test About Medicine OnLine Medicine OnLine Home Page Cancer Libraries DoseCalc Online Oncology News
Cancer Forums Medline Search Cancer Links Glossary



National Cancer Institute

PDQ® bullet Treatment  bullet Health Professionals


Important: This information is intended mainly for use by doctors and other health care professionals. If you have questions about this topic, you can ask your doctor, or call the Cancer Information Service at 1-800-4-CANCER (1-800-422-6237).

Childhood acute lymphocytic leukemia


Table of Contents

GENERAL INFORMATION
Prognostic variables
CELLULAR CLASSIFICATION
TREATMENT OPTION OVERVIEW
UNTREATED CHILDHOOD ACUTE LYMPHOCYTIC LEUKEMIA
Induction chemotherapy
Central nervous system prophylaxis
CHILDHOOD ACUTE LYMPHOCYTIC LEUKEMIA IN REMISSION
Consolidation/Intensification
Maintenance
RECURRENT CHILDHOOD ACUTE LYMPHOCYTIC LEUKEMIA

GENERAL INFORMATION

This treatment information summary on childhood acute lymphocytic leukemia (ALL) is an overview of prognosis, diagnosis, classification, and patient treatment. The National Cancer Institute (NCI) created the PDQ database to increase the availability of new treatment information and its use in treating patients. Information and references from the most recent published literature are included after review by pediatric oncology specialists.

Cancer in children and adolescents is rare. A team approach that incorporates the skills of the primary care physician, surgeon, radiation oncologists, pediatric oncologists/hematologists, rehabilitation specialists, pediatric nurse specialists, and social workers is imperative to ensure that patients receive treatment, supportive care, and rehabilitation that will achieve optimal survival and quality of life. For advances to be made in treating these patients, therapy should be delivered in the context of a clinical trial at a major medical center that has expertise in treating children. Only through entry of all eligible children into appropriate, well-designed clinical trials will progress be made against these diseases. 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]

Approximately 70% of children with ALL are cured with current protocol-based treatments that incorporate systemic therapy (e.g., combination chemotherapy) and specific central nervous system (CNS) preventive therapy (i.e., intrathecal chemotherapy with or without cranial irradiation). While more than 95% of patients can be expected to attain a complete remission (CR), the duration of CR and potential for cure are correlated with a number of prognostic variables. These variables include clinical parameters at the time of diagnosis (e.g., age and white blood cell (WBC) count) and biologic features of the leukemic cells (e.g., immunophenotype, cytogenetics, and DNA content). The NCI, in conjunction with various cooperative groups have defined two prognostic subgroups of patients with ALL: standard-risk (1 to <10 years of age and <50,000 WBC) and high-risk (1 to <10 years of age and >50,000 WBC or age > 10 years). Some groups base the intensity of induction therapy on the NCI risk classification. This risk-based approach to initial treatment has improved survival and reduced toxic effects.[2] Currently some groups determine the intensity of post-induction chemotherapy by the early clinical response to chemotherapy based on the rapidity of initial disease resolution as measured by disappearance of peripheral blood or marrow blasts.[3]

It is well appreciated that children with ALL have a better prognosis when treated in established clinical trials.[4] Additionally, despite the treatment advances noted in childhood ALL, numerous important biologic and therapeutic questions remain to be answered. The systematic investigation of these issues requires the entry of all eligible patients in clinical trials. Since treatment entails many potential complications and requires aggressive supportive care (transfusions; management of infectious complications; and emotional, financial, and developmental support), these protocols are 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 in whom specific clinical and laboratory features might confer a favorable prognosis. At the same time, 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.

Since nearly all children with ALL achieve an initial remission, the major obstacle to cure is bone marrow and/or extramedullary relapse. Relapse can occur during therapy or after completion of treatment. While the majority of children with recurrent ALL attain a second remission, the likelihood of cure, depending on the duration of the initial remission and the site of relapse, is generally poor.


Prognostic variables

Although there is no standardized staging of ALL analogous to that used for solid tumors and lymphomas, patients with ALL are usually treated according to risk groups defined by both clinical and laboratory features. When analyzed retrospectively, these features appear to have prognostic significance and have important implications for both treatment and outcome. Initial stratification of patients with ALL depends on patient-related (clinical) features and on the histochemical, morphologic, immunophenotypic, cytogenetic, and biochemical characteristics of the patient's leukemia cells.

