels differences in treatment response. Br J Haematol 119 (2): 445-53, 2002.
[PUBMED Abstract]
-
Jones LK, Saha V: Philadelphia positive acute lymphoblastic leukaemia of childhood. Br J Haematol 130 (4): 489-500, 2005.
[PUBMED Abstract]
-
Champagne MA, Capdeville R, Krailo M, et al.: Imatinib mesylate (STI571) for treatment of children with Philadelphia chromosome-positive leukemia: results from a Children's Oncology Group phase 1 study. Blood 104 (9): 2655-60, 2004.
[PUBMED Abstract]
-
Ottmann OG, Druker BJ, Sawyers CL, et al.: A phase 2 study of imatinib in patients with relapsed or refractory Philadelphia chromosome-positive acute lymphoid leukemias. Blood 100 (6): 1965-71, 2002.
[PUBMED Abstract]
-
Thomas DA, Faderl S, Cortes J, et al.: Treatment of Philadelphia chromosome-positive acute lymphocytic leukemia with hyper-CVAD and imatinib mesylate. Blood 103 (12): 4396-407, 2004.
[PUBMED Abstract]
-
Schultz KR, Aledo A, Bowman WP, et al.: Minimal toxicity of imatinib mesylate in combination with intensive chemotherapy for Philadelphia chromosome positive (Ph+) acute lymphoblastic leukemia (ALL) in children: a report of the Childrens Oncology Group (COG) AALL0031 protocol for very high risk ALL. [Abstract] Blood 108 (11): A-283, 2006.
Back to Top Recurrent Childhood Acute Lymphoblastic Leukemia
Standard Treatment Options
The prognosis for a child with acute lymphoblastic leukemia (ALL) whose disease
recurs depends on the time from diagnosis, site of relapse, and immunophenotype.[1-5][Level of evidence: 3iiDi] Patients with precursor B-cell ALL who experience either an isolated marrow relapse while on treatment or within 6 months of completion of therapy or a combined relapse within 18 months of diagnosis have a very poor prognosis. Patients with an extramedullary relapse while on treatment or within 6 months of completion of therapy, patients with precursor B-cell ALL and a marrow relapse with or without an extramedullary relapse more than 6 months after completing therapy, and patients with precursor B-cell ALL and a combined marrow relapse between 18 and 36 months from diagnosis have an intermediate prognosis. Patients with a late extramedullary relapse (occurring >6 months after completing therapy) have a good prognosis. Despite these findings, no evidence exists that early detection of relapse by frequent surveillance (complete blood counts or bone marrow tests) improves outcome.[6] Patients with T-cell ALL who experience a bone marrow relapse with or without a concurrent extramedullary relapse at any point during treatment or posttreatment have a very poor prognosis.[1-4,7-16] Treatment of children with relapsed T-cell ALL with the T-cell selective agent nelarabine has demonstrated an approximately 50% response rate.[17,18] Data suggest that minimal residual disease (MRD) status after induction of second
remission is of prognostic significance in patients with relapsed ALL.[19-21] The German Berlin-Frankfurt-Munster (BFM) group has developed a risk stratification for relapsed ALL. In this risk stratification, duration of first complete remission and immunophenotype are associated with outcome. (See Tables 2 and 3 below.)
