Childhood Acute Lymphoblastic Leukemia Treatment (PDQ®)

General Information About Childhood Acute Lymphoblastic Leukemia (ALL)
Fortunately, cancer in children and adolescents is rare, although the overall incidence of childhood cancer, including ALL, has been slowly increasing since 1975. Children and adolescents with cancer should be referred to medical centers that have a multidisciplinary team of cancer specialists with experience treating the cancers that occur during childhood and adolescence. This multidisciplinary team approach incorporates the skills of the 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.
(Refer to the PDQ Supportive and Palliative Care summaries for specific information about supportive care for children and adolescents with cancer.)
Guidelines for cancer centers and their role in the treatment of pediatric patients with cancer have been outlined by the American Academy of Pediatrics. 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 pediatric oncologists in cancer centers or hospitals with all of the necessary pediatric supportive care facilities. 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.
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 follow-up 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 and Epidemiology
ALL is the most common cancer diagnosed in children and represents approximately 25% of cancer diagnoses among children younger than 15 years. ALL occurs at an annual rate of 35 to 40 cases per 1 million people in the United States. There are approximately 2,900 children and adolescents younger than 20 years diagnosed with ALL each year in the United States. Over the past 25 years, 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 (see Figure 1).
  • Shwachman syndrome.
  • Bloom syndrome.
  • Ataxia telangiectasia.
  • Inherited genetic polymorphisms.
  • 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 acute myeloid leukemia (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) and hyperdiploidy) and unfavorable (t(9;22) or t(4;11) and hypodiploidy) 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 CRLF2 that generally result in overexpression of this gene. CRLF2 genomic alterations are observed at a much lower frequency (<10%) in children with B-precursor ALL who do not have Down syndrome. It does not appear that genomic CRLF2 aberrations in patients with Down syndrome and ALL have prognostic relevance. However, IKZF1 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 JAK2 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 B-precursor ALL. Almost all Down syndrome ALL cases with JAK2 mutations also have CRLF2 genomic alterations. Preliminary evidence suggests no correlation between JAK2 mutation status and 5-year event-free survival in children with Down syndrome and ALL, but more study is needed to address this issue and the prognostic significance of IKZF1 gene deletions.

    Inherited genetic polymorphisms
    Genome-wide association studies show that some germline (inherited) genetic polymorphisms are associated with the development of childhood ALL. For example, the risk alleles of ARID5B are strongly associated with the development of hyperdiploid B-precursor ALL. ARID5B is a gene that encodes a transcriptional factor important in embryonic development, cell type–specific gene expression, and cell growth regulation.

    Prenatal origin of childhood ALL
    Development of ALL is in most cases a multi-step 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 in support of this comes from the observation that the immunoglobulin or T-cell receptor antigen rearrangements that are unique to each patient’s leukemia cells can be detected in blood samples obtained at birth. Similarly, in ALL characterized by specific chromosomal abnormalities, some patients appear to have blood cells carrying 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.
    There is also evidence 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 ETV6-RUNX1 translocation, far exceeding the number of cases of ETV6-RUNX1 ALL in children. Other reports confirm or do not confirm this finding. Nonetheless, if confirmed, it would support the hypothesis that additional postnatal genomic changes are needed for the development of this type of ALL and that in most cases in which a leukemia-associated alteration is present at birth, the additional leukemogenic genomic changes do not occur and no leukemia develops.

    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.

    Overall Outcome for ALL
    Among children with ALL, more than 95% attain remission, and approximately 80% of patients aged 1 to 18 years with newly diagnosed ALL treated on current regimens are expected to be long-term event-free survivors.
    Despite the treatment advances noted 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/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 Web site.

    Current Clinical Trials
    Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with childhood acute lymphoblastic leukemia. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.
    General information about clinical trials is also available from the NCI Web site.

    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 and the National Cancer Institute (NCI) risk group classification. The NCI risk group classification 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.
