National Cancer Institute


For acute lymphoblastic leukemia (ALL), the 5-year survival rate rose from 60% to about 90% for children younger than 15 years and from 28% to about 75% for adolescents aged 15–19 years between 1975 and 2010. Get information about risk factors, signs, diagnosis, genomics, survival, risk-based treatment assignment, and induction and postinduction therapy for children and adolescents with newly diagnosed and recurrent ALL.

This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the treatment of childhood acute lymphoblastic leukemia. It is intended as a resource to inform and assist clinicians who care for cancer patients. It does not provide formal guidelines or recommendations for making health care decisions.

This summary is reviewed regularly and updated as necessary by the PDQ Pediatric Treatment Editorial Board, which is editorially independent of the National Cancer Institute (NCI). The summary reflects an independent review of the literature and does not represent a policy statement of NCI or the National Institutes of Health (NIH).

Childhood ALL Treatment

Childhood Acute Lymphoblastic Leukemia Treatment

General Information About Childhood Acute Lymphoblastic Leukemia (ALL)

Cancer in children and adolescents is rare, although the overall incidence of childhood cancer, including ALL, has been slowly increasing since 1975. Dramatic improvements in survival have been achieved in children and adolescents with cancer. Between 1975 and 2010, childhood cancer mortality decreased by more than 50%. For ALL, the 5-year survival rate has increased over the same time from 60% to approximately 90% for children younger than 15 years and from 28% to more than 75% for adolescents aged 15 to 19 years. Childhood and adolescent cancer survivors require close monitoring because cancer therapy side effects may persist or develop months or years after treatment. (Refer to the PDQ summary on Late Effects of Treatment for Childhood Cancer for specific information about the incidence, type, and monitoring of late effects in childhood and adolescent cancer survivors.)

Incidence

ALL is the most common cancer diagnosed in children and represents approximately 25% of cancer diagnoses among children younger than 15 years. In the United States, ALL occurs at an annual rate of approximately 41 cases per 1 million people aged 0 to 14 years and approximately 17 cases per 1 million people aged 15 to 19 years. There are approximately 3,100 children and adolescents younger than 20 years diagnosed with ALL each year in the United States. Since 1975, there has been a gradual increase in the incidence of ALL.

A sharp peak in ALL incidence is observed among children aged 2 to 3 years (>90 cases per 1 million per year), with rates decreasing to fewer than 30 cases per 1 million by age 8 years. The incidence of ALL among children aged 2 to 3 years is approximately fourfold greater than that for infants and is likewise fourfold to fivefold greater than that for children aged 10 years and older.

The incidence of ALL appears to be highest in Hispanic children (43 cases per 1 million). The incidence is substantially higher in white children than in black children, with a nearly threefold higher incidence of ALL from age 2 to 3 years in white children than in black children.

Anatomy

Childhood ALL originates in the T and B lymphoblasts in the bone marrow (refer to Figure 1).

Blood cell development; drawing shows the steps a blood stem cell goes through to become a red blood cell, platelet, or white blood cell. A myeloid stem cell becomes a red blood cell, a platelet, or a myeloblast, which then becomes a granulocyte (the types of granulocytes are eosinophils, basophils, and neutrophils). A lymphoid stem cell becomes a lymphoblast and then becomes a B-lymphocyte, T-lymphocyte, or natural killer cell.Figure 1. Blood cell development. Different blood and immune cell lineages, including T and B lymphocytes, differentiate from a common blood stem cell.

Marrow involvement of acute leukemia as seen by light microscopy is defined as follows:

  • M1: Fewer than 5% blast cells.
  • M2: 5% to 25% blast cells.
  • M3: Greater than 25% blast cells.

Almost all patients with ALL present with an M3 marrow.

Risk Factors for Developing ALL

Few factors associated with an increased risk of ALL have been identified. The primary accepted risk factors for ALL and associated genes (when relevant) include the following:

  • Prenatal exposure to x-rays.
  • Postnatal exposure to high doses of radiation (e.g., therapeutic radiation as previously used for conditions such as tinea capitis and thymus enlargement).
  • Previous treatment with chemotherapy.
  • Genetic conditions that include the following:
    • Down syndrome. (Refer to the Down syndrome section of this summary for more information.)
    • Neurofibromatosis ().
    • Bloom syndrome ().
    • Fanconi anemia (multiple genes; ALL is observed much less frequently than acute myeloid leukemia [AML]).
    • Ataxia telangiectasia ().
    • Li-Fraumeni syndrome ().
    • Constitutional mismatch repair deficiency (biallelic mutation of , , , and ).
  • Low- and high-penetrance inherited genetic variants. (Refer to the Low- and high-penetrance inherited genetic variants section of this summary for more information.)
  • Carriers of a constitutional Robertsonian translocation that involves chromosomes 15 and 21 are specifically and highly predisposed to developing iAMP21 ALL.

Down syndrome

Children with Down syndrome have an increased risk of developing both ALL and AML, with a cumulative risk of developing leukemia of approximately 2.1% by age 5 years and 2.7% by age 30 years.

Approximately one-half to two-thirds of cases of acute leukemia in children with Down syndrome are ALL, and about 2% to 3% of childhood ALL cases occur in children with Down syndrome. While the vast majority of cases of AML in children with Down syndrome occur before the age of 4 years (median age, 1 year), 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.

Patients with ALL and Down syndrome have a lower incidence of both favorable (t(12;21)(p13;q22)/ []) and hyperdiploidy [51–65 chromosomes]) and unfavorable (t(9;22)(q34;q11.2)) or t(4;11)(q21;q23) and hypodiploidy [<44 chromosomes]) cytogenetic findings and a near absence of T-cell phenotype.

Approximately 50% to 60% of cases of ALL in children with Down syndrome have genomic alterations affecting that generally result in overexpression of the protein produced by this gene, which dimerizes with the interleukin-7 receptor alpha to form the receptor for the cytokine thymic stromal lymphopoietin. genomic alterations are observed at a much lower frequency (<10%) in children with precursor B-cell ALL who do not have Down syndrome. Based on the relatively small number of published series, it does not appear that genomic aberrations in patients with Down syndrome and ALL have prognostic relevance. However, gene deletions, observed in up to 35% of patients with Down syndrome and ALL, have been associated with a significantly worse outcome in this group of patients.

Approximately 20% of ALL cases arising in children with Down syndrome have somatically acquired mutations, a finding that is uncommon among younger children with ALL but that is observed in a subset of primarily older children and adolescents with high-risk precursor B-cell ALL. Almost all Down syndrome ALL cases with mutations also have genomic alterations. Preliminary evidence suggests no correlation between mutation status and 5-year event-free survival in children with Down syndrome and ALL, but more study is needed to address this issue, as well as the prognostic significance of alterations and gene deletions in this patient population.

Low- and high-penetrance inherited genetic variants

Genetic predisposition to ALL can be divided into the following several broad categories:

  • Association with genetic syndromes. Increased risk can be associated with the genetic syndromes listed above in which ALL is observed, although it is not the primary manifestation of the condition.
  • Common alleles. Another category for genetic predisposition includes common alleles with relatively small effect sizes that are identified by genome-wide association studies. Genome-wide association studies have identified a number of germline (inherited) genetic polymorphisms that are associated with the development of childhood ALL. For example, the risk alleles of are associated with the development of hyperdiploid (51–65 chromosomes) precursor B-cell ALL. is a gene that encodes a transcriptional factor important in embryonic development, cell type–specific gene expression, and cell growth regulation. Other genes with polymorphisms associated with increased risk of ALL include , , , , , , and .
  • Rare germline variants with high penetrance. A germline variant in that substitutes serine for glycine at amino acid 183 and that reduces activity has been identified in several families that experienced multiple cases of ALL. Similarly, several germline variants that lead to loss of ETV6 function have been identified in kindreds affected by both thrombocytopenia and ALL. Sequencing of in remission (i.e., germline) specimens identified variants that were potentially related to ALL in approximately 1% of children with ALL that were evaluated. This suggests a previously unrecognized contribution to ALL risk that will need to be assessed in future studies.

Prenatal origin of childhood ALL

Development of ALL is in most cases a multistep process, with more than one genomic alteration required for frank leukemia to develop. In at least some cases of childhood ALL, the initial genomic alteration appears to occur in utero. Evidence to support 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. Similarly, in ALL characterized by specific chromosomal abnormalities, some patients have blood cells that carry at least one leukemic genomic abnormality at the time of birth, with additional cooperative genomic changes acquired postnatally. Genomic studies of identical twins with concordant leukemia further support the prenatal origin of some leukemias.

Evidence also exists that some children who never develop ALL are born with very rare blood cells carrying a genomic alteration associated with ALL. For example, in one study, 1% of neonatal blood spots (Guthrie cards) tested positive for the translocation, far exceeding the number of cases of ALL in children. Other reports confirm or do not confirm this finding, and methodological issues related to fluorescence hybridization testing complicate interpretation of the initial 1% estimate.

Clinical Presentation

The typical and atypical symptoms and clinical findings of childhood ALL have been published.

Diagnosis

The diagnostic evaluation needed to definitively diagnose childhood ALL has been published.

The 2016 revision to the World Health Organization classification of tumors of the hematopoietic and lymphoid tissues lists the following entities for acute lymphoid leukemias:

  • B-lymphoblastic leukemia/lymphoma, not otherwise specified (NOS).
  • B-lymphoblastic leukemia/lymphoma with recurrent genetic abnormalities.
  • B-lymphoblastic leukemia/lymphoma with t(9;22)(q34.1;q11.2); .
  • B-lymphoblastic leukemia/lymphoma with t(v;11q23.3); rearranged.
  • B-lymphoblastic leukemia/lymphoma with t(12;21)(p13.2;q22.1); .
  • B-lymphoblastic leukemia/lymphoma with hyperdiploidy.
  • B-lymphoblastic leukemia/lymphoma with hypodiploidy.
  • B-lymphoblastic leukemia/lymphoma with t(5;14)(q31.1;q32.3); .
  • B-lymphoblastic leukemia/lymphoma with t(1;19)(q23;p13.3); .
  • Provisional entity: B-lymphoblastic leukemia/lymphoma, .
  • Provisional entity: B-lymphoblastic leukemia/lymphoma with iAMP21.
  • Provisional entity: Early T-cell precursor lymphoblastic leukemia.

Key clinical and biological characteristics, as well as the prognostic significance for these entities, are discussed in the Cytogenetics/genomics alterations section of this summary.

Overall Outcome for ALL

Among children with ALL, approximately 98% attain remission, and approximately 85% of patients aged 1 to 18 years with newly diagnosed ALL treated on current regimens are expected to be long-term event-free survivors, with over 90% surviving at 5 years.

Despite the treatment advances in childhood ALL, numerous important biologic and therapeutic questions remain to be answered before the goal of curing every child with ALL with the least associated toxicity can be achieved. The systematic investigation of these issues requires large clinical trials, and the opportunity to participate in these trials is offered to most patients and families.

Clinical trials for children and adolescents with ALL are generally designed to compare therapy that is currently accepted as standard with investigational regimens that seek to improve cure rates and/or decrease toxicity. In certain trials in which the cure rate for the patient group is very high, therapy reduction questions may be asked. Much of the progress made in identifying curative therapies for childhood ALL and other childhood cancers has been achieved through investigator-driven discovery and tested in carefully randomized, controlled, multi-institutional clinical trials. Information about ongoing clinical trials is available from the NCI website.

Current Clinical Trials

Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.

Risk-Based Treatment Assignment

Introduction to Risk-Based Treatment

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 patients with favorable clinical and biological features who are likely to have a very good outcome with modest therapy can be spared more intensive and toxic treatment, while a more aggressive, and potentially more toxic, therapeutic approach can be provided for patients who have a lower probability of long-term survival.

Certain ALL study groups, such as the Children’s Oncology Group (COG), use a more- or less-intensive induction regimen based on a subset of pretreatment factors, while other groups give a similar induction regimen to all patients. Factors used by the COG to determine the intensity of induction include immunophenotype, the presence or absence of extramedullary disease, steroid pretreatment, the presence or absence of Down syndrome, and the National Cancer Institute (NCI) risk group classification. The NCI risk group classification for B-cell ALL stratifies risk according to age and white blood cell (WBC) count:

  • Standard risk—WBC count less than 50,000/μL and age 1 to younger than 10 years.
  • High risk—WBC count 50,000/μL or greater and/or age 10 years or older.

All study groups modify the intensity of postinduction therapy based on a variety of prognostic factors, including NCI risk group, immunophenotype, early response determinations, and cytogenetics and genomic alterations. Detection of the Philadelphia chromosome leads to immediate changes in induction therapy.

Risk-based treatment assignment requires the availability of prognostic factors that reliably predict outcome. For children with ALL, a number of factors have demonstrated prognostic value, some of which are described below. Factors affecting prognosis are grouped into the following three categories:

  • Patient and clinical disease characteristics.
  • Leukemic characteristics.
  • 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. Because prognostic factors are treatment dependent, improvements in therapy may diminish or abrogate the significance of any of these presumed prognostic factors.