Table 2. BFM Relapse Risk Group Assignment for Precursor B-cell ALLa
|
Extramedullary Relapse
|
Combined Bone Marrow and Extramedullary Relapse
|
Marrow Relapse
|
aAdapted from Roy et al. [14] and Borgmann et al.[22]
|
Very Early Relapse (<18 months from diagnosis)
|
Intermediate |
High |
High |
Early Relapse (>18 months from diagnosis and <6 months from completion of therapy)
|
Intermediate |
Intermediate |
High |
Late Relapse (>6 months from completion of therapy)
|
Standard |
Intermediate |
Intermediate |
Table 3. BFM Relapse Risk Group Assignment for T-cell ALLa
|
Extramedullary Relapse
|
Combined Bone Marrow and Extramedullary Relapse
|
Marrow Relapse
|
aAdapted from Roy et al. [14] and Borgmann et al.[22]
|
Very Early Relapse (<18 months from diagnosis)
|
Intermediate |
High |
High |
Early Relapse (>18 months from diagnosis and <6 months from completion of therapy)
|
Intermediate |
High |
High |
Late Relapse (>6 months from completion of therapy)
|
Standard |
High |
High |
The selection of therapy for the child whose disease recurs on or shortly after
therapy depends on many factors including prior treatment, whether the
recurrence is medullary or extramedullary, and individual patient
considerations. Aggressive approaches, including hematopoietic stem cell transplantation
(HSCT) should be strongly considered for patients with T-cell ALL and marrow relapse; or patients with precursor B-cell ALL and marrow relapse occurring while
on treatment or within 6 months of termination of therapy; or late marrow
relapse with high tumor load as indicated by a peripheral blast count of
10,000/µL or more.[12,23,24] For such patients, allogeneic
transplant from a human leukocyte antigen (HLA)-identical sibling or matched unrelated donor that is
performed in second remission has been reported to result in longer leukemia-free survival
when compared with a chemotherapy approach;[9,22,25-30] however, the Children's Cancer Group trial (CCG-1941) comparing chemotherapy versus HSCT (either matched sibling or matched unrelated donor) was not able to show a significant advantage for HSCT over chemotherapy for patients relapsing less than 12 months after stopping therapy.[31] Two retrospective studies and a randomized trial [32] suggest that transplant conditioning regimens that include
total-body irradiation (TBI) produce higher cure rates than chemotherapy-only
preparative regimens.[25,33,32] TBI is often combined with either cyclophosphamide or etoposide. Results with either drug are generally equivalent,[34] although one study suggested that if cyclophosphamide is used, higher-dose TBI may be necessary.[35] The potential neurotoxic effects of TBI should be
considered, particularly for very young patients. For patients with a late
marrow relapse, a primary chemotherapy approach should be considered with HSCT reserved for a subsequent marrow relapse.[11,36,37] Whether transplantation benefits patients with late marrow relapse but a high level of residual disease after reinduction treatment requires additional studies.
The
value of matched unrelated stem cell or unrelated cord blood transplantation in the therapy of children
with recurrent ALL is also under investigation.[38-42]
Outcome following matched unrelated donor transplants has improved significantly over the past decade and may offer outcome similar to that obtained with matched sibling donor transplants.[29,41,43] Treatment-related mortality remains high (>20%) and rates of clinically extensive chronic graft-versus-host disease remain high in some reports for matched unrelated donor transplants.[22,43,44] However, there is some evidence that matched unrelated donor transplantation may yield a lower relapse rate.[45] A Center for International Blood and Marrow Transplant Research study suggests that outcome after one or two antigen mismatched cord blood transplant may be equivalent to that for a matched family donor or a matched unrelated donor.[46] In certain cases where no suitable donor is found or an immediate transplant is considered crucial, a haploidentical transplant utilizing large doses of stem cells may be considered.[47] For all types of transplants, pretransplant levels of MRD are an important prognostic factor; patients with high levels of pretransplant MRD have a very poor prognosis.[21,48]
For patients relapsing after an allogeneic HSCT for relapsed ALL, a second ablative allogeneic HSCT may be feasible. However, many patients will be unable to undergo a second HSCT procedure due to failure to achieve remission, early toxic death, or severe organ toxicity related to salvage chemotherapy.[49] Among the highly selected group of patients able to undergo a second ablative allogeneic HSCT, approximately 10% to 30% may achieve long-term event-free survival (EFS).[49-51] Prognosis is more favorable in patients with longer duration of remission after the first HSCT and in patients with complete remission at the time of the second HSCT.[50,51] Donor leukocyte infusion has limited benefit for patients with ALL who relapse after allogeneic HSCT.[52]
With the improved success of treatment of children with ALL, the incidence of
isolated extramedullary relapse has decreased. The incidence of isolated
central nervous system (CNS) relapse is less than 10% and testicular relapse is less than 5%. In the majority of children with isolated extramedullary relapses, submicroscopic marrow disease can be demonstrated using sensitive molecular techniques,[53] and successful treatment strategies must effectively control both local and systemic disease. The level of submicroscopic marrow involvement may also predict response to post-relapse therapy.[53] While
the prognosis for children with isolated CNS relapse had been quite poor in the
past, aggressive systemic and intrathecal therapy followed by craniospinal
radiation has improved the outlook, particularly for patients who did not
receive cranial radiation during their first remission.[54-57] In a Pediatric Oncology Group (POG) study using this strategy, children
who had not previously received radiation therapy and whose initial remission was 18 months or greater had a 4-year EFS rate of approximately 80%
compared with EFS rates of approximately 45% for children with CNS relapse within
18 months of diagnosis.[56] In a follow-up POG study,[57] children who had not previously received radiation therapy and with initial remission of 18 months or more were treated with intensive systemic and intrathecal chemotherapy for 1 year followed by 18 Gy of cranial radiation only. The 4-year EFS was 78%. Children with an initial remission of less than 18 months also received the same chemotherapy but had craniospinal radiation (24 Gy cranial / 15 Gy spinal) as in the first POG study. This group's 4-year EFS was 52%.