    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. The factors described are grouped into the following three categories:
    • Patient characteristics affecting prognosis.
    • Leukemic cell characteristics affecting prognosis.
    • Response to initial treatment affecting prognosis.
    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 characteristics affecting prognosis
    Patient characteristics affecting prognosis include the following:
  • Age at diagnosis.
  • WBC count at diagnosis.
  • Central nervous system (CNS) involvement at diagnosis.
  • Testicular involvement at diagnosis.
  • Down syndrome (trisomy 21).
  • Gender.
  • Race.
  • Age at diagnosis
    Age at diagnosis has strong prognostic significance, reflecting the different underlying biology of ALL in different age groups.
  • Infants (younger than 1 year)
    Infants with ALL have a particularly high risk of treatment failure. Treatment failure is most common in the following groups:
      Infants younger than 6 months (with an even poorer prognosis for those aged 60 to 90 days).
    • Infants with extremely high presenting leukocyte counts.
    • Infants with a poor response to a prednisone prophase.
    • Infants with an MLL gene rearrangement.
    Approximately 80% of infants with ALL have an MLL gene rearrangement. The rate of MLL gene translocations is extremely high in infants younger than 6 months; from 6 months to 1 year, the incidence of MLL translocations decreases but remains higher than that observed in older children. Black infants with ALL are significantly less likely to have MLL translocations than white infants. Infants with leukemia and MLL translocations typically have very high WBC counts and an increased incidence of CNS involvement. Overall survival (OS) is poor, especially in infants younger than 6 months. A gene expression profile analysis in infants with MLL-rearranged ALL revealed significant differences between patients younger than 90 days and older infants, suggesting distinctive age-related biological behaviors for MLL-translocation ALL that may relate to the significantly poorer outcome for the youngest infants.
    Blasts from infants with MLL translocations are typically CD10 negative and express high levels of FLT3. Conversely, infants whose leukemic cells show a germline MLL gene configuration frequently present with CD10-positive precursor-B immunophenotype. These infants have a significantly better outcome than do infants with ALL characterized by MLL translocations.
  • Young children (aged 1 to <10 years)
    Young children (aged 1 to <10 years) have a better disease-free survival than older children, adolescents, and infants. The improved prognosis in young children is at least partly explained by the more frequent occurrence of favorable cytogenetic features in the leukemic blasts including hyperdiploidy with 51 or more chromosomes and/or favorable chromosome trisomies, or the ETV6-RUNX1 (t(12;21), also known as the TEL-AML1 translocation).
  • Adolescents and young adults (aged ≥10 years)
    In general, the outcome of patients aged 10 years and older is inferior to that of patients aged 1 to younger than 10 years. However, the outcome for older children, especially adolescents, has improved significantly over time. Five-year survival rates for adolescents aged 15 to 19 years increased from 36% (1975–1984) to 72% (2003–2009). Multiple retrospective studies have suggested that adolescents aged 16 to 21 years have a better outcome when treated on pediatric versus adult protocols. (Refer to the Postinduction Treatment for Specific ALL Subgroups section of this summary for more information about adolescents with ALL.)
  • 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 B-precursor 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 B-precursor ALL (<10,000/µL), and there is no consistent effect of WBC count at diagnosis on prognosis for T-cell ALL. One factor that might explain the lack of prognostic effect for WBC count at diagnosis may be the very poor outcome observed for T-cell ALL with the early T-cell precursor phenotype, as patients with this subtype appear to have lower WBC count at diagnosis (median, <50,000/µL) than do other T-cell ALL patients.

    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 event-free survival (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 MLL gene rearrangements.
    Some clinical trial groups have approached CNS2 and traumatic lumbar puncture by utilizing more intensive therapy, primarily additional doses of intrathecal therapy during induction.; [Level of evidence: 2A] Other groups have not altered therapy based on CNS2 status.
    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.