A subset of the prognostic and clinical factors discussed below is used for the initial stratification of children with ALL for treatment assignment. (Refer to the Prognostic (risk) groups under clinical evaluation section of this summary for brief descriptions of the prognostic groupings currently applied in ongoing clinical trials in the United States.)

(Refer to the Prognostic Factors After First Relapse of Childhood ALL section of this summary for information about important prognostic factors at relapse.)

Prognostic Factors Affecting Risk-Based Treatment

Patient and clinical disease characteristics

Patient and clinical disease characteristics affecting prognosis include the following:

Age at diagnosis

Age at diagnosis has strong prognostic significance, reflecting the different underlying biology of ALL in different age groups.

WBC count at diagnosis

A WBC count of 50,000/µL is generally used as an operational cut point between better and poorer prognosis, although the relationship between WBC count and prognosis is a continuous rather than a step function. Patients with precursor B-cell ALL and high WBC counts at diagnosis have an increased risk of treatment failure compared with patients with low initial WBC counts.

The median WBC count at diagnosis is much higher for T-cell ALL (>50,000/µL) than for precursor B-cell ALL (<10,000/µL), and there is no consistent effect of WBC count at diagnosis on prognosis for T-cell ALL.

CNS involvement at diagnosis

The presence or absence of CNS leukemia 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 or absence of blasts on cytospin as follows:

  • 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 (CNS3) at diagnosis are at a higher risk of treatment failure (both within the CNS and systemically) than are patients who are classified as CNS1 or CNS2. Some studies have reported increased risk of CNS relapse and/or inferior EFS in CNS2 patients, compared with CNS1 patients, while others have not.

A traumatic lumbar puncture (≥10 erythrocytes/µL) that includes blasts at diagnosis has also been associated with increased risk of CNS relapse and overall poorer outcome in some studies, but not others. Patients with CNS2, CNS3, or traumatic lumbar puncture have a higher frequency of unfavorable prognostic characteristics than do those with CNS1, including significantly higher WBC counts at diagnosis, older age at diagnosis, an increased frequency of the T-cell ALL phenotype, and () gene rearrangements.

Most clinical trial groups have approached CNS2 and traumatic lumbar puncture by utilizing more intensive therapy, primarily additional doses of intrathecal therapy during induction.; []

To determine whether a patient with a traumatic lumbar puncture (with blasts) should be treated as CNS3, the COG uses an algorithm relating the WBC and red blood cell counts in the spinal fluid and the peripheral blood.

Testicular involvement at diagnosis

Overt testicular involvement at the time of diagnosis occurs in approximately 2% of males, most commonly in T-cell ALL.

In early ALL trials, testicular involvement at diagnosis was an adverse prognostic factor. With more aggressive initial therapy, however, it does not appear that testicular involvement at diagnosis has prognostic significance. For example, the European Organization for Research and Treatment of Cancer (EORTC [EORTC-58881]) reported no adverse prognostic significance for overt testicular involvement at diagnosis.

The role of radiation therapy for testicular involvement is unclear. A study from St. Jude Children's Research Hospital (SJCRH) suggests that a good outcome can be achieved with aggressive conventional chemotherapy without radiation. The COG has also adopted this strategy for boys with testicular involvement that resolves completely by the end of induction therapy. The COG considers patients with testicular involvement to be high risk regardless of other presenting features, but most other large clinical trial groups in the United States and Europe do not consider testicular disease to be a high-risk feature.

Down syndrome (trisomy 21)

Outcome in children with Down syndrome and ALL has generally been reported as somewhat inferior to outcomes observed in children who do not have Down syndrome. In some studies, the lower EFS and OS of children with Down syndrome appear to be related to increased frequency of treatment-related mortality, as well as higher rates of induction failure and relapse in Down syndrome patients. The inferior anti-leukemic outcome may be due, in part, to favorable biological features such as or hyperdiploidy (51–65 chromosomes) with trisomies of chromosomes 4 and 10 in Down syndrome ALL patients.

  • In a large retrospective study that included 653 patients with Down syndrome and ALL, Down syndrome patients had a lower CR rate (97% vs. 99%, < .001), higher cumulative incidence of relapse (26% vs. 15%, < .001) and higher treatment-related mortality (7% vs. < 1%, < .001) compared with non-Down syndrome patients. Amongst the Down syndrome patients, age younger than 6 years, WBC count of less than 10,000/µL, and the presence of the fusion (observed in 8% of patients) were independent predictors of favorable EFS.
  • In a report from the COG, among precursor B-cell ALL patients who lacked () rearrangements, , , and hyperdiploidy with trisomies of chromosomes 4 and 10, the EFS and OS were similar in children with and without Down syndrome.
  • Certain genomic abnormalities, such as deletions, aberrations, and mutations are seen more frequently in ALL arising in children with Down syndrome than in those without Down syndrome. Studies of Down syndrome children with ALL suggest that the presence of deletions (but not aberrations or mutations) is associated with an inferior prognosis.

Sex

In some studies, the prognosis for girls with ALL is slightly better than it is for boys with ALL. 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. While some reports describe outcomes for boys as closely approaching those of girls, larger clinical trial experiences and national data continue to show somewhat lower survival rates for boys.

Race and ethnicity

Over the last several decades in the United States, survival rates in black and Hispanic children with ALL have been somewhat lower than the rates in white children with ALL.

The following factors associated with race and ethnicity influence survival:

  • ALL subtype. The reason for better outcomes in white and Asian children than in black and Hispanic children is at least partially explained by the different spectrum of ALL subtypes. For example, black children have a higher relative incidence of T-cell ALL and lower rates of favorable genetic subtypes of precursor B-cell ALL.
  • Treatment adherence. Differences in outcome may also be related to treatment adherence, as illustrated by two studies of adherence to oral mercaptopurine (6-MP) in maintenance therapy. In the first study, there was an increased risk of relapse in Hispanic children compared with non-Hispanic white children, depending on the level of adherence, even when adjusting for other known variables. However, at adherence rates of 90% or more, Hispanic children continued to demonstrate increased rates of relapse. In the second study, adherence rates were significantly lower in Asian American and African American patients than in non-Hispanic white patients. A greater percentage of patients in these ethnic groups had adherence rates of less than 90%, which was associated with a 3.9-fold increased risk of relapse.
  • Ancestry-related genomic variations. Ancestry-related genomic variations may also contribute to racial and ethnic disparities in both the incidence and outcome of ALL. For example, the differential presence of specific host polymorphisms in different racial and ethnic groups may contribute to outcome disparities, as illustrated by the occurrence of single nucleotide polymorphisms in the gene that occur more frequently among Hispanics and are linked to both ALL susceptibility and to relapse hazard.

Weight at diagnosis and during treatment

Studies of the impact of obesity on the outcome of ALL have had variable results. In most of these studies, obesity is defined as weight above the 95th percentile for age and height.

  • Three studies have not demonstrated an independent effect of obesity on EFS.[]; []
  • Two studies have shown obesity to be an independent prognostic factor only in patients older than 10 years or in patients with intermediate-risk or high-risk disease.[]
  • The COG reported on the impact of obesity on outcome in 2,008 children, 14% of whom were obese, who were enrolled on a high-risk ALL trial ().[] Obesity was found to be an independent variable for inferior outcome compared with nonobese patients (5-year EFS, 64% vs. 74%; = .002.) However, obese patients at diagnosis who then normalized their weight during the premaintenance period of treatment had outcomes similar to patients with normal weight at diagnosis.
  • In a retrospective study of patients treated at a single institution, obesity at diagnosis was linked to an increased risk of having minimal residual disease (MRD) at the end of induction and an inferior EFS.[]

In a study of 762 pediatric patients with ALL (aged 2–17 years), the Dutch Childhood Oncology Group found that those who were underweight at diagnosis (8% of the population) had an almost twofold higher risk of relapse compared with nonunderweight patients (after adjusting for risk group and age), although this did not result in a difference in EFS or OS. Patients with loss of body mass index during the first 32 weeks of treatment had similar rates of relapse as other patients, but had significantly worse OS, primarily because of poorer salvage rates after relapse.

Leukemic characteristics

Leukemic cell characteristics affecting prognosis include the following:

Morphology

In the past, ALL lymphoblasts were classified using the French-American-British (FAB) criteria as having L1 morphology, L2 morphology, or L3 morphology. However, because of the lack of independent prognostic significance and the subjective nature of this classification system, it is no longer used.

Most cases of ALL that show L3 morphology express surface immunoglobulin (Ig) and have a gene translocation identical to those seen in Burkitt lymphoma (i.e., t(8;14)(q24;q32), t(2;8)) that join to one of the immunoglobulin genes. 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 about the treatment of B-cell ALL and Burkitt lymphoma.)

Immunophenotype

The 2016 revision to the World Health Organization (WHO) classification of myeloid neoplasms and acute leukemia classifies ALL as either B-lymphoblastic leukemia or T-lymphoblastic leukemia, with further subdivisions based on molecular characteristics. (Refer to the Diagnosis section of this summary for more information.)

Either B- or T-lymphoblastic leukemia can coexpress myeloid antigens. These cases need to be distinguished from leukemia of ambiguous lineage.

Cytogenetics/genomic alterations

A number of recurrent chromosomal abnormalities have been shown to have prognostic significance, especially in precursor B-cell ALL. Some chromosomal alterations are associated with more favorable outcomes, such as high hyperdiploidy (51–65 chromosomes) and the fusion. Others historically have been associated with a poorer prognosis, including the Philadelphia chromosome (t(9;22)(q34;q11.2)), rearrangements of the () gene, hypodiploidy, and intrachromosomal amplification of the gene (iAMP21).

In recognition of the clinical significance of many of these genomic alterations, the 2016 revision of the World Health Organization classification of tumors of the hematopoietic and lymphoid tissues lists the following entities for precursor B-cell ALL:

  • B-lymphoblastic leukemia/lymphoma, not otherwise specified (NOS).
  • B-lymphoblastic leukemia/lymphoma with recurrent genetic abnormalities.
  • B-lymphoblastic leukemia/lymphoma with t(9;22)(q34.1;q11.2); .
  • B-lymphoblastic leukemia/lymphoma with t(v;11q23.3); rearranged.
  • B-lymphoblastic leukemia/lymphoma with t(12;21)(p13.2;q22.1); .
  • B-lymphoblastic leukemia/lymphoma with hyperdiploidy.
  • B-lymphoblastic leukemia/lymphoma with hypodiploidy.
  • B-lymphoblastic leukemia/lymphoma with t(5;14)(q31.1;q32.3); .
  • B-lymphoblastic leukemia/lymphoma with t(1;19)(q23;p13.3); .
  • Provisional entity: B-lymphoblastic leukemia/lymphoma, .
  • Provisional entity: B-lymphoblastic leukemia/lymphoma with iAMP21.

These and other chromosomal and genomic abnormalities for childhood ALL are described below.

Response to initial treatment

The rapidity with which leukemia cells are eliminated after initiation of treatment and the level of residual disease at the end of induction are associated with long-term outcome. Because treatment response is influenced by the drug sensitivity of leukemic cells and host pharmacodynamics and pharmacogenomics, early response has strong prognostic significance. Various ways of evaluating the leukemia cell response to treatment have been utilized, including the following:

MRD determination

Morphologic assessment of residual leukemia in blood or bone marrow is often difficult and is relatively insensitive. Traditionally, a cutoff of 5% blasts in the bone marrow (detected by light microscopy) has been used to determine remission status. This corresponds to a level of 1 in 20 malignant cells. If one wishes to detect lower levels of leukemic cells in either blood or marrow, specialized techniques such as PCR assays, which determine unique Ig/T-cell receptor gene rearrangements, fusion transcripts produced by chromosome translocations, or flow cytometric assays, which detect leukemia-specific immunophenotypes, are required. With these techniques, detection of as few as 1 leukemia cell in 100,000 normal cells is possible, and MRD at the level of 1 in 10,000 cells can be detected routinely.

Multiple studies have demonstrated that end-induction MRD is an important, independent predictor of outcome in children and adolescents with B-lineage ALL. MRD response discriminates outcome in subsets of patients defined by age, leukocyte count, and cytogenetic abnormalities. Patients with higher levels of end-induction MRD have a poorer prognosis than those with lower or undetectable levels.

End-induction MRD is used by almost all groups as a factor determining the intensity of postinduction treatment, with patients found to have higher levels allocated to more intensive therapies. MRD levels at earlier time points during induction (e.g., day 8 and day 15) and later time points (e.g., week 12 of therapy) also predict outcome.; []

MRD levels obtained 10 to 12 weeks after the start of treatment (end-consolidation) have also been shown to be prognostically important; patients with high levels of MRD at this time point have a significantly inferior EFS compared with other patients.