A number of case series describing stem cell transplantation in the treatment of isolated CNS relapse have been published. This approach may be of value in patients with high risk of relapse using chemoradiation treatment.[58] In a study comparing outcome of patients treated with either HLA-matched sibling transplants or chemoradiotherapy as in the POG studies above, however, 8-year probablities of leukemia-free survival adjusted for age and duration of first remission were similar (58% and 66%, respectively).[59]
The standard approach for treating isolated testicular relapse is to administer chemotherapy plus radiation therapy. While there is limited clinical data concerning outcome without the use of radiation therapy, the use of chemotherapy (e.g. high-dose methotrexate) that may be able to achieve antileukemia levels in the testes,[60] is being tested in clinical trials. The results of treatment of isolated testicular
relapse depend on the timing of the relapse. The 3-year EFS of boys with overt testicular relapse during therapy is approximately
40%; it is approximately 85% for boys with late testicular relapse.[61] A
study that looked at testicular biopsy at the end of therapy failed to
demonstrate a survival benefit for patients with early detection of occult
disease.[62]
Treatment Options Under Clinical Evaluation
The following are examples of national and/or institutional clinical trials that are currently being conducted. Information about ongoing clinical trials is available from the NCI Web site.
Children's Oncology Group (COG)
-
ADVL04P2:
Patients with bone marrow relapse are eligible for this study. In the initial prephase of this protocol, a new experimental antileukemic drug, epratuzumab (an anti-CD22 monoclonal antibody), will be given followed by three blocks of induction chemotherapy. Epratuzumab will also be combined with Block 1 of induction therapy. After the prephase testing is completed in a limited number of institutions, the protocol without the prephase will be available for all COG institutions. MRD will be determined by flow cytometry after each course once a remission is achieved.
- Block 1: vincristine, prednisone, PEG-L-asparaginase, doxorubicin; cytarabine (by lumbar puncture) and methotrexate (by lumbar puncture).
- Block 2: etoposide, cyclophosphamide, methotrexate (intravenously and by lumbar puncture).
- Block 3: high-dose cytarabine, L-asparaginase.
-
AALL02P2:
Patients with isolated CNS or isolated testicular relapse occurring more than 18 months after initial remission are eligible for this study.
For patients with isolated testicular relapse, the hypothesis of this protocol is that testicular radiation is not necessary if intensive systemic chemotherapy, including high-dose methotrexate, is administered. Patients will initially receive high-dose methotrexate followed by standard induction therapy. With complete clinical response, treatment with intensive chemotherapy as per a prior successful relapse protocol (POG-9412) [57] will be administered. Testicular radiation therapy is not given. For patients with isolated CNS relapse, the hypothesis of this protocol is that reduced-dose cranial radiation (12 Gy) will be adequate to prevent subsequent CNS relapse when combined with a protocol of intensive systemic and coordinated intrathecal therapy. Treatment will be similar to that successfully utilized in POG-9412.
Clinical trials investigating new agents [63,64] and new combinations of agents are
available for children with recurrent ALL and should be considered. Targeted
therapies specific for ALL are being developed, including monoclonal antibody-based therapies and using drugs that inhibit signal transduction pathways
required for leukemia cell growth and survival.