    The lower EFS and OS of children with Down syndrome appear to be related to higher rates of treatment-related mortality and the lower frequency of favorable biological features such as ETV6-RUNX1 or trisomies of chromosomes 4 and 10. In a report from the COG, among B-precursor ALL patients who lacked MLL translocations, BCR-ABL1, ETV6-RUNX1, or trisomies of chromosomes 4 and 10, the EFS and OS were similar in children with and without Down syndrome. In a large retrospective study of patients with Down syndrome and ALL (N = 653), age younger than 6 years, WBC count of less than 10,000/µL, and the presence of the ETV6-RUNX1 fusion (observed in 8% of patients) were independent predictors of favorable EFS. Failure to achieve remission and treatment-related mortality are also higher in patients with Down syndrome. Certain genomic abnormalities, such as IKZF1 deletions, CRLF2 aberrations, and JAK mutations are seen more frequently in ALL arising in children with Down syndrome than in those without Down syndrome. In one study of Down syndrome children with ALL, the presence of IKZF1 deletions (but not CRLF2 aberrations or JAK mutations) was associated with an inferior prognosis.

    Gender
    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
    Survival rates in black and Hispanic children with ALL have been somewhat lower than the rates in white children with ALL. Asian children with ALL fare slightly better than white children.
    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. Differences in outcome may also be related to treatment adherence, as illustrated by a study of adherence to oral 6-mercaptopurine in maintenance therapy. In this 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. Ancestry-related genomic variations may also contribute to racial/ethnic disparities in both the incidence and outcome of ALL. For example, the differential presence of specific host polymorphisms in different racial/ethnic groups may contribute to outcome disparities, as illustrated by the occurrence of single nucleotide polymorphisms in the ARID5B gene that occur more frequently among Hispanics and are linked to both ALL susceptibility and to relapse hazard.

    Leukemic cell characteristics affecting prognosis
    Leukemic cell characteristics affecting prognosis include the following:
  • Morphology.
  • Immunophenotype.
  • Cytogenetics/genomic alterations.
  • 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 C-MYC gene translocation identical to that seen in Burkitt lymphoma (i.e., t(8;14)). Patients with this specific rare form of leukemia (mature B-cell or Burkitt leukemia) should be treated according to protocols for Burkitt lymphoma. (Refer to the PDQ summary on Childhood Non-Hodgkin Lymphoma Treatment for more information about the treatment of B-cell ALL and Burkitt lymphoma.)

    Immunophenotype
    The World Health Organization (WHO) classifies ALL as either:
    • B lymphoblastic leukemia.
    • T lymphoblastic leukemia.
    Either B or T lymphoblastic leukemia can coexpress myeloid antigens. These cases need to be distinguished from leukemia of ambiguous lineage.
  • Precursor B-cell ALL (WHO B lymphoblastic leukemia)
    Before 2008, the WHO classified B lymphoblastic leukemia as precursor-B lymphoblastic leukemia, and this terminology is still frequently used in the literature of childhood ALL to distinguish it from mature B-cell ALL. Mature B-cell ALL is now termed Burkitt leukemia and requires different treatment than has been given for precursor B-cell ALL. The older terminology will continue to be used throughout this summary.
    Precursor B-cell ALL, defined by the expression of cytoplasmic CD79a, CD19, HLA-DR, and other B cell-associated antigens, accounts for 80% to 85% of childhood ALL. Approximately 90% of precursor B-cell ALL cases express the CD10 surface antigen (formerly known as common ALL antigen [cALLa]). Absence of CD10 is associated with MLL translocations, particularly t(4;11), and a poor outcome. It is not clear whether CD10-negativity has any independent prognostic significance in the absence of an MLL gene rearrangement.
    The major subtypes of precursor B-cell ALL are as follows:
      Common precursor B-cell ALL (CD10 positive and no surface or cytoplasmic Ig)
      Approximately three-quarters of patients with precursor B-cell ALL have the common precursor B-cell immunophenotype and have the best prognosis. Patients with favorable cytogenetics almost always show a common precursor B-cell immunophenotype.