  • B-cell ALL: For patients with B-cell ALL, evaluating MRD at two time points (end-induction and end-consolidation) can identify the following three prognostically distinct patient subsets:
  • T-cell ALL: There are fewer studies documenting the prognostic significance of MRD in patients with T-cell ALL. In the Associazione Italiana Ematologia Oncologia Pediatrica (AIEOP) trial, MRD status at day 78 (week 12) was the most important predictor for relapse in patients with T-cell ALL. Patients with detectable MRD at end-induction who had negative MRD by day 78 generally had a favorable prognosis similar to that of patients who achieved MRD-negativity at the earlier end-induction time point.

MRD measurements, in conjunction with other presenting features, have also been used to identify subsets of patients with an extremely low risk of relapse. The COG reported a very favorable prognosis (5-year EFS of 97% ± 1%) for patients with precursor B-cell phenotype, NCI standard risk age/leukocyte count, CNS1 status, and favorable cytogenetic abnormalities (either high hyperdiploidy with favorable trisomies or the fusion) who had less than 0.01% MRD levels at both day 8 (from peripheral blood) and end-induction (from bone marrow). The excellent outcomes in patients with low MRD at the end of induction is sustained for more than 10 years from diagnosis.

Modifying therapy based on MRD determination has been shown to improve outcome.

  • The study demonstrated that reduction of therapy (i.e., one rather than two courses of delayed intensification) did not adversely impact outcome in non-high–risk patients with favorable end-induction MRD.[] In a randomized controlled trial, the UKALL2003 study also demonstrated improved EFS for standard-risk and intermediate-risk patients who received augmented therapy if end-induction MRD was greater than 0.01% (5-year EFS, 89.6% for augmented therapy vs. 82.8% for standard therapy).
  • The Dutch AAL10 trial stratified patients into the following three risk groups on the basis of MRD after the first month of treatment and after the second cycle of chemotherapy:[]
    • Standard risk (low MRD after the first month of treatment).
    • Moderate risk (high MRD after the first month of treatment, low MRD after the second cycle of chemotherapy).
    • High risk (high MRD after the second cycle of chemotherapy).

    Compared with previous trials conducted by the same group, therapy was deintensified for standard-risk patients but more intensive for moderate-risk and high-risk patients. The overall 5-year EFS (87%) and OS (92%) were superior to the previous Dutch studies.

Day 7 and day 14 bone marrow responses

Patients who have a rapid reduction in leukemia cells to less than 5% in their bone marrow within 7 or 14 days after the initiation of multiagent chemotherapy have a more favorable prognosis than do patients who have slower clearance of leukemia cells from the bone marrow. MRD assessments at the end of induction therapy have generally replaced day 7 and day 14 morphological assessments as prognostic indicators because the latter lose their prognostic significance in multivariate analysis once MRD is included in the analyses.

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). Poor prednisone response is observed in fewer than 10% of patients. Treatment stratification for protocols of the Berlin-Frankfurt-Münster (BFM) clinical trials group is partially based on early response to the 7-day prednisone prophase (administered immediately before the initiation of multiagent remission induction).

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. Rate of clearance of peripheral blasts has been found to be of prognostic significance in both T-cell and B-lineage ALL.

Peripheral blood MRD before end of induction (day 8, day 15)

MRD using peripheral blood obtained 1 week after the initiation of multiagent induction chemotherapy has also been evaluated as an early response-to-therapy prognostic factor.

  • In a COG study involving nearly 2,000 children with ALL, the presence of MRD in the peripheral blood at day 8 was associated with adverse prognosis, with increasing MRD levels being associated with a progressively poorer outcome.
  • In multivariate analysis, end of induction therapy MRD was the most powerful prognostic factor, but day 8 peripheral blood MRD maintained its prognostic significance, as did NCI risk group and the presence of favorable trisomies. A smaller study assessed the prognostic significance of peripheral blood MRD at day 15 after 1 week of a steroid prophase and 1 week of multiagent induction therapy. This study also observed multivariate significance for peripheral blood MRD levels after 1 week of multiagent induction therapy.

Both studies identified a group of patients who achieved low MRD levels after 1 week of multiagent induction therapy who had a low rate of subsequent treatment failure.

Marrow morphology at the end of induction (induction failure)

The vast majority of children with ALL achieve complete morphologic remission by the end of the first month of treatment. The presence of greater than 5% lymphoblasts at the end of the induction phase is observed in 1% to 2% of children with ALL.

Patients at highest risk of induction failure have one or more of the following features:

  • T-cell phenotype (especially without a mediastinal mass).
  • Precursor B-cell ALL with very high presenting leukocyte counts.
  • () gene rearrangement.
  • Older age.
  • Philadelphia chromosome (before the use of tyrosine kinase inhibitors).

In a large retrospective study, the OS of patients with induction failure was only 32%. However, there was significant clinical and biological heterogeneity. A relatively favorable outcome was observed in patients with precursor B-cell ALL between the ages of 1 and 5 years without adverse cytogenetics ( [] rearrangement or ). This group had a 10-year survival exceeding 50%, and HSCT in first remission was not associated with a survival advantage compared with chemotherapy alone for this subset. Patients with the poorest outcomes (<20% 10-year survival) included those who were aged 14 to 18 years, or who had the Philadelphia chromosome or rearrangement. B-cell ALL patients younger than 6 years and T-cell ALL patients (regardless of age) appeared to have better outcomes if treated with allogeneic HSCT after achieving CR than those who received further treatment with chemotherapy alone.

Some investigators have suggested that the definition of induction failure should be expanded to include end-of-induction MRD of more than 5%, regardless of morphologic findings. In the study, 59 of 3,113 patients (1.9%) had morphologic induction failure; the 5-year EFS was 51%, and the OS was 58%. However, 2.3% of patients had a morphologic remission, with MRD of 5% or more measured by real-time quantitative IgH-T-cell receptor (TCR) PCR; this group had a 5-year EFS of 47%, similar to those with morphologic induction failure. The authors suggest that using both morphologic and MRD criteria to define induction failure more precisely identifies patients with poor outcomes.

Prognostic (Risk) Groups

For decades, clinical trial groups studying childhood ALL have utilized risk classification schemes to assign patients to therapeutic regimens based on their estimated risk of treatment failure. Initial risk classification systems utilized clinical factors such as age and presenting WBC count. Response to therapy measures were subsequently added, with some groups utilizing early morphologic bone marrow response (e.g., at day 8 or day 15) and with other groups utilizing response of circulating leukemia cells to single agent prednisone. Modern risk classification systems continue to utilize clinical factors such as age and presenting WBC count, and in addition, incorporate cytogenetics and genomic lesions of leukemia cells at diagnosis (e.g., favorable and unfavorable translocations) and response to therapy based on detection of MRD at end of induction (and in some cases at later time points). The risk classification systems of the COG and the BFM groups are briefly described below.

Children’s Oncology Group (COG) risk groups

In COG protocols, children with ALL are initially stratified into treatment groups (with varying degrees of risk of treatment failure) based on a subset of prognostic factors, including the following:

  • Age.
  • WBC count at diagnosis.
  • Immunophenotype.
  • Cytogenetics/genomic alterations.
  • Presence of extramedullary disease.
  • Down syndrome.
  • Steroid pretreatment.

EFS rates exceed 85% in children meeting good-risk criteria (aged 1 to <10 years, WBC count <50,000/μL, and precursor B-cell immunophenotype); in children meeting high-risk criteria, EFS rates are approximately 75%. Additional factors, including cytogenetic abnormalities and measures of early response to therapy (e.g., day 7 and/or day 14 marrow blast percentage for patients with Down syndrome and MRD levels in peripheral blood on day 8 and in bone marrow samples at the end of induction), considered in conjunction with presenting age, WBC count, immunophenotype, the presence of extramedullary disease, and steroid pretreatment can identify patient groups for postinduction therapy with expected EFS rates ranging from less than 40% to more than 95%.

Patients who are at very high risk of treatment failure include the following:

  • Infants with () rearrangements.
  • Patients with hypodiploidy (<44 chromosomes).
  • Patients with initial induction failure.

Berlin-Frankfurt-Münster (BFM) risk groups

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 time points, end induction (week 5) and end consolidation (week 12).

The BFM risk groups include the following:

  • Standard risk: Patients who are MRD-negative (i.e., <10) at both time points are classified as standard risk.
  • Intermediate risk: Patients who have positive MRD at week 5 and low MRD (<10) at week 12 are considered intermediate risk.
  • High risk: Patients with high MRD (≥10) 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, and CNS status at diagnosis do not factor into the current risk classification schema. However, patients with either the t(9;22)(q34;q11.2) or the t(4;11)(q21;q23) are considered high risk, regardless of early response measures.

Prognostic (risk) groups under clinical evaluation

(Classification of Newly Diagnosed ALL): COG protocol AALL08B1 stratifies four risk groups for patients with precursor B-cell ALL (low risk, average risk, high risk, and very high risk) based on the following criteria:

  • Age and presenting leukocyte count (using NCI risk-group criteria).
  • Extramedullary disease (presence or absence of CNS and/or testicular leukemia).
  • Genomic alterations in leukemia cells.
  • Day 8 peripheral blood MRD.
  • Day 29 bone marrow morphologic response and MRD.
  • Down syndrome.
  • Steroid pretreatment.

Morphologic assessment of early response in the bone marrow is no longer performed on days 8 and 15 of induction as part of risk stratification. Patients with T-cell phenotype are treated on a separate study and are not risk classified in this way.

For patients with precursor B-cell ALL:

  • Favorable genetics are defined as the presence of either hyperdiploidy with trisomies of chromosomes 4 and 10 (double trisomy) or the fusion.
  • Unfavorable characteristics are defined as CNS3 status at diagnosis, induction failure (M3 marrow at day 29), age 13 years and older, and the following unfavorable genomic alterations: hypodiploidy (<44 chromosomes or DNA index <0.81), () rearrangement, t(17;19), and iAMP21. The presence of any of these unfavorable characteristics is sufficient to classify a patient as very high risk, regardless of other presenting features. Infants and children with (Ph+ ALL) are treated on a separate clinical trial.
  • MRD levels at day 8 from peripheral blood and at day 29 from bone marrow are used in risk classification.

The four risk groups for precursor B-cell ALL are defined in Table 1.

(Combination Chemotherapy With or Without Bortezomib in Treating Younger Patients With Newly Diagnosed T-Cell ALL or Stage II-IV T-Cell Lymphoblastic Lymphoma): For patients with T-cell ALL, COG uses the following criteria to assign risk category:

  • M1 marrow with MRD <0.01% on day 29.
  • CNS1 status and no testicular disease at diagnosis.
  • No steroid therapy pretreatment.
  • M1 or M2 marrow at day 29 with MRD ≥0.01%.
  • MRD <0.1% at end of consolidation.
  • Any CNS status at diagnosis.
  • M3 marrow at day 29 or MRD ≥0.1% at end of consolidation.
  • Any CNS status.

SJCRH (Total XVI): Patients are classified into one of three categories (low, standard, or high risk) based on the presenting age, leukocyte count, presence or absence of CNS3 status or testicular leukemia, immunophenotype, cytogenetics and molecular genetics, DNA index, and early response to therapy. Hence, definitive risk assignment (for provisional low-risk or standard-risk cases based on presenting features) will be made after completion of remission induction therapy. The criteria and the estimated proportion of patients in each category (based on data from the Total XV study) are provided below.

  • Precursor B-cell ALL with DNA index ≥1.16, fusion, or age 1 to 9.9 years and presenting WBC <50 × 10/L.
  • Must not have:
    • CNS3 status (≥5 WBC/µl of CSF with morphologically identifiable blasts or cranial nerve palsy).
    • Overt testicular leukemia (evidenced by ultrasonogram).
    • Adverse genetic features—t(9;22)(q34;q11.2) or fusion; t(1;19) with fusion; rearranged () (as measured by FISH and/or PCR); or hypodiploidy (<44 chromosomes).
    • Poor early response (≥1% lymphoblasts on day 15 of remission induction, ≥0.01% lymphoblasts by immunologic or molecular methods on remission date).
  • All cases of T-cell ALL and those of precursor B-cell ALL that do not meet the criteria for low-risk or high-risk ALL.
  • t(9;22)(q34;q11.2) or fusion.
  • Infants with t(4;11)(q21;q23) or () fusion.
  • Induction failure or >1% leukemia lymphoblasts in the bone marrow on remission date.
  • >0.1% leukemic lymphoblasts in the bone marrow in week 7 of continuation treatment (i.e., before reinduction 1, about 14 weeks postremission induction).
  • Re-emergence of leukemic lymphoblasts by MRD (at any level) in patients previously MRD negative.
  • Persistently detectable MRD at lower levels.
  • Early T-cell precursor ALL, defined by low expression of T-cell markers together with aberrant expression of myeloid markers. The following features characterize early T-cell precursor ALL:
    • Levels of CD5 expression at least tenfold lower than that of normal peripheral blood T-lymphocytes. In the study that identified this subset of T-cell ALL, CD5 expression was tenfold to more than 200-fold lower than that of normal lymphocytes and median percentage of leukemic cells expressing CD5 in the 17 atypical cases was 45%; in contrast to more than 98% for the 122 cases in the typical group.
    • Absence (<10%) of CD1a and CD8 expression.
    • Expression of cytoplasmic CD3 together with the expression of one or more markers associated with myeloid leukemia such as HLA-Dr, CD34, CD13, CD33, or CD11b, while myeloperoxidase is less than 3% by cytochemistry and/or flow cytometry.