A number of clinical and laboratory features have demonstrated prognostic value for children with ALL. These include age at diagnosis, WBC count at diagnosis, sex, CNS leukemia at diagnosis, lymphomatous presentation (mediastinal mass, massive organomegaly, and/or massive adenopathy), platelet count, hemoglobin level, race, serum immunoglobulin levels, peripheral blood and marrow response to treatment including rate of cytoreduction and induction failure, blast cell morphology (FAB), immunophenotype, DNA content (ploidy), and certain chromosomal translocations.[5-9] Infants less than 6 months of age and infants 6-12 months of age with a 4;11 translocation are in an extremely high-risk category for treatment failure and may benefit from intensified therapy.[3,10] The Philadelphia chromosome t(9;22) is present in about 5% of pediatric ALL patients and confers an unfavorable prognosis, especially when it is associated with either a high WBC count or slow early response.[11,12] Philadelphia- positive ALL is more common in older patients with B lineage ALL and high WBC count. In patients with Philadelphia chromosome positive ALL, initial good response to steroids appears to be an indication of responsiveness to treatment and improved survival.[11] The t(12;21) (tel-AML-1 fusion) is associated with an excellent prognosis.[13-15] In patients with T-cell ALL, pro-thymocyte ALL (CD7+, CD2-, CD5-) appears to have a less favorable outcome than patients with more mature T-cell phenotypes.[8] 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.[8] Only age, WBC count at diagnosis, and the Philadelphia chromosome have been consistently associated with outcome regardless of the treatment.

Representatives of the major pediatric oncology cooperative groups in the United States have developed a uniform approach to risk classification and treatment assignment for children with ALL. For patients with B-precursor (i.e., non-T, non-B) ALL, the standard-risk category includes patients 1-9 years of age who have a WBC count at diagnosis less than 50,000 per microliter. The remaining patients are classified as having high-risk ALL. Other pretreatment prognostic factors that may modify the age/WBC risk category include DNA index, cytogenetics, immunophenotype, and CNS disease at diagnosis. Early response to induction chemotherapy and levels of minimal residual disease are significant prognostic variables regardless of initial risk group assignment.[16,17]

It should be emphasized that improvements in therapy may diminish the importance of or abrogate any of these presumed prognostic factors. For example, a recent report from the Childrens Cancer Group showed that the adverse prognostic significance of slow early response disappears when these patients receive intensified post induction chemotherapy.[3]

References:

  1. Sanders J, Glader B, Cairo M, et al.: 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): 139-141, 1997.

  2. Smith M, Arthur D, Camitta B, et al.: Uniform approach to risk classification and treatment assignment for children with acute lymphoblastic leukemia. Journal of Clinical Oncology 14(1): 18-24, 1996.

  3. 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. New England Journal of Medicine 338(23): 1663-1671, 1998.

  4. Shah NR: The community physician's involvement in clinical trials and home treatment. Cancer 58(2, Suppl): 504-507, 1986.

  5. Heerema NA, Arthur DC, Sather H, et al.: Cytogenetic features of infants less than 12 months of age at diagnosis of acute lymphoblastic leukemia: impact of the 11q23 breakpoint on outcome: a report of the Childrens Cancer Group. Blood 83(8): 2274-2284, 1994.

  6. Rubnitz JE, Look AT: Molecular genetics of childhood leukemias. Journal of Pediatric Hematology/Oncology 20(1): 1-11, 1998.

  7. Shuster JJ, Wacker P, Pullen J, et al.: Prognostic significance of sex in childhood B-precursor acute lymphoblastic leukemia: a Pediatric Oncology Group study. Journal of Clinical Oncology 16(8): 2854-2863, 1998.

  8. Uckun FM, Sensel MG, Sun L, et al.: Biology and treatment of childhood T-lineage acute lymphoblastic leukemia. Blood 91(3): 735-746, 1998.

  9. Silverman LB, Gelber RD, Young ML, et al.: Induction failure in acute lymphoblastic leukemia of childhood. Cancer 85(6): 1395-1404, 1999.

  10. 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. Journal of Clinical Oncology 17(2): 445-455, 1999.

  11. Schrappe M, Arico 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): 2730-2741, 1998.

  12. 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): 1493-1496, 1997.

  13. 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): 4252-4258, 1996.

  14. Rubnitz JE, Shuster JJ, Land VJ, et al.: Case-control study suggests a favorable impact of TEL rearrangement in patients with B-lineage acute lymphoblastic leukemia treated with antimetabolite-based therapy: a Pediatric Oncology Group study. Blood 89(4): 1143-1146, 1997.

  15. 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. Blood 90(2): 571-577, 1997.

  16. Coustan-Smith E, Behm FG, Sanchez J, et al.: Immunological detection of minimal residual disease in children with acute lymphoblastic leukaemia. Lancet 351(9102): 550-554, 1998.

  17. Cave H, van der Werff ten Bosch J, Suciu S, et al.: Clinical significance of minimal residual disease in childhood acute lymphoblastic leukemia. European Organization for Research and Treatment of Cancer--Childhood Leukemia Cooperative Group. New England Journal of Medicine 339(9): 591-598, 1998.