    • Pro-B ALL (CD10 negative and no surface or cytoplasmic Ig)
      Approximately 5% of patients have the pro-B immunophenotype. Pro-B is the most common immunophenotype seen in infants and is often associated with MLL gene rearrangements.
    • Pre-B ALL (presence of cytoplasmic Ig)
      The leukemic cells of patients with pre-B ALL contain cytoplasmic Ig, and 25% of patients with pre-B ALL have the t(1;19) translocation with TCF3-PBX1 (also known as E2A-PBX1) fusion (see below).
      Approximately 3% of patients have transitional pre-B ALL with expression of surface Ig heavy chain without expression of light chain, C-MYC gene involvement, or L3 morphology. Patients with this phenotype respond well to therapy used for precursor B-cell ALL.
      Approximately 2% of patients present with mature B-cell leukemia (surface Ig expression, generally with FAB L3 morphology and a translocation involving the C-MYC gene), also called Burkitt leukemia. The treatment for mature B-cell ALL is based on therapy for non-Hodgkin lymphoma and is completely different from that for precursor B-cell ALL. Rare cases of mature B-cell leukemia that lack surface Ig but have L3 morphology with C-MYC gene translocations should also be treated as mature B-cell leukemia. (Refer to the PDQ summary on Childhood Non-Hodgkin Lymphoma Treatment for more information about the treatment of children with B-cell ALL and Burkitt lymphoma.)
  • T-cell ALL
    T-cell ALL is defined by expression of the T cell–associated antigens (cytoplasmic CD3, with CD7 plus CD2 or CD5) on leukemic blasts. T-cell ALL is frequently associated with a constellation of clinical features, including the following:
      Male gender.
    • Older age.
    • Leukocytosis.
    • Mediastinal mass.
    With appropriately intensive therapy, children with T-cell ALL have an outcome approaching that of children with B-lineage ALL.
    There are few commonly accepted prognostic factors for patients with T-cell ALL. Conflicting data exist regarding the prognostic significance of presenting leukocyte counts in T-cell ALL. The presence or absence of a mediastinal mass at diagnosis has no prognostic significance. In patients with a mediastinal mass, the rate of regression of the mass lacks prognostic significance.
    Cytogenetic abnormalities common in B-lineage ALL (e.g., hyperdiploidy) are rare in T-cell ALL.
    Multiple chromosomal translocations have been identified in T-cell ALL, with many genes encoding for transcription factors (e.g., TAL1, LMO1 and LMO2, LYL1, TLX1/HOX11, and TLX3/HOX11L2) fusing to one of the T-cell receptor loci and resulting in aberrant expression of these transcription factors in leukemia cells. These translocations are often not apparent by examining a standard karyotype, but are identified using more sensitive screening techniques, such as fluorescence in situ hybridization (FISH) or polymerase chain reaction (PCR). High expression of TLX1/HOX11 resulting from translocations involving this gene occurs in 5% to 10% of pediatric T-cell ALL cases and is associated with more favorable outcome in both adults and children with T-cell ALL. Overexpression of TLX3/HOX11L2 resulting from the cryptic t(5;14)(q35;q32) translocation occurs in approximately 20% of pediatric T-cell ALL cases and appears to be associated with increased risk of treatment failure, although not in all studies.
    Notch pathway signaling is commonly activated by NOTCH1 and FBXW7 gene mutations in T-cell ALL. NOTCH1-activating gene mutations occur in approximately 50% to 60% of T-cell ALL cases, and FBXW7-inactivating gene mutations occur in approximately 15% of cases, with the result that approximately 60% of cases have Notch pathway activation by mutations in at least one of these genes. The prognostic significance of Notch pathway activation by NOTCH1 and FBXW7 mutations in pediatric T-cell ALL is not clear, as some studies have shown a favorable prognosis for mutated cases, while other studies have not shown prognostic significance for the presence of NOTCH1 and/or FBXW7 mutations.