DFCI ALL (Risk Classification Schemes in Identifying Better Treatment Options for Children and Adolescents with ALL): Patients are assigned an initial risk group by day 10 of therapy on the basis of presenting features and leukemia biology:

  • Initial low risk: All of the following criteria are met: B-cell ALL, age 1 to younger than 15 years, WBC count less than 50 x 10/L, CNS1 or CNS2, no intrachromosomal amplification of chromosome 21 (iAMP21), no very high-risk features.
  • Initial high risk: Any of the following criteria are met: Aged 15 years or older, WBC count greater than 50 x 10/L, T-cell ALL, CNS3, presence of iAMP21. Very high-risk features must be absent.
  • Initial very high risk: Any of the following criteria are met: deletion, gene-rearrangement, low hypodiploidy (<40 chromosomes).

Patients with are removed from protocol therapy at day 15. The final risk group is based on the initial risk group and MRD (assessed by next-generation sequencing) at the end of induction (day 32; first time point) and week 10 of therapy (second time point):

  • Final low risk: Initial low risk and MRD less than10 at the first time point.
  • Final high risk: Initial low risk with MRD greater than 10 at the first time point and less than 10 at the second time point or initial high risk with MRD less than 10 at the second time point.
  • Final very high risk: Initial very high-risk patients or any patient with MRD greater than 10 at the second time point.

Current Clinical Trials

Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.

Treatment Option Overview for Childhood ALL

Special Considerations for the Treatment of Children With Cancer

Because treatment of children with ALL entails complicated risk assignment and therapies and the need for intensive supportive care (e.g., transfusions; management of infectious complications; and emotional, financial, and developmental support), evaluation and treatment are best coordinated by a multidisciplinary team in cancer centers or hospitals with all of the necessary pediatric supportive care facilities. A multidisciplinary team approach incorporates the skills of the following health care professionals and others to ensure that children receive treatment, supportive care, and rehabilitation that will achieve optimal survival and quality of life:

  • Primary care physicians.
  • Pediatric surgical subspecialists.
  • Radiation oncologists.
  • Pediatric medical oncologists/hematologists.
  • Rehabilitation specialists.
  • Pediatric nurse specialists.
  • Social workers.
  • Child life professionals.
  • Psychologists.

Guidelines for cancer centers and their role in the treatment of pediatric patients with cancer have been outlined by the American Academy of Pediatrics. Treatment of childhood ALL typically involves chemotherapy given for 2 to 3 years. Because myelosuppression and generalized immunosuppression are anticipated consequences of leukemia and chemotherapy treatment, adequate facilities must be immediately available both for hematologic support and for the treatment of infections and other complications throughout all phases of therapy. Approximately 1% to 3% of patients die during induction therapy and another 1% to 3% die during the initial remission from treatment-related complications. It is 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.

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 therapeutic innovations that produced increased survival rates in children with ALL were established through clinical trials, and it is appropriate for children and adolescents with ALL to be offered participation in a clinical trial.

Risk-based treatment assignment is an important therapeutic strategy utilized for children with ALL. This approach allows children who historically have a very good outcome to be treated with less intensive therapy and to be spared more toxic treatments, while allowing children with a historically lower probability of long-term survival to receive more intensive therapy that may increase their chance of cure. (Refer to the Risk-Based Treatment Assignment section of this summary for more information about a number of clinical and laboratory features that have demonstrated prognostic value.)

Phases of Therapy

Treatment for children with ALL is typically divided as follows:

Sanctuary Sites

Historically, certain extramedullary sites have been considered (i.e., anatomic spaces that are poorly penetrated by many of the orally and intravenously administered chemotherapy agents typically used to treat ALL). The two most important sanctuary sites in childhood ALL are the central nervous system (CNS) and the testes. Successful treatment of ALL requires therapy that effectively addresses clinical or subclinical involvement of leukemia in these extramedullary sanctuary sites.

Central nervous system (CNS)

At diagnosis, approximately 3% of patients have CNS3 disease (defined as cerebrospinal fluid specimen with ≥5 white blood cells/μL with lymphoblasts and/or the presence of cranial nerve palsies). However, unless specific therapy is directed toward the CNS, most children will eventually develop overt CNS leukemia whether or not lymphoblasts were detected in the spinal fluid at initial diagnosis. CNS-directed treatments include intrathecal chemotherapy, CNS-directed systemic chemotherapy, and cranial radiation; some or all of these are included in current regimens for ALL. (Refer to the CNS-Directed Therapy for Childhood ALL section of this summary for more information.)

Testes

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. 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. The Children's Oncology Group has also adopted this strategy for boys with testicular involvement that resolves completely during induction chemotherapy.

Treatment for Newly Diagnosed Childhood ALL

Standard Treatment Options for Newly Diagnosed ALL

Standard treatment options for newly diagnosed childhood acute lymphoblastic leukemia (ALL) include the following:

Remission induction chemotherapy

The goal of the first phase of therapy (remission induction) is to induce a complete remission (CR). This phase typically lasts 4 weeks. Overall, approximately 98% of patients with newly diagnosed precursor B-cell ALL achieve CR by the end of this phase, with somewhat lower rates in infants and in noninfant patients with T-cell ALL or high presenting leukocyte counts.

Induction chemotherapy typically consists of the following drugs, with or without an anthracycline (either doxorubicin or daunorubicin):

  • Vincristine.
  • Corticosteroid (either prednisone or dexamethasone).
  • L-asparaginase.

The Children's Oncology Group (COG) protocols administer a three-drug induction (vincristine, corticosteroid, and pegaspargase) to National Cancer Institute (NCI) standard-risk B-cell ALL patients and a four-drug induction (vincristine, corticosteroid, and pegaspargase plus anthracycline) to NCI high-risk B-cell ALL and all T-cell ALL patients. Other groups use a four-drug induction for all patients.

Corticosteroid therapy

Many current regimens utilize dexamethasone instead of prednisone during remission induction and later phases of therapy, although controversy exists as to whether dexamethasone benefits all subsets of patients. Some trials also suggest that dexamethasone during induction may be associated with more toxicity than prednisone, including higher rates of infection, myopathy, and behavioral changes. The COG reported that dexamethasone during induction was associated with a higher risk of osteonecrosis in older children (aged >10 years), although this finding has not been confirmed in other randomized studies.

Evidence (dexamethasone vs. prednisone during induction):

The ratio of dexamethasone to prednisone dose used may influence outcome. Studies in which the dexamethasone to prednisone ratio was 1:5 to 1:7 have shown a better result for dexamethasone, while studies that used a 1:10 ratio have shown similar outcomes.

L-asparaginase

Several forms of L-asparaginase have been used in the treatment of children with ALL, including the following:

  • Pegaspargase (PEG-asparaginase).
  • Asparaginase Erwinia chrysanthemi (Erwinia L-asparaginase).
  • Native () L-asparaginase.

Only pegaspargase and L-asparaginase are available in the United States. Native L-asparaginase remains available in other countries.

Pegaspargase (PEG-asparaginase)

Pegaspargase, a form of L-asparaginase in which the –derived enzyme is modified by the covalent attachment of polyethylene glycol, is the most common preparation used during both induction and postinduction phases of treatment in newly diagnosed patients treated in the United States and Western Europe.

Pegaspargase may be given either intramuscularly (IM) or intravenously (IV). Pharmacokinetics and toxicity profiles are similar for IM and IV pegaspargase administration. There is no evidence that IV administration of pegaspargase is more toxic than IM administration.

Pegaspargase has a much longer serum half-life than native L-asparaginase, producing prolonged asparagine depletion after a single injection.

Serum asparaginase enzyme activity levels of more than 0.1 IU/mL have been associated with serum asparagine depletion. Studies have shown that a single dose of pegaspargase given either IM or IV as part of multiagent induction results in serum enzyme activity of more than 0.1 IU/mL in nearly all patients for at least 2 to 3 weeks.

Evidence (use of pegaspargase instead of native L-asparaginase):

Patients with an allergic reaction to pegaspargase are typically switched to L-asparaginase. Measurement of SAA levels after a mild or questionable reaction to pegaspargase may help to differentiate patients for whom the switch to is indicated (because of inadequate SAA) versus those for whom a change in preparation may not be necessary.

Several studies have identified a subset of patients who experience silent inactivation of asparaginase, defined as absence of therapeutic SAA levels without overt allergy. In a trial conducted by the Dana-Farber Cancer Institute (DFCI) Consortium, 12% of patients treated initially with native L-asparaginase demonstrated silent inactivation; these patients had a superior EFS if their asparaginase preparation was changed. The frequency of silent inactivation in patients initially treated with pegaspargase appears to be low (<10%). Determination of the optimal frequency of pharmacokinetic monitoring for pegaspargase-treated patients, and whether such screening impacts outcome, awaits further investigation.

Asparaginase Erwinia chrysanthemi (Erwinia L-asparaginase)

L-asparaginase is typically used in patients who have experienced allergy to native or pegaspargase.

The half-life of L-asparaginase (0.65 days) is much shorter than that of native (1.2 days) or pegaspargase (5.7 days). If L-asparaginase is utilized, the shorter half-life of the preparation requires more frequent administration to achieve adequate asparagine depletion.

Evidence (increased dose frequency of L-asparaginase needed to achieve goal therapeutic effect):

Anthracycline during induction

The COG protocols administer a three-drug induction (vincristine, corticosteroid, and pegaspargase) to NCI standard-risk B-cell ALL patients and a four-drug induction (vincristine, corticosteroid, and pegaspargase plus anthracycline) to NCI high-risk B-cell ALL and all T-cell ALL patients. Other groups use a four-drug induction for all patients.

In induction regimens that include an anthracycline, either daunorubicin or doxorubicin are typically utilized. In a randomized trial comparing the two agents during induction, there were no differences in early response measures, including reduction in peripheral blood blast counts during the first week of therapy, day 15 marrow morphology, and end-induction minimal residual disease (MRD) levels.[]

Response to remission induction chemotherapy

More than 95% of children with newly diagnosed ALL will achieve a CR within the first 4 weeks of treatment. Of those who fail to achieve CR within the first 4 weeks, approximately one-half will experience a toxic death during the induction phase (usually caused by infection) and the other half will have resistant disease (persistent morphologic leukemia).; []

Most patients with persistent leukemia at the end of the 4-week induction phase have a poor prognosis and may benefit from an allogeneic hematopoietic stem cell transplant (HSCT) once CR is achieved. In a large retrospective series, the 10-year OS for patients with persistent leukemia was 32%. A trend for superior outcome with allogeneic HSCT compared with chemotherapy alone was observed in patients with T-cell phenotype (any age) and precursor B-cell patients younger than 6 years. Precursor B-cell ALL patients who were aged 1 to 5 years at diagnosis and did not have any adverse cytogenetic abnormalities ( () rearrangement, ) had a relatively favorable prognosis, without any advantage in outcome with the utilization of HSCT compared with chemotherapy alone.

For patients who achieve CR, measures of the rapidity of blast clearance and MRD determinations have important prognostic significance, particularly the following:

  • The percentage of morphologically detectable marrow blasts at 7 and 14 days after starting multiagent remission induction therapy has been correlated with relapse risk, and has been used in the past by the COG to risk-stratify patients. However, in multivariate analyses, when end-induction MRD is included, these early marrow findings lose their prognostic significance.
  • End-induction levels of submicroscopic MRD, assessed either by multiparameter flow cytometry or polymerase chain reaction, strongly correlates with long-term outcome. Intensification of postinduction therapy for patients with high levels of end-induction MRD is a common component of most ALL treatment regimens. In a randomized trial conducted by the UK-ALL group, augmented postinduction therapy was shown to improve outcome for standard-risk and intermediate-risk patients with high end-induction MRD.
  • MRD levels earlier in induction (e.g., days 8 and 15) and at later postinduction time points (e.g., week 12 after starting therapy) have also been shown to have prognostic significance in both B-cell and T-cell ALL.

(Refer to the Response to initial treatment section of this summary for more information.)

(Refer to the CNS-Directed Therapy for Childhood ALL section of this summary for specific information about CNS therapy to prevent CNS relapse in children with newly diagnosed ALL.)

Current Clinical Trials

Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.

Postinduction Treatment for Childhood ALL

Standard Postinduction Treatment Options for Childhood ALL

Standard treatment options for consolidation/intensification and maintenance therapy include the following:

Central nervous system (CNS)-directed therapy is provided during premaintenance chemotherapy by all groups. Some protocols (Children’s Oncology Group [COG], St. Jude Children's Research Hospital [SJCRH], and Dana-Farber Cancer Institute [DFCI]) provide ongoing intrathecal chemotherapy during maintenance, while others (Berlin-Frankfurt-Münster [BFM]) do not. (Refer to the CNS-Directed Therapy for Childhood ALL section of this summary for specific information about CNS therapy to prevent CNS relapse in children with acute lymphoblastic leukemia [ALL] who are receiving postinduction therapy.)