Current Clinical Trials
Check for U.S. clinical trials from NCI's PDQ Cancer Clinical Trials Registry that are now accepting patients with recurrent childhood acute lymphoblastic leukemia. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.
General information about clinical trials is also available from the NCI Web site.
References
-
Gaynon PS, Qu RP, Chappell RJ, et al.: Survival after relapse in childhood acute lymphoblastic leukemia: impact of site and time to first relapse--the Children's Cancer Group Experience. Cancer 82 (7): 1387-95, 1998.
[PUBMED Abstract]
-
Uderzo C, Conter V, Dini G, et al.: Treatment of childhood acute lymphoblastic leukemia after the first relapse: curative strategies. Haematologica 86 (1): 1-7, 2001.
[PUBMED Abstract]
-
Chessells JM, Veys P, Kempski H, et al.: Long-term follow-up of relapsed childhood acute lymphoblastic leukaemia. Br J Haematol 123 (3): 396-405, 2003.
[PUBMED Abstract]
-
Rivera GK, Zhou Y, Hancock ML, et al.: Bone marrow recurrence after initial intensive treatment for childhood acute lymphoblastic leukemia. Cancer 103 (2): 368-76, 2005.
[PUBMED Abstract]
-
Malempati S, Gaynon PS, Sather H, et al.: Outcome after relapse among children with standard-risk acute lymphoblastic leukemia: Children's Oncology Group study CCG-1952. J Clin Oncol 25 (36): 5800-7, 2007.
[PUBMED Abstract]
-
Rubnitz JE, Hijiya N, Zhou Y, et al.: Lack of benefit of early detection of relapse after completion of therapy for acute lymphoblastic leukemia. Pediatr Blood Cancer 44 (2): 138-41, 2005.
[PUBMED Abstract]
-
Einsiedel HG, von Stackelberg A, Hartmann R, et al.: Long-term outcome in children with relapsed ALL by risk-stratified salvage therapy: results of trial acute lymphoblastic leukemia-relapse study of the Berlin-Frankfurt-Münster Group 87. J Clin Oncol 23 (31): 7942-50, 2005.
[PUBMED Abstract]
-
Schroeder H, Garwicz S, Kristinsson J, et al.: Outcome after first relapse in children with acute lymphoblastic leukemia: a population-based study of 315 patients from the Nordic Society of Pediatric Hematology and Oncology (NOPHO). Med Pediatr Oncol 25 (5): 372-8, 1995.
[PUBMED Abstract]
-
Wheeler K, Richards S, Bailey C, et al.: Comparison of bone marrow transplant and chemotherapy for relapsed childhood acute lymphoblastic leukaemia: the MRC UKALL X experience. Medical Research Council Working Party on Childhood Leukaemia. Br J Haematol 101 (1): 94-103, 1998.
[PUBMED Abstract]
-
Buchanan GR, Rivera GK, Pollock BH, et al.: Alternating drug pairs with or without periodic reinduction in children with acute lymphoblastic leukemia in second bone marrow remission: a Pediatric Oncology Group Study. Cancer 88 (5): 1166-74, 2000.
[PUBMED Abstract]
-
Rivera GK, Hudson MM, Liu Q, et al.: Effectiveness of intensified rotational combination chemotherapy for late hematologic relapse of childhood acute lymphoblastic leukemia. Blood 88 (3): 831-7, 1996.
[PUBMED Abstract]
-
Bührer C, Hartmann R, Fengler R, et al.: Peripheral blast counts at diagnosis of late isolated bone marrow relapse of childhood acute lymphoblastic leukemia predict response to salvage chemotherapy and outcome. Berlin-Frankfurt-Münster Relapse Study Group. J Clin Oncol 14 (10): 2812-7, 1996.
[PUBMED Abstract]
-
Sadowitz PD, Smith SD, Shuster J, et al.: Treatment of late bone marrow relapse in children with acute lymphoblastic leukemia: a Pediatric Oncology Group study. Blood 81 (3): 602-9, 1993.
[PUBMED Abstract]
-
Roy A, Cargill A, Love S, et al.: Outcome after first relapse in childhood acute lymphoblastic leukaemia - lessons from the United Kingdom R2 trial. Br J Haematol 130 (1): 67-75, 2005.