CELLULAR CLASSIFICATION

A number of cell-related findings have an impact on prognosis and potentially on therapy:

1. Morphology: Acute lymphocytic leukemia (ALL) cells can be classified using the French-American-British (FAB) criteria.[1] Using this schema, 80%-85% of patients with pediatric ALL demonstrate L1 morphology, 15% demonstrate L2 morphology, and 1%-3% demonstrate L3 morphology. In most studies, L1 morphology has been associated with a better prognosis, while L2 morphology conveys a worse prognosis regardless of risk group assignment. However, current U.S. trials do not stratify patients by morphology. L3 morphology is usually associated with surface immunoglobulin (mature B-cell phenotype) and is morphologically and cytogenetically identical to Burkitt's lymphoma cells. For more detailed information on the treatment of children with B-cell ALL, refer to the PDQ summary on childhood non-Hodgkin's lymphoma.

2. Immunologic and molecular characterization: Immunologic and molecular differences in leukemic lymphoblasts of both B-cell precursor and T-cell types reflect the fact that malignant transformation and clonal expansion can occur at different stages of lymphoid differentiation. Monoclonal antibodies specific to B-cell or T-cell antigenic determinants and oligonucleotide probes derived by recombinant DNA technology have allowed examination of rearrangements and/or deletions of genes for immunoglobulin or the T-cell receptor.

B-cell precursor (or B-lineage) ALL, defined by the expression of CD19, DR, CD10 (cALLa), and other B-cell associated antigens, represents 80%-85% of childhood ALL. Approximately 80% of B-cell precursor ALL express the cALLa, CD10 antigen. The lack of cALLa expression has also been shown in some series to be associated with a worse prognosis. There are three major subtypes of B-lineage ALL: early pre-B (no surface or cytoplasmic immunoglobulin), pre-B (presence of cytoplasmic immunoglobulin), and B-cell (presence of surface immunoglobulin). Approximately two thirds of patients will have the early pre-B phenotype and have the best prognosis. The leukemic cells of patients with pre-B ALL contain cytoplasmic immunoglobulin (cIg) and appear to represent an intermediate level of differentiation. Twenty-five percent of patients with pre-B ALL have a 1;19 chromosomal translocation, and require intensive treatment to achieve optimal survival.[2,3] It has been shown that antimetabolite treatment is inadequate for this population and therapy with additional chemotherapeutic agents is necessary. Only rarely (1%) do patients demonstrate an immunophenotype of B-cell ALL that is characterized by surface Ig expression and L3 FAB morphology. Infants younger than 1 year of age have leukemic cells with an immunophenotype and molecular genotype characteristic of the earliest stages of B-cell differentiation.[4]

T-cell ALL is defined by the leukemic cell expression of the T-cell- associated antigens CD2, CD7, CD5, or CD3 and is frequently associated with a constellation of clinical features including male sex, older age, leukocytosis, and mediastinal mass.[5] Approximately 15% of children with newly diagnosed ALL have the T-cell phenotype. In patients with T-cell ALL, CD2 appears to confer a favorable prognosis,[5] whereas CD7+, CD2-, and CD5- immunophenotype ("pro-thymocyte") infers a less favorable prognosis.[6]

Although most cases of ALL express surface antigens and molecular markers that identify them as derived from a specific lineage, situations in which cells express both T- and B-cell surface antigens and/or molecular markers, as well as cases in which both lymphoid and myeloid markers exist on the same cell, have been reported. There is no adverse prognostic significance of myeloid markers in ALL.[7] A small subset of patients with biphenotype characteristics i.e., positive for CD2 (a T- lineage antigen) and CD19 (a B-lineage antigen), have been studied and found generally to have good outcomes with treatment, due in part to their favorable presenting features.[8]

3. Cytogenetics: Technological improvements now make it possible to demonstrate abnormalities in chromosomal number and/or structure in the majority of cases of ALL.[9] The presence of hyperdiploidy (modal chromosome number >50 or DNA index >1.16 as determined by flow cytometry) is associated with a favorable prognosis.[10] Hypodiploidy (<45 chromosomes) is also associated with a poor prognosis. Using molecular techniques, the t(12;21) translocation has been found to be the most common genetic lesion in ALL, occurring in approximately 20% of patients. Fluorescence in situ hybridization and polymerase chain reaction studies of ALL specimens detect more translocations than traditional cytogenetics.[11] Children with the t(12;21) translocation have an excellent prognosis. Specific nonrandom chromosomal translocations such as t(4;11) and t(9;22) are associated with a poor prognosis.[12,13] The t(4;11) (q21;q23) is the most common translocation in infants younger than 12 months of age and almost always involves the MLL gene. Infants with molecular MLL rearrangements have an almost fivefold increased risk of adverse events compared with other infants.[14] The MLL gene rearrangement outside of the setting of the translocation of t(4;11) infant ALL does not appear to have prognostic significance.[15,16]

References:

  1. Bennett JM, Catovsky D, Daniel MT, et al.: The morphological classification of acute lymphoblastic leukemia: concordance among observers and clinical correlations. British Journal of Haematology 47(4): 553-561, 1981.