Consolidation/intensification therapy

Once complete remission (CR) has been achieved, systemic treatment in conjunction with CNS-directed therapy follows. The intensity of the postinduction chemotherapy varies considerably depending on risk group assignment, but all patients receive some form of intensification after the achievement of CR and before beginning maintenance therapy.

The most commonly used intensification schema is the BFM backbone. This therapeutic backbone, first introduced by the BFM clinical trials group, includes the following:

This backbone has been adopted by many groups, including the COG. Variation of this backbone includes the following:

  • Intensification for higher-risk patients by including additional doses of vincristine and pegaspargase, as well as repeated interim maintenance and delayed intensification phases.
  • Elimination or truncation of some of the phases for lower-risk patients to minimize acute and long-term toxicity.

Other clinical trial groups utilize a different therapeutic backbone during postinduction treatment phases:

  • DFCI: The DFCI ALL Consortium protocols include 20 to 30 weeks of pegaspargase therapy beginning at week 7 of therapy, given in conjunction with maintenance regimen (vincristine/dexamethasone pulses, low-dose methotrexate, nightly mercaptopurine). These protocols also do not include a delayed intensification phase, but high-risk patients receive additional doses of doxorubicin (instead of methotrexate) during intensification.
  • SJCRH: SJCRH follows a BFM backbone but augments the reinduction and maintenance phases for some patients by including intensified dosing of pegaspargase, frequent vincristine/corticosteroid pulses, and rotating drug pairs during maintenance.

Standard-risk ALL

In children with standard-risk B-cell ALL, there has been an attempt to limit exposure to drugs such as anthracyclines and alkylating agents that may be associated with an increased risk of late toxic effects. For regimens utilizing a BFM backbone (such as COG), a single reinduction/delayed intensification phase, given with interim maintenance phases consisting of escalating doses of methotrexate (without leucovorin rescue) and vincristine, have been associated with favorable outcomes. Favorable outcomes for standard-risk patients have also been reported by the Pediatric Oncology Group (POG), utilizing a limited number of courses of intermediate-dose or high-dose methotrexate as consolidation followed by maintenance therapy (without a reinduction phase), and by the DFCI ALL Consortium utilizing multiple doses of pegaspargase (20–30 weeks) as consolidation, without postinduction exposure to alkylating agents or anthracyclines.

However, the prognostic impact of end-induction and/or consolidation minimal residual disease (MRD) has influenced the treatment of patients originally diagnosed as National Cancer Institute (NCI) standard risk. Multiple studies have demonstrated that higher levels of end-induction MRD are associated with poorer prognosis. Augmenting therapy has been shown to improve the outcome in standard-risk patients with elevated MRD levels at the end of induction. Therefore, standard-risk patients with higher levels of end-induction MRD are not treated with the approaches described for standard-risk patients who have low end-induction MRD, but are usually treated with high-risk regimens.

Evidence (intensification for standard-risk ALL):

High-risk ALL

In high-risk patients, a number of different approaches have been used with comparable efficacy.; [] Treatment for high-risk patients generally is more intensive than that for standard-risk patients and typically includes higher cumulative doses of multiple agents, including anthracyclines and/or alkylating agents. Higher doses of these agents increase the risk of both short-term and long-term toxicities, and many clinical trials have focused on reducing the side effects of these intensified regimens.

Evidence (intensification for high-risk ALL):

Because treatment for high-risk ALL involves more intensive therapy, leading to a higher risk of acute and long-term toxicities, a number of clinical trials have tested interventions to prevent side effects without adversely impacting EFS. Interventions that have been investigated include the use of the cardioprotectant dexrazoxane (to prevent anthracycline-related cardiac toxic effects) and alternative scheduling of corticosteroids (to reduce the risk of osteonecrosis).

Evidence (cardioprotective effect of dexrazoxane):

Evidence (reducing risk of osteonecrosis):

(Refer to the Osteonecrosis section of this summary for more information.)

Very high-risk ALL

Approximately 10% to 20% of patients with ALL are classified as very high risk, including the following:

  • Infants younger than 1 year, especially if there is an () gene rearrangement present. (Refer to the Infants With ALL subsection in the Postinduction Treatment for Specific ALL Subgroups section of this summary for more information about infants with ALL.)
  • Patients with adverse cytogenetic abnormalities, including t(9;22)(q34;q11.2), t(17;19), gene rearrangements, and low hypodiploidy (<44 chromosomes).
  • Patients who achieve CR but have a slow early response to initial therapy, including those with a high absolute blast count after a 7-day steroid prophase, and patients with high MRD levels at the end of induction (week 4) or later time points (e.g., week 12).
  • Patients who have morphologically persistent disease after the first 4 weeks of therapy (induction failure), even if they later achieve CR.

COG also considers patients who are aged 13 years or older to be very high risk, although this age criterion is not utilized by other groups.

Patients with very high-risk features have been treated with multiple cycles of intensive chemotherapy during the consolidation phase (usually in addition to the typical BFM backbone intensification phases). These additional cycles often include agents not typically used in frontline ALL regimens for standard-risk and high-risk patients, such as high-dose cytarabine, ifosfamide, and etoposide. However, even with this intensified approach, reported long-term EFS rates range from 30% to 50% for this patient subset.

On some clinical trials, very high-risk patients have also been considered candidates for allogeneic hematopoietic stem cell transplantation (HSCT) in first CR. However, there are limited data regarding the outcome of very high-risk patients treated with allogeneic HSCT in first CR. Controversy exists regarding which subpopulations could potentially benefit from HSCT.

Evidence (allogeneic HSCT in first remission for very high-risk patients):

Maintenance therapy

Backbone of maintenance therapy

The backbone of maintenance therapy in most protocols includes daily oral mercaptopurine and weekly oral or parenteral methotrexate. Clinical practice generally calls for the administration of oral mercaptopurine in the evening, based on evidence from older studies that this practice may improve EFS. On many protocols, intrathecal chemotherapy for CNS sanctuary therapy is continued during maintenance therapy. 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. Studies conducted by the COG have demonstrated significant differences in compliance with mercaptopurine (6-MP) amongst various racial and socioeconomic groups. Importantly, nonadherence to treatment with mercaptopurine in the maintenance phase was associated with a significant increase in the risk of relapse.

Some patients may develop severe hematologic toxicity when receiving conventional dosages of mercaptopurine because of an inherited deficiency (homozygous mutant) of thiopurine S-methyltransferase, an enzyme that inactivates mercaptopurine. These patients are able to tolerate mercaptopurine only if dosages much lower than those conventionally used are administered. Patients who are heterozygous for this mutant enzyme gene generally tolerate mercaptopurine without serious toxicity, but they do require more frequent dose reductions for hematologic toxicity than do patients who are homozygous for the normal allele. Polymorphisms of the gene, observed most frequently in East Asian and Hispanic patients, have also been linked to extreme sensitivity to the myelosuppressive effects of mercaptopurine.

Evidence (maintenance therapy):

Vincristine/corticosteroid pulses

Pulses of vincristine and corticosteroid are often added to the standard maintenance backbone, although the benefit of these pulses within the context of contemporary multiagent chemotherapy regimens remains controversial.

Evidence (vincristine/corticosteroid pulses):

For regimens that include vincristine/steroid pulses, a number of studies have addressed which steroid (dexamethasone or prednisone) should be used. From these studies, it appears that dexamethasone is associated with superior EFS, but also may lead to a greater frequency of steroid-associated complications, including bone toxicity and infections, especially in older children and adolescents. Dexamethasone has not been associated with an increased frequency of these complications in younger patients.

Evidence (dexamethasone vs. prednisone):

The benefit of using dexamethasone in children aged 10 to 18 years requires further investigation because of the increased risk of steroid-induced osteonecrosis in this age group.

Duration of maintenance therapy

Maintenance chemotherapy generally continues until 2 to 3 years of continuous CR. On some studies, boys are treated longer than girls; on others, there is no difference in the duration of treatment based on sex. It is not clear whether longer duration of maintenance therapy reduces relapse in boys, especially in the context of current therapies.[] Extending the duration of maintenance therapy beyond 3 years does not improve outcome.

Adherence to oral medications during maintenance therapy

Nonadherence to treatment with mercaptopurine during maintenance therapy is associated with a significant risk of relapse.

Evidence (adherence to treatment):

Treatment options under clinical evaluation

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 of treatment failure. The Risk-Based Treatment Assignment section of this summary describes the clinical and laboratory features used for the initial stratification of children with ALL into risk-based treatment groups.

Ongoing clinical trials include the following:

COG studies for precursor B-cell ALL

Standard-risk ALL

High-risk and very high-risk ALL

Other studies

Current Clinical Trials

Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.

CNS-Directed Therapy for Childhood ALL

At diagnosis, approximately 3% of patients have central nervous system 3 (CNS3) disease (defined as cerebrospinal fluid [CSF] specimen with ≥5 white blood cells [WBC]/μL with lymphoblasts and/or the presence of cranial nerve palsies). However, unless specific therapy is directed toward the CNS, most children will eventually develop overt CNS leukemia whether or not lymphoblasts were detected in the spinal fluid at initial diagnosis. Therefore, all children with acute lymphoblastic leukemia (ALL) should receive systemic combination chemotherapy together with some form of CNS prophylaxis.

Because the CNS is a (i.e., an anatomic space that is poorly penetrated by many of the systemically administered chemotherapy agents typically used to treat ALL), specific CNS-directed therapies must be instituted early in treatment to eliminate clinically evident CNS disease at diagnosis and to prevent CNS relapse in all patients. Historically, survival rates for children with ALL improved dramatically after CNS-directed therapies were added to treatment regimens.

Standard treatment options for CNS-directed therapy include the following:

All of these treatment modalities have a role in the treatment and prevention of CNS leukemia. The combination of intrathecal chemotherapy plus CNS-directed systemic chemotherapy is standard; cranial radiation is reserved for selective situations.

The type of CNS-therapy that is used is based on a patient’s risk of CNS-relapse, with higher-risk patients receiving more intensive treatments. Data suggest that the following groups of patients are at increased risk of CNS relapse:

  • Patients with 5 or more WBC/µL and blasts in the CSF (CNS3), obtained at diagnosis.
  • Patients with blasts in the CSF but fewer than 5 WBC/µL (CNS2) may be at increased risk of CNS relapse, although this risk appears to be nearly fully abrogated if they receive more doses of intrathecal chemotherapy, especially during the induction phase.
  • Patients with T-cell ALL, especially those with high presenting peripheral blood leukocyte counts.
  • Patients who have a traumatic lumbar puncture showing blasts at the time of diagnosis may have an increased risk of CNS relapse. These patients receive more intensive CNS-directed therapy on some treatment protocols.

CNS-directed treatment regimens for newly diagnosed childhood ALL are presented in Table 2:

A major goal of current ALL clinical trials is to provide effective CNS therapy while minimizing neurologic toxic effects and other late effects.

Intrathecal Chemotherapy

All therapeutic regimens for childhood ALL include intrathecal chemotherapy. Intrathecal chemotherapy is usually started at the beginning of induction, intensified during consolidation and, in many protocols, continued throughout the maintenance phase.

Intrathecal chemotherapy typically consists of one of the following:

Unlike intrathecal cytarabine, intrathecal methotrexate has a significant systemic effect, which may contribute to prevention of marrow relapse.

CNS-Directed Systemic Chemotherapy

In addition to therapy delivered directly to the brain and spinal fluid, systemically administered agents are also an important component of effective CNS prophylaxis. The following systemically administered drugs provide some degree of CNS prophylaxis:

  • Dexamethasone.
  • L-asparaginase (does not penetrate into CSF itself, but leads to CSF asparagine depletion).
  • High-dose methotrexate with leucovorin rescue.
  • Escalating dose intravenous (IV) methotrexate without leucovorin rescue.

Evidence (CNS-directed systemic chemotherapy):

Cranial Radiation

The proportion of patients receiving cranial radiation has decreased significantly over time. At present, most newly diagnosed children with ALL are treated without cranial radiation. Many groups administer cranial radiation only to those patients considered to be at highest risk of subsequent CNS relapse, such as those with documented CNS leukemia at diagnosis (as defined above) (≥5 WBC/μL with blasts; CNS3) and/or T-cell phenotype with high presenting WBC count. In patients who do receive radiation, the cranial radiation dose has been significantly reduced and administration of spinal irradiation is not standard.

Ongoing trials seek to determine whether radiation can be eliminated from the treatment of all children with ALL without compromising survival or leading to increased rate of toxicities from upfront and salvage therapies. A meta-analysis of randomized trials of CNS-directed therapy has confirmed that radiation therapy can be replaced by intrathecal chemotherapy in most patients with ALL. Additional systemic therapy may be required depending on the agents and intensity used.; []

CNS Therapy for Standard-risk Patients

Intrathecal chemotherapy without cranial radiation, given in the context of appropriate systemic chemotherapy, results in CNS relapse rates of less than 5% for children with standard-risk ALL.