[PUBMED Abstract]
-
Rizzari C, Valsecchi MG, Aricò M, et al.: Outcome of very late relapse in children with acute lymphoblastic leukemia. Haematologica 89 (4): 427-34, 2004.
[PUBMED Abstract]
-
Abshire TC, Buchanan GR, Jackson JF, et al.: Morphologic, immunologic and cytogenetic studies in children with acute lymphoblastic leukemia at diagnosis and relapse: a Pediatric Oncology Group study. Leukemia 6 (5): 357-62, 1992.
[PUBMED Abstract]
-
Berg SL, Blaney SM, Devidas M, et al.: Phase II study of nelarabine (compound 506U78) in children and young adults with refractory T-cell malignancies: a report from the Children's Oncology Group. J Clin Oncol 23 (15): 3376-82, 2005.
[PUBMED Abstract]
-
Kurtzberg J, Ernst TJ, Keating MJ, et al.: Phase I study of 506U78 administered on a consecutive 5-day schedule in children and adults with refractory hematologic malignancies. J Clin Oncol 23 (15): 3396-403, 2005.
[PUBMED Abstract]
-
Eckert C, Biondi A, Seeger K, et al.: Prognostic value of minimal residual disease in relapsed childhood acute lymphoblastic leukaemia. Lancet 358 (9289): 1239-41, 2001.
[PUBMED Abstract]
-
Coustan-Smith E, Gajjar A, Hijiya N, et al.: Clinical significance of minimal residual disease in childhood acute lymphoblastic leukemia after first relapse. Leukemia 18 (3): 499-504, 2004.
[PUBMED Abstract]
-
Sramkova L, Muzikova K, Fronkova E, et al.: Detectable minimal residual disease before allogeneic hematopoietic stem cell transplantation predicts extremely poor prognosis in children with acute lymphoblastic leukemia. Pediatr Blood Cancer 48 (1): 93-100, 2007.
[PUBMED Abstract]
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Borgmann A, von Stackelberg A, Hartmann R, et al.: Unrelated donor stem cell transplantation compared with chemotherapy for children with acute lymphoblastic leukemia in a second remission: a matched-pair analysis. Blood 101 (10): 3835-9, 2003.
[PUBMED Abstract]
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Thomson B, Park JR, Felgenhauer J, et al.: Toxicity and efficacy of intensive chemotherapy for children with acute lymphoblastic leukemia (ALL) after first bone marrow or extramedullary relapse. Pediatr Blood Cancer 43 (5): 571-9, 2004.
[PUBMED Abstract]
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Hahn T, Wall D, Camitta B, et al.: The role of cytotoxic therapy with hematopoietic stem cell transplantation in the therapy of acute lymphoblastic leukemia in children: an evidence-based review. Biol Blood Marrow Transplant 11 (11): 823-61, 2005.
[PUBMED Abstract]
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Eapen M, Raetz E, Zhang MJ, et al.: Outcomes after HLA-matched sibling transplantation or chemotherapy in children with B-precursor acute lymphoblastic leukemia in a second remission: a collaborative study of the Children's Oncology Group and the Center for International Blood and Marrow Transplant Research. Blood 107 (12): 4961-7, 2006.
[PUBMED Abstract]
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Barrett AJ, Horowitz MM, Pollock BH, et al.: Bone marrow transplants from HLA-identical siblings as compared with chemotherapy for children with acute lymphoblastic leukemia in a second remission. N Engl J Med 331 (19): 1253-8, 1994.
[PUBMED Abstract]
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Uderzo C, Valsecchi MG, Bacigalupo A, et al.: Treatment of childhood acute lymphoblastic leukemia in second remission with allogeneic bone marrow transplantation and chemotherapy: ten-year experience of the Italian Bone Marrow Transplantation Group and the Italian Pediatric Hematology Oncology Association. J Clin Oncol 13 (2): 352-8, 1995.
[PUBMED Abstract]
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Harrison G, Richards S, Lawson S, et al.: Comparison of allogeneic transplant versus chemotherapy for relapsed childhood acute lymphoblastic leukaemia in the MRC UKALL R1 trial. MRC Childhood Leukaemia Working Party. Ann Oncol 11 (8): 999-1006, 2000.