  2. Crist W, Boyett J, Roper M, et al.: Pre-B cell leukemia responds poorly to treatment: a Pediatric Oncology Group study. Blood 63(2): 407-414, 1984.

  3. 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): 117-122, 1990.

  4. Felix CA, Reaman GH, Korsmeyer SJ, et al.: Immunoglobulin and T-cell receptor gene configuration in acute lymphoblastic leukemia of infancy. Blood 70(2): 536-541, 1987.

  5. Uckun FM, Sensel MG, Sun L, et al.: Biology and treatment of childhood T-lineage acute lymphoblastic leukemia. Blood 91(3): 735-746, 1998.

  6. Uckun FM, Gaynon PS, Sensel MG, et al.: Clinical features and treatment outcome of childhood T-lineage acute lymphoblastic leukemia according to the apparent maturational stage of T-lineage leukemia blasts: A Children's Cancer Group study. Journal of Clinical Oncology 15(6): 2214-2221, 1997.

  7. Putti MC, Rondelli R, Cocito MG, et al.: Expression of myeloid markers lacks prognostic impact in children treated for acute lymphoblastic leukemia: Italian experience in AIEOP-ALL 88-91 studies. Blood 92(3): 795-801, 1998.

  8. Uckun FM, Gaynon P, Sather H, et al.: Clinical features and treatment outcome of children with biphenotypic CD2+ CD19+ acute lymphoblastic leukemia: a Children's Cancer Group study. Blood 89(7): 2488-2493, 1997.

  9. Raimondi SC: Current status of cytogenetic research in childhood acute lymphoblastic leukemia. Blood 81(9): 2237-2251, 1993.

  10. Jackson JF, Boyett J, Pullen J, et al.: Favorable prognosis associated with hyperdiploidy in children with acute lymphocytic leukemia correlates with extra chromosome 6: a Pediatric Oncology Group study. Cancer 66(6): 1183-1189, 1990.

  11. 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): 4252-4258, 1996.

  12. 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): 440-447, 1991.

  13. Fletcher JA, Lynch EA, Kimball VM, et al.: Translocation (9;22) is associated with extremely poor prognosis in intensively treated children with acute lymphoblastic leukemia. Blood 77(3): 435-439, 1991.

  14. Pui C, Behm FG, Downing JR, et al.: 11q23/MLL rearrangement confers a poor prognosis in infants with acute lymphoblastic leukemia. Journal of Clinical Oncology 12(5): 909-915, 1994.

  15. Behm FG, Raimondi SC, Frestedt JL, et al.: Rearrangement of the MLL gene confers a poor prognosis in childhood acute lymphoblastic leukemia, regardless of presenting age. Blood 87(7): 2870-2877, 1996.

  16. Uckun FM, Herman-Hatten K, Crotty ML, et al.: Clinical significance of MLL-AF4 fusion transcript expression in the absence of a cytogenetically detectable t(4;11)(q21;q23) chromosomal translocation. Blood 92(3): 810-821, 1998.


TREATMENT OPTION OVERVIEW

Many of the improvements in survival in childhood cancer have been made using new therapies that have attempted to improve on the best available, accepted therapy. Clinical trials in pediatric leukemia are designed to compare potentially better therapy with therapy that is currently accepted as standard. This comparison may be done in a randomized study of two treatment arms or by evaluating a single new treatment and comparing the results with those previously obtained with standard therapy.

Because of the relative rarity of cancer in children and adolescents, all patients with leukemia should be considered for entry into a clinical trial. 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 pediatric cancer center.

Successful treatment of children with acute lymphocytic leukemia (ALL) requires the control of bone marrow or systemic disease (marrow, liver and spleen, lymph nodes, etc.) as well as the treatment (or prevention) of extramedullary disease in sanctuary sites, particularly in the central nervous system (CNS). Only 3% of patients have detectable CNS involvement by accepted criteria at diagnosis. However, unless specific therapy is directed toward the CNS (intrathecal medication, cranial irradiation, high-dose systemic chemotherapy with methotrexate or ara-C) 50% of children will eventually develop overt CNS leukemia. Therefore all children with ALL should receive systemic combination chemotherapy together with CNS prophylaxis. Patients with established CNS leukemia at diagnosis require the use of intrathecal therapy followed by cranial irradiation.