The use of cranial radiation is not a necessary component of CNS-directed therapy for these patients. Some regimens use triple intrathecal chemotherapy (methotrexate, cytarabine, and hydrocortisone), while others use intrathecal methotrexate alone throughout therapy.

Evidence (triple intrathecal chemotherapy vs. intrathecal methotrexate):

CNS Therapy for High-risk and Very High-risk Patients

Controversy exists as to whether high-risk and very high-risk patients should be treated with cranial radiation. Depending on the protocol, up 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. Patients receiving cranial radiation on many treatment regimens include the following:

  • Patients with T-cell phenotype and high initial WBC count.
  • Patients with high-risk precursor B-cell ALL (e.g., extremely high presenting leukocyte counts and/or adverse cytogenetic abnormalities and/or CNS3 disease).

Both the proportion of patients receiving radiation and the dose of radiation administered has decreased over the last 2 decades.

Evidence (cranial radiation):

CNS Therapy for Patients With CNS Involvement (CNS3 Disease) at Diagnosis

Therapy for ALL patients with clinically evident CNS disease (≥5 WBC/hpf with blasts on cytospin; CNS3) at diagnosis typically includes intrathecal chemotherapy and cranial radiation (usual dose is 18 Gy). Spinal radiation is no longer used.

Evidence (cranial radiation):

Larger prospective studies will be necessary to fully elucidate the safety of omitting cranial radiation in CNS3 patients.

Presymptomatic CNS Therapy Options Under Clinical Evaluation

Treatment options under clinical evaluation include the following:

Toxicity of CNS-Directed Therapy

Toxic effects of CNS-directed therapy for childhood ALL can be acute and subacute or late developing. (Refer to the Late Effects of the Central Nervous System section in the PDQ summary on Late Effects of Treatment for Childhood Cancer for more information.)

Acute and subacute toxicities

The most common acute side effect associated with intrathecal chemotherapy alone is seizures. Up to 5% of nonirradiated patients with ALL treated with frequent doses of intrathecal chemotherapy will have at least one seizure during therapy. Higher rates of seizure were observed with consolidation regimens that included multiple doses of high-dose methotrexate in addition to intrathecal chemotherapy. Intrathecal and high-dose intravenous methotrexate has also been associated with a stroke-like syndrome, which, in most cases, appears to be reversible.

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. Gabapentin or valproic acid are alternative anticonvulsants with less enzyme-inducing capabilities.

Late-developing toxicities

Late effects associated with CNS-directed therapies include subsequent neoplasms, neuroendocrine disturbances, leukoencephalopathy, and neurocognitive impairments.

Subsequent neoplasms are observed primarily in survivors who received cranial radiation. Meningiomas are common and typically of low malignant potential, but high-grade lesions also occur. In a SJCRH retrospective study of more than 1,290 ALL patients who had never relapsed, the 30-year cumulative incidence of a subsequent neoplasm occurring in the CNS was 3%; excluding meningiomas, the 30-year cumulative incidence was 1.17%. Nearly all of these CNS subsequent neoplasms occurred in previously irradiated patients.

Neurocognitive impairments, which can range in severity and functional consequences, have been documented in long-term ALL survivors treated both with and without radiation therapy. In general, patients treated without cranial radiation have less severe neurocognitive sequelae than irradiated patients, and the deficits that do develop represent relatively modest declines in a limited number of domains of neuropsychological functioning. For patients who receive cranial radiation therapy, the frequency and severity of toxicities appear dose-related; patients treated with 18 Gy of cranial radiation therapy appear to be at lower risk for severe impairments compared with those treated with doses of 24 Gy or higher. Younger age at diagnosis and female sex have been reported in many studies to be associated with a higher risk of neurocognitive late effects.

Several studies have also evaluated the impact of other components of treatment on the development of late neurocognitive impairments. A comparison of neurocognitive outcomes of patients treated with methotrexate versus triple intrathecal chemotherapy showed no clinically meaningful difference.[] Controversy exists about whether patients who receive dexamethasone have a higher risk of neurocognitive disturbances. In a SJCRH study of nonirradiated long-term survivors, treatment with dexamethasone was associated with increased risk for impairments in attention and executive function. Conversely, long-term neurocognitive testing in 92 children with a history of standard-risk ALL who had received either dexamethasone or prednisone during treatment did not demonstrate any meaningful differences in cognitive functioning based on corticosteroid randomization.

Evidence (neurocognitive late effects of cranial radiation):

Evidence (neurocognitive late effects in nonirradiated patients):

Postinduction Treatment for Specific ALL Subgroups

T-Cell ALL

Historically, patients with T-cell acute lymphoblastic leukemia (ALL) have had a worse prognosis than children with precursor B-cell ALL. In a review of a large number of patients treated on Children's Oncology Group (COG) trials over a 15-year period, T-cell immunophenotype still proved to be a negative prognostic factor on multivariate analysis. However, 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 10-year overall survival (OS) for children with T-cell ALL treated on the Dana-Farber Cancer Institute (DFCI) trial was 90.1%, compared with 88.7% for patients with B-cell disease. Another example is the COG trial for T-cell ALL () that observed a 4-year disease-free survival (DFS) of 89.3%.

Treatment options for T-cell ALL

Treatment options under clinical evaluation for T-cell ALL

Treatment options under clinical evaluation for T-cell ALL include the following:

Current Clinical Trials

Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.

Infants With ALL

Infant ALL is uncommon, representing approximately 2% to 4% of cases of childhood ALL. Because of their distinctive biological characteristics and their high risk of leukemia recurrence, infants with ALL are treated on protocols specifically designed for this patient population. 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.

Infants diagnosed within the first few months of life have a particularly poor outcome. In one study, patients diagnosed within 1 month of birth had a 2-year OS rate of 20%.[] In another study, the 5-year EFS for infants diagnosed at younger than 90 days was 16%.[]

For infants with () gene rearrangement, the EFS rates continue to be in the 35% range.[] Factors predicting poor outcome for infants with rearrangements include the following:; []

  • A very young age (≤90 days).
  • Extremely high presenting leukocyte count (≥200,000–300,000/μL).
  • Poor early response, as reflected by a poor response to a prednisone prophase or high levels of MRD at the end of induction and consolidation phases of treatment.

Infants have significantly higher relapse rates than older children with ALL and are at higher risk of developing treatment-related toxicity, especially infection. With current treatment approaches for this population, treatment-related mortality has been reported to occur in about 10% of infants, a rate that is much higher than the rate in older children with ALL. On the COG trial, an intensified induction regimen resulted in an induction death rate of 15.4% (4 of 26 patients); the trial was subsequently amended to include a less-intensive induction and enhanced supportive care guidelines, resulting in a significantly lower induction death rate (1.6%; 2 of 123 patients) and significantly higher complete remission (CR) rate (94% vs. 68% with the previous, more intensified induction regimen).

Treatment options for infants with MLL (KMT2A) rearrangements

Infants with () gene rearrangements are generally treated on intensified chemotherapy regimens using agents not typically incorporated into frontline therapy for older children with ALL. However, despite these intensified approaches, EFS rates remain poor for these patients.

Evidence (intensified chemotherapy regimens for infants with [] rearrangements):

The role of allogeneic hematopoietic stem cell transplant (HSCT) during first remission in infants with () gene rearrangements remains controversial.

Evidence (allogeneic HSCT in first remission for infants with [] rearrangements):

Treatment options for infants without MLL (KMT2A) rearrangements

The optimal treatment for infants without () rearrangements also remains unclear.

Treatment options under clinical evaluation for infants with ALL

Treatment options under clinical evaluation include the following:

Adolescents and Young Adults With ALL

Adolescents and young adults with ALL have been recognized as high risk for decades. Outcomes in almost all studies of treatment are inferior in this age group compared with children younger than 10 years. The reasons for this difference include more frequent presentation of adverse prognostic factors at diagnosis, including the following:

  • T-cell immunophenotype.
  • Philadelphia chromosome–positivity (Ph+) and -like (Ph-like) disease.
  • Lower incidence of favorable cytogenetic abnormalities.

In addition to more frequent adverse prognostic factors, patients in this age group have higher rates of treatment-related mortality and nonadherence to therapy.

Treatment options

Studies from the United States and France were among the first to identify the difference in outcome based on treatment regimens. Other studies have confirmed that older adolescent and young adult patients fare better on pediatric rather than adult regimens.; [] These study results are summarized in Table 3.

Given the relatively favorable outcome that can be obtained in these patients with chemotherapy regimens used for high-risk pediatric ALL, there is no role for the routine use of allogeneic HSCT for adolescents and young adults with ALL in first remission.

Evidence (use of a pediatric treatment regimen for adolescents and young adults with ALL):

Other studies have confirmed that older adolescent patients and young adults fare better on pediatric rather than adult regimens (refer to Table 3).; []

The reason that adolescents and young adults achieve superior outcomes with pediatric regimens is not known, although possible explanations include the following:

  • Treatment setting (i.e., site experience in treating ALL).
  • Adherence to protocol therapy.
  • The components of protocol therapy.

Osteonecrosis

Adolescents with ALL appear to be at higher risk than younger children for developing therapy-related complications, including osteonecrosis, deep venous thromboses, and pancreatitis. Before the use of postinduction intensification for treatment of ALL, osteonecrosis was infrequent. The improvement in outcome for children and adolescents aged 10 years and older was accompanied by an increased incidence of osteonecrosis.

The weight-bearing joints are affected in 95% of patients who develop osteonecrosis and operative interventions are needed for management of symptoms and impaired mobility in more than 40% of cases. The majority of the cases are diagnosed within the first 2 years of therapy and often the symptoms are recognized during maintenance.

Evidence (osteonecrosis):

Treatment options under clinical evaluation for adolescent and young adult patients with ALL

Treatment options under clinical evaluation include the following:

Philadelphia Chromosome–positive (BCR-ABL1–positive) ALL

Philadelphia chromosome–positive (Ph+) ALL is seen in about 3% of pediatric ALL cases, increases in adolescence, and is seen in 15% to 25% of adults. In the past, this subtype of ALL has been recognized as extremely difficult to treat with poor outcome. In 2000, an international pediatric leukemia group reported a 7-year EFS of 25%, with an OS of 36%. In 2010, the same group reported a 7-year EFS of 31% and an overall survival of 44% in Ph+ ALL patients treated without tyrosine kinase inhibitors. Treatment of this subgroup has evolved from emphasis on aggressive chemotherapy, to bone marrow transplantation, and currently to combination therapy using chemotherapy plus a tyrosine kinase inhibitor.

Treatment options

Pre-tyrosine kinase inhibitor era

Before the use of imatinib mesylate, HSCT from a matched sibling donor was the treatment of choice for patients with Ph+ ALL. Data to support this include a retrospective multigroup analysis of children and young adults with Ph+ ALL, in which HSCT from a matched sibling donor was associated with a better outcome than standard (pre-imatinib mesylate) chemotherapy. In this retrospective analysis, Ph+ ALL patients undergoing HSCT from an unrelated donor had a very poor outcome. However, in a follow-up study by the same group evaluating outcomes in the subsequent decade (pre-imatinib mesylate era), transplantation with matched-related or matched-unrelated donors were equivalent. DFS at the 5-year time point showed an advantage for transplantation in first remission compared with chemotherapy that was borderline significant ( = .049), and OS was also higher for transplantation compared with chemotherapy, although the advantage at 5 years was not significant.

Factors significantly associated with favorable prognosis in the pre-tyrosine kinase inhibitor era included the following:

  • Younger age at diagnosis.
  • Lower leukocyte count at diagnosis.
  • Early response measures.
  • Ph+ ALL with a rapid morphologic response or rapid peripheral blood response to induction therapy.

Following MRD by reverse transcription polymerase chain reaction for the fusion transcript may also be useful to help predict outcome for Ph+ patients.

Tyrosine kinase inhibitor era

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.

Clinical trials in adults and children with Ph+ ALL have demonstrated the feasibility of administering imatinib mesylate in combination with multiagent chemotherapy. Outcome of results for Ph+ ALL demonstrated a better outcome after HSCT if imatinib was given before or after transplant. Clinical trials have also demonstrated that many pediatric Ph+ ALL patients can be successfully treated without transplant using a combination of intensive chemotherapy and a tyrosine kinase inhibitor.

Evidence (tyrosine kinase inhibitor):

Dasatinib, a second-generation inhibitor of tyrosine kinases, is currently being studied in the initial treatment of Ph+ ALL. Dasatinib has shown significant activity in the CNS, both in a mouse model and a series of patients with CNS-positive leukemia. The results of a phase I trial of dasatinib in pediatric patients indicated that once-daily dosing was associated with an acceptable toxicity profile, with few nonhematologic grade 3 or 4 adverse events.

Current Clinical Trials

Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.

Treatment of Relapsed Childhood ALL

Prognostic Factors After First Relapse of Childhood ALL

The prognosis for a child with acute lymphoblastic leukemia (ALL) whose disease recurs depends on multiple factors.; []

The two most important prognostic risk factors after first relapse of childhood ALL are the following:

  • Site of relapse.
  • Time from diagnosis to relapse.