    A NUP214–ABL1 fusion has been noted in 4% to 6% of T-cell ALL cases and is observed in both adults and children with a male predominance. The fusion is cytogenetically cryptic and is seen in FISH on amplified episomes or more rarely, as a small homogeneous staining region. T-cell ALL may also uncommonly show ABL1 fusion proteins with other gene partners (e.g., ETV6, BCR, and EML1). ABL tyrosine kinase inhibitors, such as imatinib or dasatinib, may have therapeutic benefit in this T-cell ALL subtype, although clinical experience with this strategy is very limited.
    Early T-cell precursor ALL
    Early T-cell precursor ALL, a distinct subset of childhood T-cell ALL, was initially defined by identifying T-cell ALL cases with gene expression profiles highly related to expression profiles for normal early T-cell precursors. The subset of T-cell ALL cases, identified by these analyses represented 13% of all cases and they were characterized by a distinctive immunophenotype (CD1a and CD8 negativity, with weak expression of CD5 and coexpression of stem cell or myeloid markers). Detailed molecular characterization of early T-cell precursor ALL showed this entity to be highly heterogeneous at the molecular level, with no single gene affected by mutation or copy number alteration in more than one-third of cases. Compared with other T-ALL cases, the early T-cell precursor group had a lower rate of NOTCH1 mutations and significantly higher frequencies of alterations in genes regulating cytokine receptors and Ras signaling, hematopoietic development, and histone modification. The transcriptional profile of early T-cell precursor ALL shows similarities to that of normal hematopoietic stem cells and myeloid leukemia stem cells. Initial reports describing early T-cell precursor ALL suggested that this subset has a poorer prognosis than other cases of T-cell ALL. However, another study indicated that the early T-cell precursor ALL subgroup had nonsignificantly inferior 5-year EFS compared with non–early T-cell precursor cases (76% vs. 84%). Further study in additional patient cohorts is needed to firmly establish the prognostic significance of early T-cell precursor ALL.
    Studies have found that the absence of biallelic deletion of the TCRgamma locus (ABGD), as detected by comparative genomic hybridization and/or quantitative DNA-PCR, was associated with early treatment failure in patients with T-cell ALL. ABGD is characteristic of early thymic precursor cells, and many of the T-cell ALL patients with ABGD have an immunophenotype consistent with the diagnosis of early T-cell precursor phenotype.
  • Myeloid antigen expression
    Up to one-third of childhood ALL cases have leukemia cells that express myeloid-associated surface antigens. Myeloid-associated antigen expression appears to be associated with specific ALL subgroups, notably those with MLL translocations and those with the ETV6-RUNX1 gene rearrangement. No independent adverse prognostic significance exists for myeloid-surface antigen expression.
    Leukemia of ambiguous lineage
    Less than 5% of cases of acute leukemia in children are of ambiguous lineage, expressing features of both myeloid and lymphoid lineage. These cases are distinct from ALL with myeloid coexpression in that the predominant lineage cannot be determined by immunophenotypic and histochemical studies. The definition of leukemia of ambiguous lineage varies among studies. However, most investigators now use criteria established by the European Group for the Immunological Characterization of Leukemias (EGIL) or the more stringent WHO criteria. In the WHO classification, the presence of myeloperoxidase is required to establish myeloid lineage. This is not the case for the EGIL classification.
    Leukemias of mixed phenotype comprise the following two groups:
      Bilineal leukemias in which there are two distinct populations of cells, usually one lymphoid and one myeloid.
    • Biphenotypic leukemias in which individual blast cells display features of both lymphoid and myeloid lineage. Biphenotypic cases represent the majority of mixed phenotype leukemias. Patients with B-myeloid biphenotypic leukemias lacking the ETV6-RUNX1 fusion have a lower rate of complete remission and a significantly worse EFS than do patients with B-precursor ALL. Some studies suggest that patients with biphenotypic leukemia may fare better with a lymphoid, as opposed to a myeloid, treatment regimen, although the optimal treatment for patients remains unclear.