Infants with ALL represent a distinctive category of children at higher risk for treatment failure, with the poorest prognosis for those with MLL gene rearrangements.[1-4] Resistance to therapy among infants may be due to the primitive nature of their leukemic cells. In vitro tests show that infant cells have greater resistance to treatment with prednisone, L-asparaginase, and teniposide than do leukemic cells from older children. Infant leukemic cells also are resistant to cell death by growth factor deprivation.[5] Children less than 1 year of age are generally treated with regimens designed specifically for infants.[6-9] Current regimens for infants with ALL employ intensified treatment approaches and may offer improved outcome compared to previously used, less intensive approaches.[4,9,10] Treatment is divided into stages: remission induction, CNS prophylaxis, consolidation or intensification, and maintenance. A delayed intensification phase of therapy following remission induction is used for all patients. The intensity of post-induction therapy is determined by the clinical and biologic prognostic factors. The average duration of maintenance therapy for children with ALL ranges between 2 and 3 years. Subgroups of patients who have a poor prognosis with current standard therapy may be treated differently. For example, children less than 1 year of age represent a distinct category of patients at higher risk for treatment failure, with the poorest prognosis for those with MLL gene rearrangements.[1-3] These children are generally treated with regimens designed specifically for infants.[6-9]. Current regimens for infants employ intensified treatment approaches and may offer improved outcome compared to previously utilized, less intensive approaches.[9,10] In these and other high risk groups, such as Philadelphia chromosome positive patients, bone marrow transplantation in first remission may be considered.

Since myelosuppression is an anticipated consequence of both leukemia and its treatment with chemotherapy, it is imperative that patients be closely monitored during treatment. Adequate facilities must be immediately available both for hematologic support and for the treatment of infectious complications.

The designations in PDQ that treatments are "standard" or "under clinical evaluation" are not to be used as a basis for reimbursement determinations.

References:

  1. 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): 570-573, 1994.

  2. Hilden JM, Frestedt JL, Moore RO, et al.: Molecular analysis of infant acute lymphoblastic leukemia: MLL gene rearrangement and reverse transcriptase-polymerase chain reaction for t(4;11)(q21;q23). Blood 86(10): 3876-3882, 1995.

  3. Pui C, Behm FG, Downing JR, et al.: 11q23/MLL rearrangement confers a poor prognosis in infants with acute lymphoblastic leukemia. Journal of Clinical Oncology 12(5): 909-915, 1994.

  4. 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. Journal of Clinical Oncology 17(2): 445-455, 1999.

  5. Pieters R, den Boer ML, Durian M, et al.: Relation between age, immunophenotype and in vitro drug resistance in 395 children with acute lymphoblastic leukemia--implications for treatment of infants. Leukemia 12(9): 1344-1348, 1998.

  6. Frankel LS, Ochs J, Shuster JJ, et al.: Therapeutic trial for infant acute lymphoblastic leukemia: the Pediatric Oncology Group experience (POG 8493). Journal of Pediatric Hematology/Oncology 19(1): 35-42, 1997.

  7. Chessells JM, Eden OB, Bailey CC, et al.: Acute lymphoblastic leukaemia in infancy: experience in MRC UKALL trials. Report from the Medical Research Council Working Party on Childhood Leukaemia. Leukemia 8(8): 1275-1279, 1994.

  8. Ferster A, Bertrand Y, Benoit Y, et al.: Improved survival for acute lymphoblastic leukaemia in infancy: the experience of EORTC-Childhood Leukaemia Cooperative Group. British Journal of Haematology 86(2): 284-290, 1994.

  9. 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): 2285-2295, 1997.

  10. Dreyer ZE, Steuber CP, Bowman WP, et al.: Induction intensification for infant acute lymphoid leukemia (ALL) (Meeting abstract). Proceedings of the American Society of Clinical Oncology 15: A1094, 1996.


UNTREATED CHILDHOOD ACUTE LYMPHOCYTIC LEUKEMIA


Induction chemotherapy

Three-drug induction regimens using vincristine, prednisone/dexamethasone, plus L-asparaginase in conjunction with intrathecal therapy have resulted in complete remission rates of greater than 95%.[1] Some data suggest that a more intense induction regimen (4 or 5 agents) results in improved event-free survival for patients considered high-risk at diagnosis;[1] however, since patients in these studies received an intensified treatment after remission induction, it is difficult to prove that the intensity of induction is directly related to long-term survival. Because of the likelihood of increased induction toxicity, most centers treat patients at lower-risk with prednisone, vincristine, and asparaginase and reserve the use of induction regimens using four or more agents for patients at higher-risk.[2]

In general, patients will achieve a complete remission within the first 4 weeks. Patients who require more than 4 weeks to achieve remission have a poor prognosis.[3] 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 induction therapy.[1,4,5] See the PDQ protocol file for a listing of ongoing clinical trials.