Other prognostic factors include the following:

  • Patient characteristics (e.g., age and peripheral blast count at time of relapse).
  • Risk group classification at initial diagnosis.
  • Response to reinduction therapy.
  • Cytogenetics/genomic alterations.
  • Immunophenotype.

Site of relapse

Patients who have isolated extramedullary relapse fare better than those who have relapse involving the marrow. In some studies, patients with combined marrow/extramedullary relapse had a better prognosis than did those with a marrow relapse; however, other studies have not confirmed this finding.

Time from diagnosis to relapse

For patients with relapsed precursor B-cell ALL, early relapses fare worse than later relapses, and marrow relapses fare worse than isolated extramedullary relapses. For example, survival rates range from less than 20% for patients with marrow relapses occurring within 18 months from diagnosis to 40% to 50% for those whose relapses occur more than 36 months from diagnosis.

For patients with isolated central nervous system (CNS) relapses, the overall survival (OS) rates for early relapse (<18 months from diagnosis) are 40% to 50% and 75% to 80% for those with late relapses (>18 months from diagnosis). No evidence exists that early detection of relapse by frequent surveillance (complete blood counts or bone marrow tests) in off-therapy patients improves outcome.

Patient characteristics

Age 10 years and older at diagnosis and at relapse have been reported as independent predictors of poor outcome. A Children’s Oncology Group (COG) study further showed that although patients aged 10 to 15 years at initial diagnosis do worse than patients aged 1 to 9 years (35% vs. 48%, 3-year postrelapse survival), those older than age 15 years did much worse (3-year OS, 15%; = .001).

The Berlin-Frankfurt-Münster (BFM) group has also reported that high peripheral blast counts (>10,000/μL) at the time of relapse were associated with inferior outcomes in patients with late marrow relapses.

Children with Down syndrome with relapse of ALL have generally had inferior outcomes resulting from increased induction deaths, treatment-related mortality, and relapse.

  • The BFM group showed that since 2000, improvements in supportive care have led to decreases in treatment-related mortality in children with Down syndrome, but the risk of relapse remains high.
  • An analysis of data from the Center for International Blood and Marrow Transplant Research (CIBMTR) on 27 Down syndrome patients with ALL who underwent hematopoietic stem cell transplantation (HSCT) between 2000 and 2009 substantiated this finding. They noted that with current transplant practices, hematopoietic recovery, graft-versus-host disease (GVHD), and transplant-related mortality were within the expected range compared with non–Down syndrome ALL patients. However, relapse was higher than expected (>50%) and was the primary cause of treatment failure, leading to poor survival (24% disease-free survival [DFS] at 3 years).[]

Risk group classification at initial diagnosis

The COG reported that risk group classification at the time of initial diagnosis was prognostically significant after relapse; patients who met National Cancer Institute (NCI) standard-risk criteria at initial diagnosis fared better after relapse than did NCI high-risk patients.

Response to reinduction therapy

Patients with marrow relapses who have persistent morphologic disease at the end of the first month of reinduction therapy have an extremely poor prognosis, even if they subsequently achieve a second complete remission (CR).[]; [] Several studies have demonstrated that minimal residual disease (MRD) levels after the achievement of second CR are of prognostic significance in relapsed ALL.; [] High levels of MRD at the end of reinduction and at later time points have been correlated with an extremely high risk of subsequent relapse.

Cytogenetics/genomic alterations

Changes in mutation profiles from diagnosis to relapse have been identified by gene sequencing. While oncogenic gene fusions (e.g., , ) are almost always observed between the time of initial diagnosis and relapse, single nucleotide variants and copy number variants may be present at diagnosis, but not at relapse, and vice versa. For example, while family mutations are common at both diagnosis and relapse, the specific family mutations may change from diagnosis to relapse as specific leukemic subclones rise and fall during the course of treatment. By contrast, relapse-specific mutations in (a gene involved in nucleotide metabolism) have been noted in as many as 45% of ALL cases with early relapse.

alterations (mutations and/or copy number alterations) are observed in approximately 11% of patients with ALL at first relapse and have been associated with an increased likelihood of persistent leukemia after initial reinduction (38.5% alteration vs. 12.5% wild-type) and poor event-free survival (EFS) (9% alteration vs. 49% wild-type). Approximately one-half of the alterations were present at initial diagnosis and half were newly observed at time of relapse. A second genomic alteration found to predict for poor prognosis in patients with precursor B-cell ALL in first bone marrow relapse is deletion. The frequency of deletion in precursor B-cell ALL patients at first relapse patients was 33% in patients in the Acute Lymphoblastic Leukemia Relapse (ALL-REZ) BFM 2002 ( ) study, which was approximately twice as high as the frequency described in children at initial diagnosis of ALL.

RAS pathway mutations (, , , and ) are common at relapse in precursor B-cell ALL patients, and they were found in approximately 40% of patients at first relapse in one study of 206 children. As observed at diagnosis, the frequency of RAS pathway mutations at relapse differs by cytogenetic subtype (e.g., high frequency in hyperdiploid cases and low frequency in cases). The presence of RAS pathway mutations at relapse was associated with early relapse. However, presence of RAS pathway mutations at relapse was not an independent predictor of outcome.

Patients with -positive ALL appear to have a relatively favorable prognosis at first relapse, consistent with the high percentage of such patients who relapse more than 36 months after diagnosis.

  • In the ALL-REZ BFM 2002 () study, an EFS of 84% ± 7% was observed for patients with ALL with bone marrow relapse. In this study, 94% of patients with had a duration of first remission that extended at least 6 months beyond completion of their primary treatment, and on multivariate analysis, time to relapse (and not the presence of ) was an independent predictor of outcome.
  • Similarly, the 5-year OS for patients enrolled on the French Acute Lymphoblastic Leukaemia (FRALLE) 93 study who relapsed at any site more than 36 months after diagnosis was 81%, and the presence of was associated with a favorable survival outcome compared with other late relapsing patients. However, the 3-year OS of patients who experienced an early relapse (<36 months) was only 31%.

Immunophenotype

Immunophenotype is an important prognostic factor at relapse. Patients with T-cell ALL who experience a marrow relapse (isolated or combined) at any time during treatment or posttreatment are less likely to achieve a second remission and long-term EFS than are patients with B-cell ALL.

Standard Treatment Options for First Bone Marrow Relapse of Childhood ALL

Standard treatment options for first bone marrow relapse include the following:

Reinduction chemotherapy

Initial treatment of relapse consists of reinduction therapy to achieve a second CR. Using either a four-drug reinduction regimen (similar to that administered to newly diagnosed high-risk patients) or an alternative regimen including high-dose methotrexate and high-dose cytarabine, approximately 85% of patients with a marrow relapse achieve a second CR at the end of the first month of treatment.; []; [] Patients with early marrow relapses have a lower rate of achieving a morphologic second CR (approximately 70%) than do those with late marrow relapses (approximately 95%).

Evidence (reinduction chemotherapy):

Patients with relapsed T-cell ALL have much lower rates of achieving second CR with standard reinduction regimens than do patients with precursor B-cell phenotype. Treatment of children with first relapse of T-cell ALL in the bone marrow with single-agent therapy using the T-cell selective agent, nelarabine, has resulted in response rates of approximately 50%. The combination of nelarabine, cyclophosphamide, and etoposide has produced remissions in patients with relapsed/refractory T-cell ALL.

Reinduction failure is a poor prognostic factor, but subsequent attempts to obtain remission can be successful and lead to survival after HSCT. Approaches have traditionally included the use of drug combinations distinct from the first attempt at treatment; these regimens often contain newer agents under investigation in clinical trials. Although survival is progressively less likely after each attempt, two to four additional attempts are often pursued, with diminishing levels of success measured after each attempt.

Postreinduction therapy for patients achieving a second complete remission

Early-relapsing precursor B-cell ALL

For precursor B-cell patients with an early marrow relapse, allogeneic transplant from a human leukocyte antigen (HLA)-identical sibling or matched unrelated donor that is performed in second remission has been reported in most studies to result in higher leukemia-free survival than a chemotherapy approach. However, even with transplantation, the survival rate for patients with early marrow relapse is less than 50%. (Refer to the Hematopoietic Stem Cell Transplantation for First and Subsequent Bone Marrow Relapse section of this summary for more information.)

Late-relapsing precursor B-cell ALL

For patients with a late marrow relapse of precursor B-cell ALL, a primary chemotherapy approach after achievement of second CR has resulted in survival rates of approximately 50%, and it is not clear whether allogeneic transplantation is associated with superior cure rate.; [] End-reinduction MRD levels may help to identify patients with a high risk of subsequent relapse if treated with chemotherapy alone (no HSCT) in second CR. Results from one study suggest that patients with a late marrow relapse who have high end-reinduction MRD may have a better outcome if they receive an allogeneic HSCT in second CR.

Evidence (MRD-based risk stratification for late-relapse of precursor B-cell ALL):

T-cell ALL

For patients with T-cell ALL who achieved remission after bone marrow relapse, outcomes with postreinduction chemotherapy alone have generally been poor, and these patients are usually treated with allogeneic HSCT in second CR, regardless of time to relapse. At 3 years, OS after allogeneic transplant for T-cell ALL in second remission was reported to be 48% and DFS was 46%.[]

Treatment Options for Second and Subsequent Bone Marrow Relapse

Although there are no studies directly comparing chemotherapy with HSCT for patients in third or subsequent CR, because cure with chemotherapy alone is rare, transplant is generally considered a reasonable approach for those achieving remission. Long-term survival for all patients after a second relapse is particularly poor, in the range of less than 10% to 20%. One of the main reasons for this is failure to obtain a third remission. In spite of numerous attempts at novel combination approaches, only about 40% of children with second relapse are able to achieve remission. If these patients achieve CR, HSCT has been shown to cure 20% to 35%, with failures occurring due to high rates of relapse and transplant-related mortality.[]

Hematopoietic Stem Cell Transplantation for First and Subsequent Bone Marrow Relapse

Components of the transplantation process

An expert panel review of indications for HSCT was published in 2012. Components of the transplant process that have been shown to be important in improving or predicting outcome of HSCT for children with ALL include the following:

TBI-containing transplant preparative regimens

For patients proceeding to allogeneic HSCT, TBI appears to be an important component of the conditioning regimen. Two retrospective studies and a randomized trial suggest that transplant conditioning regimens that include TBI produce higher cure rates than do chemotherapy-only preparative regimens. Fractionated TBI (total dose, 12–14 Gy) is often combined with cyclophosphamide, etoposide, thiotepa, or a combination of these agents. Study findings with these combinations have generally resulted in similar rates of survival, although one study suggested that if cyclophosphamide is used without other chemotherapy drugs, a dose of TBI in the higher range may be necessary. Many standard regimens include cyclophosphamide with TBI dosing between 13.2 and 14 Gy. On the other hand, when cyclophosphamide and etoposide were used with TBI, doses above 12 Gy resulted in worse survival resulting from excessive toxicity.

Although some studies of non-TBI approaches have shown reasonable outcomes and have prompted a large BFM study comparing TBI versus non-TBI regimens, TBI for all but the youngest children (age <3 or <4 years) remains the most commonly used therapy in most centers in North America.

MRD detection just before transplant

Remission status at the time of transplantation has long been known to be an important predictor of outcome, with patients not in CR at HSCT having very poor survival rates. Several studies have also demonstrated that the level of MRD at the time of transplant is a key risk factor in children with ALL in CR undergoing allogeneic HSCT.[]; [] Survival rates of patients who are MRD-positive pretransplant have been reported between 20% and 47%, compared with 60% to 88% in patients who are MRD-negative.

When patients have received two to three cycles of chemotherapy in an attempt to achieve an MRD-negative remission, the benefit of further intensive therapy for achieving MRD negativity must be weighed against the potential for significant toxicity. In addition, there is not clear evidence showing that MRD positivity in a patient who has received multiple cycles of therapy is a biological disease marker for poor outcome that cannot be modified, or whether further intervention bringing such patients into an MRD negative remission will overcome this risk factor and improve survival.

  • In one report, 13 patients with ALL and high MRD at the time of planned transplant received an additional cycle of chemotherapy in an attempt to lower MRD before proceeding to HSCT. Ten of the 13 patients (77%) remained in CR post-HSCT, with no relapses observed in the eight patients who achieved low MRD after the additional chemotherapy cycle. In comparison, only 6 of 21 high-MRD patients (29%) who proceeded directly to HSCT without receiving additional pre-HSCT chemotherapy remained in CR.

MRD detection posttransplant

The presence of detectable MRD post-HSCT has been associated with an increased risk of subsequent relapse. The accuracy of MRD for predicting relapse increases as time from HSCT elapses and relapse risk is also higher for patients who have higher levels of MRD detected at any given time. One study showed higher sensitivity for predicting relapse using next-generation sequencing assays than with flow cytometry, especially early after HSCT.