[PUBMED Abstract]
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Bunin N, Carston M, Wall D, et al.: Unrelated marrow transplantation for children with acute lymphoblastic leukemia in second remission. Blood 99 (9): 3151-7, 2002.
[PUBMED Abstract]
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Saarinen-Pihkala UM, Heilmann C, Winiarski J, et al.: Pathways through relapses and deaths of children with acute lymphoblastic leukemia: role of allogeneic stem-cell transplantation in Nordic data. J Clin Oncol 24 (36): 5750-62, 2006.
[PUBMED Abstract]
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Gaynon PS, Harris RE, Altman AJ, et al.: Bone marrow transplantation versus prolonged intensive chemotherapy for children with acute lymphoblastic leukemia and an initial bone marrow relapse within 12 months of the completion of primary therapy: Children's Oncology Group study CCG-1941. J Clin Oncol 24 (19): 3150-6, 2006.
[PUBMED Abstract]
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Bunin N, Aplenc R, Kamani N, et al.: Randomized trial of busulfan vs total body irradiation containing conditioning regimens for children with acute lymphoblastic leukemia: a Pediatric Blood and Marrow Transplant Consortium study. Bone Marrow Transplant 32 (6): 543-8, 2003.
[PUBMED Abstract]
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Davies SM, Ramsay NK, Klein JP, et al.: Comparison of preparative regimens in transplants for children with acute lymphoblastic leukemia. J Clin Oncol 18 (2): 340-7, 2000.
[PUBMED Abstract]
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Gassas A, Sung L, Saunders EF, et al.: Comparative outcome of hematopoietic stem cell transplantation for pediatric acute lymphoblastic leukemia following cyclophosphamide and total body irradiation or VP16 and total body irradiation conditioning regimens. Bone Marrow Transplant 38 (11): 739-43, 2006.
[PUBMED Abstract]
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Marks DI, Forman SJ, Blume KG, et al.: A comparison of cyclophosphamide and total body irradiation with etoposide and total body irradiation as conditioning regimens for patients undergoing sibling allografting for acute lymphoblastic leukemia in first or second complete remission. Biol Blood Marrow Transplant 12 (4): 438-53, 2006.
[PUBMED Abstract]
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Borgmann A, Baumgarten E, Schmid H, et al.: Allogeneic bone marrow transplantation for a subset of children with acute lymphoblastic leukemia in third remission: a conceivable alternative? Bone Marrow Transplant 20 (11): 939-44, 1997.
[PUBMED Abstract]
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Schroeder H, Gustafsson G, Saarinen-Pihkala UM, et al.: Allogeneic bone marrow transplantation in second remission of childhood acute lymphoblastic leukemia: a population-based case control study from the Nordic countries. Bone Marrow Transplant 23 (6): 555-60, 1999.
[PUBMED Abstract]
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Hongeng S, Krance RA, Bowman LC, et al.: Outcomes of transplantation with matched-sibling and unrelated-donor bone marrow in children with leukaemia. Lancet 350 (9080): 767-71, 1997.
[PUBMED Abstract]
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Casper J, Camitta B, Truitt R, et al.: Unrelated bone marrow donor transplants for children with leukemia or myelodysplasia. Blood 85 (9): 2354-63, 1995.
[PUBMED Abstract]
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Weisdorf DJ, Billett AL, Hannan P, et al.: Autologous versus unrelated donor allogeneic marrow transplantation for acute lymphoblastic leukemia. Blood 90 (8): 2962-8, 1997.
[PUBMED Abstract]
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Saarinen-Pihkala UM, Gustafsson G, Ringdén O, et al.: No disadvantage in outcome of using matched unrelated donors as compared with matched sibling donors for bone marrow transplantation in children with acute lymphoblastic leukemia in second remission. J Clin Oncol 19 (14): 3406-14, 2001.
[PUBMED Abstract]
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Jacobsohn DA, Hewlett B, Ranalli M, et al.: Outcomes of unrelated cord blood transplants and allogeneic-related hematopoietic stem cell transplants in children with high-risk acute lymphocytic leukemia. Bone Marrow Transplant 34 (10): 901-7, 2004.