Central nervous system prophylaxis

The early institution of adequate central nervous system (CNS) prophylaxis is critical in preventing CNS relapse. While the combination of cranial irradiation and intrathecal (IT) chemotherapy (usually with methotrexate) is effective, attention has focused on the long-term neurotoxicity associated with this combination. Thus, a current goal is to achieve effective CNS prophylaxis while minimizing neurotoxicity.[6-10] Some methods of CNS prophylaxis have been found to cause unacceptably high levels of neurological toxicity and should be avoided, including use of 2400 cGy of cranial irradiation followed by intravenous methotrexate (dose >/=40 mg/m2 weekly)[11] and use of repeated courses of high-dose methotrexate given at 2-week intervals.[10] Lower doses of radiation appear to be associated with less toxic effects. Treatment regimens have varied according to the prognostic category of the patient.

The majority of patients with acute lymphocytic leukemia (ALL) receive intrathecal chemotherapy with either methotrexate or "triple" therapy (methotrexate, hydrocortisone, and cytarabine), with or without moderate or high-dose systemic methotrexate for CNS prophylaxis.[12-15] Early intensive IT therapy may significantly decrease the CNS relapse rate.[12] Intensive IT therapy may also have a significant systemic effect resulting in a decrease in marrow relapse rate. Significant control of bone marrow relapse did not occur until CNS prophylaxis was instituted. The type and extent of systemic intensification also appear to influence the efficacy of the CNS prophylaxis, especially in average-risk patients.[2,14,15] Whether patients at high risk of CNS relapse (e.g., those older than 10 years of age, presence of hyperleukocytosis, T-cell ALL with a high white blood cell count, or lymphomatous presentation) continue to require cranial irradiation in addition to extended intrathecal therapy is controversial, although high risk patients with a rapid early response to therapy appear to have adequate CNS prophylaxis with intrathecal therapy alone.[12,16,17] In a Childrens Cancer Group trial, the use of dexamethasone during induction, consolidation, and maintenance resulted in a significant reduction in CNS relapse.[18]

References:

  1. Gaynon PS, Bleyer WA, Steinherz PG, et al.: Day 7 marrow response and outcome for children with acute lymphoblastic leukemia and unfavorable presenting features. Medical and Pediatric Oncology 18(4): 273-279, 1990.

  2. Veerman AJ, Hahlen 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. Journal of Clinical Oncology 14(3): 911-918, 1996.

  3. Silverman LB, Gelber RD, Young ML, et al.: Induction failure in acute lymphoblastic leukemia of childhood. Cancer 85(6): 1395-1404, 1999.

  4. 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): 1292-1295, 1995.

  5. 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. Journal of Clinical Oncology 14(2): 389-398, 1996.

  6. Pinkel D, Woo S: Prevention and treatment of meningeal leukemia in children. Blood 84(2): 355-366, 1994.

  7. Waber DP, Tarbell NJ, Fairclough D, et al.: Cognitive sequelae of treatment in childhood acute lymphoblastic leukemia: cranial radiation requires an accomplice. Journal of Clinical Oncology 13(10): 2490-2496, 1995.

  8. Smibert E, Anderson V, Godber T, et al.: Risk factors for intellectual and educational sequelae of cranial irradiation in childhood acute lymphoblastic leukaemia. British Journal of Cancer 73(6): 825-830, 1996.

  9. Copeland DR, Moore BD III, Francis DJ, et al.: Neuropsychologic effects of chemotherapy on children with cancer: a longitudinal study. Journal of Clinical Oncology 14(10): 2826-2835, 1996.

  10. Mahoney DH, 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. Journal of Clinical Oncology 16(5): 1712-1722, 1998.

  11. Ochs JJ: Neurotoxicity due to central nervous system therapy for childhood leukemia. American Journal of Pediatric Hematology/Oncology 11(1): 93-105, 1989.

  12. 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): 411-415, 1998.

  13. 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. Journal of Clinical Oncology 11(5): 839-849, 1993.

  14. 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. Journal of Clinical Oncology 11(3): 520-526, 1993.

  15. Conter V, Arico 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-Munster-based intensive chemotherapy. Journal of Clinical Oncology 13(10): 2497-2502, 1995.

  16. Cherlow JM, Steinherz PG, Sather HN, et al.: The role of radiation therapy in the treatment of acute lymphoblastic leukemia with lymphomatous presentation: a report from the Childrens Cancer Group. International Journal of Radiation Oncology, Biology, Physics 27(5): 1001-1009, 1993.

  17. Nachman J, Sather HN, Cherlow JM, et al.: Response of children with high-risk acute lymphoblastic leukemia treated with and without cranial irradiation: a report from the Children's Cancer Group. Journal of Clinical Oncology 16(3): 920-930, 1998.

  18. Bostrom B, Gaynon PS, Sather S, et al.: Dexamethasone (DEX) decreases central nervous system (CNS) relapse and improves event-free survival (EFS) in lower risk acute lymphoblastic leukemia (ALL). Proceedings of the American Society of Clinical Oncology 17: A2024, 527a, 1998.