    Cytogenetics/genomic alterations
    A number of recurrent chromosomal abnormalities have been shown to have prognostic significance, especially in B-precursor ALL. Some chromosomal abnormalities are associated with more favorable outcomes, such as high hyperdiploidy (51–65 chromosomes) and the ETV6-RUNX1 fusion. Others historically have been associated with a poorer prognosis, including the Philadelphia chromosome (t(9;22)), rearrangements of the MLL gene (chromosome 11q23), and intrachromosomal amplification of the AML1 gene (iAMP21).
    Prognostically significant chromosomal abnormalities in childhood ALL include the following:
  • Chromosome number
      High hyperdiploidy
      High hyperdiploidy, defined as 51 to 65 chromosomes per cell or a DNA index greater than 1.16, occurs in 20% to 25% of cases of precursor B-cell ALL, but very rarely in cases of T-cell ALL. Hyperdiploidy can be evaluated by measuring the DNA content of cells (DNA index) or by karyotyping. In cases with a normal karyotype or in which standard cytogenetic analysis was unsuccessful, interphase FISH may detect hidden hyperdiploidy. High hyperdiploidy generally occurs in cases with clinically favorable prognostic factors (patients aged 1 to <10 years with a low WBC count) and is itself an independent favorable prognostic factor. Within the hyperdiploid range of 51 to 66 chromosomes, patients with higher modal numbers (58–66) appeared to have a better prognosis in one study. Hyperdiploid leukemia cells are particularly susceptible to undergoing apoptosis and accumulate higher levels of methotrexate and its active polyglutamate metabolites, which may explain the favorable outcome commonly observed in these cases.
      While the overall outcome of patients with high hyperdiploidy is considered to be favorable, factors such as age, WBC count, specific trisomies, and early response to treatment have been shown to modify its prognostic significance.
      Patients with trisomies of chromosomes 4, 10, and 17 (triple trisomies) have been shown to have a particularly favorable outcome as demonstrated by both Pediatric Oncology Group (POG) and Children's Cancer Group analyses of NCI standard-risk ALL. POG data suggest that NCI standard-risk patients with trisomies of 4 and 10, without regard to chromosome 17 status, have an excellent prognosis.
      Chromosomal translocations may be seen with high hyperdiploidy, and in those cases, patients are more appropriately risk-classified based on the prognostic significance of the translocation. For instance, in one study, 8% of patients with the Philadelphia chromosome (t(9;22)) also had high hyperdiploidy, and the outcome of these patients (treated without tyrosine kinase inhibitors) was inferior to that observed in non-Philadelphia chromosome–positive (Ph+) high hyperdiploid patients.
      Certain patients with hyperdiploid ALL may have a hypodiploid clone that has doubled (masked hypodiploidy). These cases may be interpretable based on the pattern of gains and losses of specific chromosomes. These patients have an unfavorable outcome, similar to those with hypodiploidy.
      Near triploidy (68–80 chromosomes) and near tetraploidy (>80 chromosomes) are much less common and appear to be biologically distinct from high hyperdiploidy. Unlike high hyperdiploidy, a high proportion of near tetraploid cases harbor a cryptic ETV6-RUNX1 fusion. Near triploidy and tetraploidy were previously thought to be associated with an unfavorable prognosis, but later studies suggest that this may not be the case.
    • Hypodiploidy (<44 chromosomes)
      Precursor B-cell ALL cases with fewer than the normal number of chromosomes have been subdivided in various ways, with one report stratifying based on modal chromosome number into the following four groups:
      Near-haploid: 24 to 29 chromosomes (n = 46).
    • Low-hypodiploid: 33 to 39 chromosomes (n = 26).
    • High-hypodiploid: 40 to 43 chromosomes (n = 13).
    • Near-diploid: 44 chromosomes (n = 54).