Donor type and HLA match

Survival rates after matched unrelated donor and umbilical cord blood transplantation have improved significantly over the past decade and offer an outcome similar to that obtained with matched sibling donor transplants.; []; []; [] Rates of clinically extensive GVHD and treatment-related mortality remain higher after unrelated donor transplantation compared with matched sibling donor transplants. However, there is some evidence that matched unrelated donor transplantation may yield a lower relapse rate, and National Marrow Donor Program and CIBMTR analyses have demonstrated that rates of GVHD, treatment-related mortality, and OS have improved over time.; []

Another CIBMTR study suggests that outcome after one or two antigen mismatched cord blood transplants may be equivalent to that for a matched family donor or a matched unrelated donor. In certain cases in which no suitable donor is found or an immediate transplant is considered crucial, a haploidentical transplant utilizing large doses of stem cells may be considered.

Role of GVHD/GVL in ALL and immune modulation after transplant to prevent relapse

Most studies of pediatric and young adult patients that address this issue suggest an effect of both acute and chronic GVHD in decreasing relapse.

  • In a COG trial of transplantation for children with ALL, grades I to III acute GVHD were associated with lower relapse risk (hazard ratio [HR], 0.4; = .04) and better EFS (multivariate analysis, HR, 0.5; = .02). Any effect of grade IV acute GVHD in decreasing relapse risk was obscured by a marked increase in transplant-related mortality (HR, 6.4; = .003), while grades I to III acute GVHD had no statistically detectable effect on transplant-related mortality (HR, 0.6; = .42).
  • In a multivariate model, both pretransplant MRD and acute GVHD were independent predictors of relapse, with the lowest risk of relapse observed in patients with both low pretransplant MRD and grades I to III acute GVHD. For patients who did not develop acute GVHD by day 55 post-HSCT, nearly all relapses occurred between days 100 and 400 post-HSCT.

Harnessing this GVL effect, a number of approaches to prevent relapse after transplantation have been studied, including withdrawal of immune suppression or donor lymphocyte infusion and targeted immunotherapies, such as monoclonal antibodies and natural killer cell therapy. Trials in Europe and the United States have shown that patients defined as having a high risk of relapse based upon increasing recipient chimerism (i.e., increased percentage of recipient DNA markers) can successfully undergo withdrawal of immune suppression without excessive toxicity.

  • One study showed that in 46 patients with increasing recipient chimerism, the 31 patients who underwent immune suppression withdrawal, donor lymphocyte infusion, or both therapies had a 3-year EFS of 37% versus 0% in the nonintervention group ( < .001).
  • Other studies have shown better-than-expected rates of survival of pre-HSCT, MRD-positive patients when tapering has occurred for MRD detected after HSCT.

Intrathecal medication after HSCT to prevent relapse

The use of post-HSCT intrathecal chemotherapy chemoprophylaxis is controversial.

Relapse after allogeneic HSCT for relapsed ALL

For patients relapsing after an allogeneic HSCT for ALL, a second ablative allogeneic HSCT may be feasible. However, many patients will be unable to undergo a second HSCT procedure because of failure to achieve remission, early toxic death, or severe organ toxicity related to salvage chemotherapy. Among the highly selected group of patients able to undergo a second ablative allogeneic HSCT, approximately 10% to 30% will achieve long-term EFS.; [] Prognosis is more favorable in patients with longer duration of remission after the first HSCT and in patients with CR at the time of the second HSCT. In addition, one study showed an improvement in survival after second HSCT if acute GVHD occurred, especially if it had not occurred after the first transplant.

Reduced-intensity approaches can also cure a percentage of patients when used as a second allogeneic transplant approach, but only if patients achieve a CR confirmed by flow cytometry.[] Donor leukocyte infusion has limited benefit for patients with ALL who relapse after allogeneic HSCT.; []

Whether a second allogeneic transplant is necessary to treat isolated CNS and testicular relapse after HSCT is unknown. A small series has shown survival in selected patients using chemotherapy alone or chemotherapy followed by a second transplant.[]

Immunotherapeutic Approaches for Refractory ALL

Immunotherapeutic approaches to the treatment of refractory ALL include monoclonal antibody therapy and chimeric antigen receptor (CAR) T-cell therapy.

Monoclonal antibody therapy

The following two immunotherapeutic agents have been studied for the treatment of refractory B-cell ALL:

  • Blinatumomab. Blinatumomab is a bispecific monoclonal antibody with one site for CD3 (T cells) and the other site for CD19 (present on most B-ALL cells). Thus, blinatumomab promotes the binding of the patient’s own cytotoxic T cells to B lymphoblasts, resulting in tumor being killed. In a phase I/II trial of children younger than 18 years with relapsed/refractory B-cell ALL, 27 of 70 patients (39%) treated at the recommended phase II dose achieved a CR with single-agent blinatumomab; 52% of those achieving CR were MRD negative.
  • Inotuzumab. Inotuzumab is an anti-CD22 monoclonal antibody that is conjugated to calicheamicin. In trials of adult patients with relapsed/refractory B-cell ALL, CR was achieved in approximately 80% of patients. Inotuzumab has not been extensively studied in pediatric patients with B-cell ALL and is not yet labeled for use in children.

CAR T-cell therapy

CAR T-cell therapy is a new strategy under clinical investigation for the treatment of relapsed and refractory ALL in second or subsequent relapse. This strategy includes engineering T cells with a CAR that redirects T-cell specificity and function. One widely utilized target of CAR-modified T cells is the CD19 antigen expressed on almost all normal B cells and most B-cell malignancies. Several clinical trials of CAR T cells targeting CD19 in relapsed/refractory ALL are being conducted, with encouraging initial results, including the following:

Treatment of Isolated Extramedullary Relapse

With improved success in treating children with ALL, the incidence of isolated extramedullary relapse has decreased. The incidence of isolated CNS relapse is less than 5%, and testicular relapse is less than 1% to 2%. As with bone marrow and mixed relapses, time from initial diagnosis to relapse is a key prognostic factor in isolated extramedullary relapses. In addition, age older than 6 years at relapse was noted in one study as an adverse prognostic factor for patients with an isolated extramedullary relapse, while a second study suggested age 10 years as a better cutoff. Of note, 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. Patients with an isolated CNS relapse who show greater than 0.01% MRD in a morphologically normal marrow have a worse prognosis (5-year EFS, 30%) than do patients with either no MRD or MRD less than 0.01% (5-year EFS, 60%).

Isolated CNS relapse

Standard treatment options for childhood ALL that has recurred in the CNS include the following:

While the prognosis for children with isolated CNS relapse had been quite poor in the past, aggressive systemic and intrathecal therapy followed by cranial or craniospinal radiation has improved the outlook, particularly for patients who did not receive cranial radiation during their first remission.

Evidence (chemotherapy and radiation therapy):

A number of case series describing HSCT in the treatment of isolated CNS relapse have been published. Although some reports have suggested a possible role for HSCT for patients with isolated CNS disease with very early relapse and T-cell disease, there is less evidence for the need for HSCT in early relapse and no evidence in late relapse. The use of transplantation to treat isolated CNS relapse occurring less than 18 months from diagnosis, especially T-cell CNS relapse, requires further study.

Evidence (HSCT):

Isolated testicular relapse

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.

Standard treatment options in North America for childhood ALL that has recurred in the testes include the following:

The standard approach for treating isolated testicular relapse in North America is to administer intensive chemotherapy that includes high-dose methotrexate. Patients who do not respond with a CR after induction also receive local radiation therapy.

In some European clinical trial groups, orchiectomy of the involved testicle is performed instead of radiation. Biopsy of the other testicle is performed at the time of relapse to determine if additional local control (surgical removal or radiation) is to be performed. A study that looked at testicular biopsy at the end of frontline therapy failed to demonstrate a survival benefit for patients with early detection of occult disease. While there are limited clinical data concerning outcome without the use of radiation therapy or orchiectomy, the use of chemotherapy (e.g., high-dose methotrexate) that may be able to achieve antileukemic levels in the testes is being tested in clinical trials.

Evidence (treatment of testicular relapse [case reports]):

Treatment Options Under Clinical Evaluation for Relapsed Childhood ALL

Trials for ALL in first relapse

Treatment options under clinical evaluation for ALL in first relapse include the following:

Trials for ALL in second or subsequent relapse or refractory ALL

Multiple clinical trials investigating new agents and new combinations of agents are available for children with second or subsequent relapsed or refractory ALL and should be considered. These trials are testing targeted treatments specific for ALL, including monoclonal antibody–based therapies and drugs that inhibit signal transduction pathways required for leukemia cell growth and survival.

Current Clinical Trials

Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.

Changes to This Summary (09/28/2017)

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.

Risk-Based Treatment Assignment

Added Winick et al. as reference 45.

Revised text to state that –like acute lymphoblastic leukemia (ALL) occurs in 10% to 20% of pediatric ALL patients, increasing in frequency with age, and has been associated with a poor prognosis and with deletion or mutation (cited Reshmi et al. as reference 213).

Added Schmäh et al. as reference 221.

Postinduction Treatment for Childhood ALL

Added text about a follow-up study that explored mercaptopurine ingestion habits, red cell thioguanine nucleotide levels, adherence, and relapse risk (cited Landier et al. as reference 70 and level of evidence 2Diii).

Treatment of Relapsed Childhood ALL

Added text about the results of a phase I trial of 45 children and young adults with relapsed/refractory CD19-positive B-cell ALL who received 4-1BB–based lentiviral vector expanded CAR T cells (cited Gardner et al. as reference 134).

This summary is written and maintained by the PDQ Pediatric Treatment Editorial Board, which is editorially independent of NCI. The summary reflects an independent review of the literature and does not represent a policy statement of NCI or NIH. More information about summary policies and the role of the PDQ Editorial Boards in maintaining the PDQ summaries can be found on the About This PDQ Summary and PDQ® - NCI's Comprehensive Cancer Database pages.

About This PDQ Summary

Purpose of This Summary

This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the treatment of childhood acute lymphoblastic leukemia. It is intended as a resource to inform and assist clinicians who care for cancer patients. It does not provide formal guidelines or recommendations for making health care decisions.

Reviewers and Updates

This summary is reviewed regularly and updated as necessary by the PDQ Pediatric Treatment Editorial Board, which is editorially independent of the National Cancer Institute (NCI). The summary reflects an independent review of the literature and does not represent a policy statement of NCI or the National Institutes of Health (NIH).

Board members review recently published articles each month to determine whether an article should:

  • be discussed at a meeting,
  • be cited with text, or
  • replace or update an existing article that is already cited.

Changes to the summaries are made through a consensus process in which Board members evaluate the strength of the evidence in the published articles and determine how the article should be included in the summary.

The lead reviewers for Childhood Acute Lymphoblastic Leukemia Treatment are:

  • Alan Scott Gamis, MD, MPH (Children's Mercy Hospital)
  • Karen J. Marcus, MD (Dana-Farber Cancer Institute/Boston Children's Hospital)
  • Michael A. Pulsipher, MD (Children's Hospital Los Angeles)
  • Arthur Kim Ritchey, MD (Children's Hospital of Pittsburgh of UPMC)
  • Lewis B. Silverman, MD (Dana-Farber Cancer Institute/Boston Children's Hospital)
  • Malcolm A. Smith, MD, PhD (National Cancer Institute)

Any comments or questions about the summary content should be submitted to Cancer.gov through the NCI website's Email Us. Do not contact the individual Board Members with questions or comments about the summaries. Board members will not respond to individual inquiries.

Levels of Evidence

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 Treatment Editorial Board uses a formal evidence ranking system in developing its level-of-evidence designations.

Permission to Use This Summary

PDQ is a registered trademark. Although the content of PDQ documents can be used freely as text, it cannot be identified as an NCI PDQ cancer information summary unless it is presented in its entirety and is regularly updated. However, an author would be permitted to write a sentence such as “NCI’s PDQ cancer information summary about breast cancer prevention states the risks succinctly: [include excerpt from the summary].”

The preferred citation for this PDQ summary is:

PDQ® Pediatric Treatment Editorial Board. PDQ Childhood Acute Lymphoblastic Leukemia Treatment. Bethesda, MD: National Cancer Institute. Updated . Available at: https://www.cancer.gov/types/leukemia/hp/child-all-treatment-pdq. Accessed . [PMID: 26389206]

Images in this summary are used with permission of the author(s), artist, and/or publisher for use within the PDQ summaries only. Permission to use images outside the context of PDQ information must be obtained from the owner(s) and cannot be granted by the National Cancer Institute. Information about using the illustrations in this summary, along with many other cancer-related images, is available in Visuals Online, a collection of over 2,000 scientific images.

Disclaimer

Based on the strength of the available evidence, treatment options may be described as either “standard” or “under clinical evaluation.” These classifications should not be used as a basis for insurance reimbursement determinations. More information on insurance coverage is available on Cancer.gov on the Managing Cancer Care page.

Contact Us

More information about contacting us or receiving help with the Cancer.gov website can be found on our Contact Us for Help page. Questions can also be submitted to Cancer.gov through the website’s Email Us.

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