CHILDHOOD ACUTE LYMPHOCYTIC LEUKEMIA IN REMISSION


Consolidation/Intensification

Once a remission has been achieved, systemic treatment in conjunction with central nervous system (CNS) prophylaxis follows. Intensity of the immediate post-induction chemotherapy varies considerably. In some protocols, drugs with little cross resistance are used to further eradicate residual disease and to prevent emergence of a drug-resistant clone. This approach has clearly resulted in improved outcome in acute lymphocytic leukemia, even in patients with a poor prognosis.[1,2] In children with standard-risk disease, there has been an attempt to limit exposure to drugs, such as the anthracyclines and the alkylating agents, that are associated with an increased risk of late toxic effects.[3-5] Effective therapies that have employed this strategy include a limited number of courses of intermediate- or high-dose methotrexate and therapies that utilize only low cumulative dosages of anthracyclines and alkylating agents.[6,7] In high-risk patients, a number of different approaches have been used with comparable efficacy.[8-11] In addition, one or two blocks of delayed intensification therapy prior to maintenance have resulted in improved long-term survival for both lower- and higher-risk patients.[12-15] For high-risk patients with slow early response to therapy (M3 marrow on day 7), augmented BFM (Berlin-Frankfurt-Munster) therapy has been shown to improve outcome.[16] See the PDQ protocol file for a listing of ongoing clinical trials.


Maintenance

Following consolidation, chemotherapy continues until 2-3 years of continuous complete remission. The backbone of maintenance therapy in most protocols is daily mercaptopurine and weekly methotrexate. Clinical trials call for giving oral mercaptopurine in the evening. There is evidence that suggests this practice is beneficial and that it may improve event-free survival.[17] Monthly pulses of vincristine and prednisone are often added to the standard maintenance regimen.[18] If the patient has not had cranial irradiation, intrathecal chemotherapy for CNS prophylaxis is generally given during maintenance. It is imperative to carefully monitor children on maintenance therapy for both drug-related toxicity and compliance.

References:

  1. Reiter A, Schrappe M, Ludwig W, et al.: Chemotherapy in 998 unselected childhood acute lymphoblastic leukemia patients: results and conclusions of the multicenter trial ALL-BFM 86. Blood 84(9): 3122-3133, 1994.

  2. Amylon MD, Shuster J, Pullen J, et al.: Intensive high-dose asparaginase consolidation improves survival for pediatric patients with T cell acute lymphoblastic leukemia and advanced stage lymphoblastic lymphoma: a Pediatric Oncology Group study. Leukemia 13(3): 335-342, 1999.

  3. Camitta B, Leventhal B, Lauer S, et al.: Intermediate-dose intravenous methotrexate and mercaptopurine therapy for non-T, non-B acute lymphocytic leukemia of childhood: a Pediatric Oncology Group study. Journal of Clinical Oncology 7(10): 1539-1544, 1989.

  4. Veerman AJ, Hahlen 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. Journal of Clinical Oncology 14(3): 911-918, 1996.

  5. Gustafsson G, Kreuger A, et al. for the Nordic Society of Paediatric Haematology and Oncology (NOPHO): 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. Acta Paediatrica 87(11): 1151-1161, 1998.

  6. Harris MB, Shuster JJ, Pullen DJ, et al.: Consolidation therapy with antimetabolite-based therapy in standard-risk acute. Journal of Clinical Oncology 16(8): 2840-2847, 1998.

  7. Schalson G, Leblanc T, Perel Y, et al.: Randomized study comparing low dose methotrexate (LDMTX) versus high dose methotrexate (HDMTX) in low and intermediate risk pre B acute Lymphoblastic leukemia (ALL) in children. Results of French protocol Fralle 93. Proceedings of the American Society of Clinical Oncology 17: A2026, 527a, 1998.

  8. Dahl GV, Rivera GK, Look AT, et al.: Teniposide plus cytarabine improves outcome in childhood acute lymphoblastic leukemia presenting with a leukocyte count greater than or equal to 100 x 10(9)/L. Journal of Clinical Oncology 5(7): 1015-1021, 1987.

  9. 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. Journal of Clinical Oncology 11(11): 2234-2242, 1993.

  10. Lauer SJ, Camitta BM, Leventhal BG, et al.: Intensive alternating drug pairs for treatment of high-risk childhood acute lymphoblastic leukemia: a Pediatric Oncology Group pilot study. Cancer 71(9): 2854-2861, 1993.

  11. Schorin MA, Blattner S, Gelber RD, et al.: Treatment of childhood acute lymphoblastic leukemia: results of Dana-Farber Cancer Institute/Children's Hospital Acute Lymphoblastic Leukemia Consortium protocol 85-01. Journal of Clinical Oncology 12(4): 740-747, 1994.

  12. 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): 1783-1788, 1996.

  13. 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. Journal of Clinical Oncology 11(3): 527-537, 1993.