[PUBMED Abstract]
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Locatelli F, Zecca M, Messina C, et al.: Improvement over time in outcome for children with acute lymphoblastic leukemia in second remission given hematopoietic stem cell transplantation from unrelated donors. Leukemia 16 (11): 2228-37, 2002.
[PUBMED Abstract]
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Woolfrey AE, Anasetti C, Storer B, et al.: Factors associated with outcome after unrelated marrow transplantation for treatment of acute lymphoblastic leukemia in children. Blood 99 (6): 2002-8, 2002.
[PUBMED Abstract]
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Gassas A, Sung L, Saunders EF, et al.: Graft-versus-leukemia effect in hematopoietic stem cell transplantation for pediatric acute lymphoblastic leukemia: significantly lower relapse rate in unrelated transplantations. Bone Marrow Transplant 40 (10): 951-5, 2007.
[PUBMED Abstract]
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Eapen M, Rubinstein P, Zhang MJ, et al.: Outcomes of transplantation of unrelated donor umbilical cord blood and bone marrow in children with acute leukaemia: a comparison study. Lancet 369 (9577): 1947-54, 2007.
[PUBMED Abstract]
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Klingebiel T, Handgretinger R, Lang P, et al.: Haploidentical transplantation for acute lymphoblastic leukemia in childhood. Blood Rev 18 (3): 181-92, 2004.
[PUBMED Abstract]
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Goulden N, Bader P, Van Der Velden V, et al.: Minimal residual disease prior to stem cell transplant for childhood acute lymphoblastic leukaemia. Br J Haematol 122 (1): 24-9, 2003.
[PUBMED Abstract]
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Mehta J, Powles R, Treleaven J, et al.: Outcome of acute leukemia relapsing after bone marrow transplantation: utility of second transplants and adoptive immunotherapy. Bone Marrow Transplant 19 (7): 709-19, 1997.
[PUBMED Abstract]
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Eapen M, Giralt SA, Horowitz MM, et al.: Second transplant for acute and chronic leukemia relapsing after first HLA-identical sibling transplant. Bone Marrow Transplant 34 (8): 721-7, 2004.
[PUBMED Abstract]
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Bosi A, Laszlo D, Labopin M, et al.: Second allogeneic bone marrow transplantation in acute leukemia: results of a survey by the European Cooperative Group for Blood and Marrow Transplantation. J Clin Oncol 19 (16): 3675-84, 2001.
[PUBMED Abstract]
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Collins RH Jr, Goldstein S, Giralt S, et al.: Donor leukocyte infusions in acute lymphocytic leukemia. Bone Marrow Transplant 26 (5): 511-6, 2000.
[PUBMED Abstract]
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Hagedorn N, Acquaviva C, Fronkova E, et al.: Submicroscopic bone marrow involvement in isolated extramedullary relapses in childhood acute lymphoblastic leukemia: a more precise definition of "isolated" and its possible clinical implications, a collaborative study of the Resistant Disease Committee of the International BFM study group. Blood 110 (12): 4022-9, 2007.
[PUBMED Abstract]
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Ribeiro RC, Rivera GK, Hudson M, et al.: An intensive re-treatment protocol for children with an isolated CNS relapse of acute lymphoblastic leukemia. J Clin Oncol 13 (2): 333-8, 1995.
[PUBMED Abstract]
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Kumar P, Kun LE, Hustu HO, et al.: Survival outcome following isolated central nervous system relapse treated with additional chemotherapy and craniospinal irradiation in childhood acute lymphoblastic leukemia. Int J Radiat Oncol Biol Phys 31 (3): 477-83, 1995.
[PUBMED Abstract]
-
Ritchey AK, Pollock BH, Lauer SJ, et al.: Improved survival of children with isolated CNS relapse of acute lymphoblastic leukemia: a pediatric oncology group study . J Clin Oncol 17 (12): 3745-52, 1999.
[PUBMED Abstract]
-
Barredo JC, Devidas M, Lauer SJ, et al.: Isolated CNS relapse of acute lymphoblastic leukemia treated with intensive systemic chemotherapy and delayed CNS radiation: a pediatric oncology group study. J Clin Oncol 24 (19): 3142-9, 2006.
