PDQ® Treatment Health Professionals
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.
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. 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.
It is well appreciated that children with ALL have a better prognosis when treated in established clinical trials. 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.
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. 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. 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. 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.
A number of cell-related findings have an impact on prognosis and potentially on therapy:
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.
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. 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, whereas CD7+, CD2-, and CD5- immunophenotype ("pro-thymocyte") infers a less favorable prognosis.
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. 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.
3. Cytogenetics: Technological improvements now make it possible to demonstrate abnormalities in chromosomal number and/or structure in the majority of cases of ALL. The presence of hyperdiploidy (modal chromosome number >50 or DNA index >1.16 as determined by flow cytometry) is associated with a favorable prognosis. 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. 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. 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]
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. 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.
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%. 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; 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.
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. 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.
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) and use of repeated courses of high-dose methotrexate given at 2-week intervals. 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. 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.
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. See the PDQ protocol file for a listing of ongoing clinical trials.
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. Monthly pulses of vincristine and prednisone are often added to the standard maintenance regimen. 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.
The prognosis for a child with acute lymphocytic leukemia (ALL) whose disease recurs depends on the time and site of relapse. 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. 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. 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. See the PDQ protocol file for a listing of ongoing clinical trials.
Date Last Modified: 11/1999