  14. Chessells JM, Bailey C, Richards SM, et al.: 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): 143-148, 1995.

  15. Frankel LS, Ochs J, Shuster JJ, et al.: Therapeutic trial for infant acute lymphoblastic leukemia: the Pediatric Oncology Group experience (POG 8493). Journal of Pediatric Hematology/Oncology 19(1): 35-42, 1997.

  16. 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. Journal of Clinical Oncology 15(6): 2222-2230, 1997.

  17. Schmieglow 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. Journal of Pediatric Hematology/Oncology 19(2): 102-109, 1997.

  18. 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. Journal of Clinical Oncology 9(6): 1012-1021, 1991.


RECURRENT CHILDHOOD ACUTE LYMPHOCYTIC LEUKEMIA

The prognosis for a child with acute lymphocytic leukemia (ALL) whose disease recurs depends on the time and site of relapse.[1] If the recurrence occurs either during front-line therapy or shortly after discontinuation of initial therapy, the prognosis for long-term survival in patients with marrow relapse is poor with only a 20% likelihood of long-term survival.[2] However, if relapse occurs more than a year after discontinuation of initial therapy, the prognosis is better with 40%-65% of these patients achieving long-term, disease-free survival with aggressive salvage therapy.[3-6]

The selection of therapy for the child whose disease recurs on therapy depends on many factors including prior treatment, whether the recurrence is medullary or extramedullary, and individual patient considerations. Aggressive approaches including bone marrow transplantation are appropriate and should be strongly considered for patients with 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 per microliter or more.[4] Allogeneic transplant from an HLA-identical sibling that is performed in second complete remission has resulted in longer leukemia- free survival when compared with a chemotherapy approach, especially following early relapse.[7-9] However, for patients with a late marrow relapse, a primary chemotherapy approach should be considered with bone marrow transplantation reserved for a subsequent marrow relapse.[3,10] The value of matched unrelated stem cell transplantation in the therapy of children with recurrent ALL is under investigation.[11-13]

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) and testicular relapse is less than 10%. While the prognosis for children with isolated CNS relapse had been quite poor in the past, aggressive systemic and intrathecal therapy combined with craniospinal irradiation has improved the outlook particularly for patients who did not receive cranial irradiation.[14,15] The results of treatment of isolated testicular relapse depend on the timing of the relapse. The 3-year event-free survival (EFS) of boys with overt testicular relapse during therapy is 39%. The 4-year EFS of boys with occult testicular relapse discovered at the end of treatment is about 55%, and it is approximately 85% for boys with a late overt testicular relapse.[16] See the PDQ protocol file for a listing of ongoing clinical trials.

References:

  1. 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): 1387-1395, 1998.

  2. Henze G, Fengler R, Hartmann B, et al.: Six-year experience with a comprehensive approach to the treatment of recurrent childhood acute lymphoblastic leukemia (ALL-REZ BFM 85): a relapse study of the BFM group. Blood 78(5): 1166-1172, 1991.

  3. 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): 831-837, 1996.

  4. Buhrer 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. Journal of Clinical Oncology 14(10): 2812-2817, 1996.

  5. 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): 602-609, 1993.

  6. Vora A, Frost L, Goodeve A, et al.: Late relapsing childhood lymphoblastic leukemia. Blood 92(7): 2334-2337, 1998.

  7. 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. New England Journal of Medicine 331(19): 1253-1258, 1994.

  8. 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. Journal of Clinical Oncology 13(2): 352-358, 1995.

  9. Wheeler K, Richards S, et al. for the Medical Research Council Working Party on Childhood Leukaemia: Comparison of bone marrow transplant and chemotherapy for relapsed childhood acute lymphoblastic leukemia: the MRC UKALL X experience. British Journal of Haematology 101(1): 94-103, 1998.

  10. 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 Transplantation 20(11): 939-944, 1997.

  11. 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): 767-771, 1997.

  12. Casper J, Camitta B, Truitt R, et al.: Unrelated bone marrow donor transplants for children with leukemia or myelodysplasia. Blood 85(9): 2354-2363, 1995.

  13. Weisdorf DJ, Billett AL, Hannan P, et al.: Autologous versus unrelated donor allogeneic marrow transplantation for acute lymphoblastic leukemia. Blood 90(8): 2962-2968, 1997.

  14. Ribeiro RC, Rivera GK, Hudson M, et al.: An intensive re-treatment protocol for children with an isolated CNS relapse of acute lymphoblastic leukemia. Journal of Clinical Oncology 13(2): 333-338, 1995.

  15. 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. International Journal of Radiation Oncology, Biology, Physics 31(3): 477-483, 1995.

  16. 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. Journal of Clinical Oncology 10(4): 624-630, 1992.

Date Last Modified: 11/1999



Home | 

test About Medicine OnLine Medicine OnLine Home Page Cancer Libraries DoseCalc Online Oncology News
Cancer Forums Medline Search Cancer Links Glossary