[PUBMED Abstract]
-
Yoshihara T, Morimoto A, Kuroda H, et al.: Allogeneic stem cell transplantation in children with acute lymphoblastic leukemia after isolated central nervous system relapse: our experiences and review of the literature. Bone Marrow Transplant 37 (1): 25-31, 2006.
[PUBMED Abstract]
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Eapen M, Zhang MJ, Raetz E, et al.: Outcomes after HLA-matched sibling transplants or chemotherapy in children with acute lymphoblastic leukemia in a second remission after an isolated central nervous system relapse. [Abstract] Blood 108 (11): A-49, 2006.
-
van den Berg H, Langeveld NE, Veenhof CH, et al.: Treatment of isolated testicular recurrence of acute lymphoblastic leukemia without radiotherapy. Report from the Dutch Late Effects Study Group. Cancer 79 (11): 2257-62, 1997.
[PUBMED Abstract]
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Wofford MM, Smith SD, Shuster JJ, et al.: Treatment of occult or late overt testicular relapse in children with acute lymphoblastic leukemia: a Pediatric Oncology Group study. J Clin Oncol 10 (4): 624-30, 1992.
[PUBMED Abstract]
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Trigg ME, Steinherz PG, Chappell R, et al.: Early testicular biopsy in males with acute lymphoblastic leukemia: lack of impact on subsequent event-free survival. J Pediatr Hematol Oncol 22 (1): 27-33, 2000 Jan-Feb.
[PUBMED Abstract]
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Jeha S, Gaynon PS, Razzouk BI, et al.: Phase II study of clofarabine in pediatric patients with refractory or relapsed acute lymphoblastic leukemia. J Clin Oncol 24 (12): 1917-23, 2006.
[PUBMED Abstract]
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Pui CH, Jeha S: New therapeutic strategies for the treatment of acute lymphoblastic leukaemia. Nat Rev Drug Discov 6 (2): 149-65, 2007.
[PUBMED Abstract]
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Back to Top Changes to this Summary (09/05/2008)
The PDQ cancer information summaries are reviewed regularly and updated as
new information becomes available. This section describes the latest
changes made to this summary as of the date above.
Cellular Classification and Prognostic Variables
Added text about chromosomal translocations that have been identified in T-cell ALL which result in the aberrant expression of transcription factors. High expression of transcription factor TLX1/HOX11 occurs in 5% to 10% of pediatric T-cell ALL patients and is associated with a more favorable outcome. Overexpression of TLX3/HOX11L2 occurs in approximately 20% of pediatric T-cell ALL patients and appears to be associated with increased risk of treatment failure. NOTCH1 mutations occur in approximately 50% of T-cell ALL cases, but the prognostic significance is unclear (cited Schneider et al. as reference 57, Armstrong et al. as reference 58, Bergeron et al. as reference 59, van Grotel et al. as reference 60, Cavé et al. as reference 61, Baak et al. as reference 62, Ferrando et al. as reference 63, Kees et al. as reference 64, Ballerini et al. as reference 65, Weng et al. as reference 66, Breit et al. as reference 67, and Zhu et al. as reference 68).
Untreated Childhood Acute Lymphoblastic Leukemia
Added Waber et al. as reference 56. Included a level of evidence ranking [Level of evidence: 1iiC].
Childhood Acute Lymphoblastic Leukemia in Remission
Added Seibel et al. as reference 24. Included a level of evidence ranking [Level of evidence: 1iiA].
Recurrent Childhood Acute Lymphoblastic Leukemia
Added Malempati et al. as reference 5. Included a level of evidence ranking [Level of evidence: 3iiDi].
Added text to state that in the majority of children with isolated extramedullary relapses, submicroscopic marrow disease can be demonstrated using sensitive molecular techniques, and successful treatment strategies must effectively control both local and systemic disease. The level of submicroscopic marrow involvement may also predict response to post-relapse therapy (cited Hagedorn et al. as reference 53).
Added text about clinical trials that are currently testing the use of chemotherapy that may be able to achieve antileukemia levels in the testes (cited van den Berg et al. as reference 60).
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About PDQ
Additional PDQ Summaries
Important:
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