    Most patients with hypodiploidy are in the near-haploid and low-hypodiploid groups, and both of these groups have an elevated risk of treatment failure compared with nonhypodiploid cases. Patients with fewer than 44 chromosomes have a worse outcome than do patients with 44 or 45 chromosomes in their leukemic cells.
    The recurring genomic alterations of near-haploid and low-hypodiploid ALL appear to be distinctive from each other and from other types of ALL. In near-haploid ALL, alterations targeting receptor tyrosine kinase signaling, Ras signaling, and IKZF3 are common. In low-hypodiploid ALL, genetic alterations involving TP53, RB1, and IKZF2 are common. Importantly, the TP53 alterations observed in low-hypodiploid ALL are also present in nontumor cells in approximately 40% of cases, suggesting that these mutations are germline and that low-hypodiploid ALL represents, in some cases, a manifestation of Li-Fraumeni syndrome.
  • Chromosomal translocations
      ETV6-RUNX1 (t(12;21) cryptic translocation, formerly known as TEL-AML1)
      Fusion of the ETV6 gene on chromosome 12 to the RUNX1 gene on chromosome 21 can be detected in 20% to 25% of cases of B-precursor ALL but is rarely observed in T-cell ALL. The t(12;21) occurs most commonly in children aged 2 to 9 years. Hispanic children with ALL have a lower incidence of t(12;21) than do white children.
      Reports generally indicate favorable EFS and OS in children with the ETV6-RUNX1 fusion; however, the prognostic impact of this genetic feature is modified by the following factors:
      Early response to treatment.
    • NCI risk category (age and WBC count at diagnosis).
    • Treatment regimen.
    In one study of the treatment of newly diagnosed children with ALL, multivariate analysis of prognostic factors found age and leukocyte count, but not ETV6-RUNX1, to be independent prognostic factors. It does not appear that the presence of secondary cytogenetic abnormalities, such as deletion of ETV6 (12p) or CDKN2A/B (9p), impacts the outcome of patients with the ETV6-RUNX1 fusion. There is a higher frequency of late relapses in patients with ETV6-RUNX1 fusion compared with other B-precursor ALL. Patients with the ETV6-RUNX1 fusion who relapse seem to have a better outcome than other relapse patients, with an especially favorable prognosis for patients who relapse more than 36 months from diagnosis. Some relapses in patients with t(12;21) may represent a new independent second hit in a persistent preleukemic clone (with the first hit being the ETV6-RUNX1 translocation).
  • Philadelphia chromosome (t(9;22) translocation)
    The Philadelphia chromosome t(9;22) is present in approximately 3% of children with ALL and leads to production of a BCR-ABL1 fusion protein with tyrosine kinase activity (see Figure 2).
  • MLL translocations
    Translocations involving the MLL (11q23) gene occur in up to 5% of childhood ALL cases and are generally associated with an increased risk of treatment failure. The t(4;11) translocation is the most common translocation involving the MLL gene in children with ALL and occurs in approximately 2% of cases.
    Patients with the t(4;11) translocation are usually infants with high WBC counts; they are more likely than other children with ALL to have CNS disease and to have a poor response to initial therapy. While both infants and adults with the t(4;11) translocation are at high risk of treatment failure, children with the t(4;11) translocation appear to have a better outcome than either infants or adults. Irrespective of the type of MLL gene rearrangement, infants with leukemia cells that have MLL gene rearrangements have a worse treatment outcome than older patients whose leukemia cells have an MLL gene rearrangement. Deletion of the MLL gene has not been associated with an adverse prognosis.
    Of interest, the t(11;19) translocation involving MLL and MLLT1/ENL occurs in approximately 1% of ALL cases and occurs in both early B-lineage and T-cell ALL. Outcome for infants with the t(11;19) translocation is poor, but outcome appears relatively favorable in older children with T-cell ALL and the t(11;19) translocation.
  • TCF3-PBX1 (E2A-PBX1; t(1;19) translocation)
    The t(1;19) translocation occurs in approximately 5% of childhood ALL cases and involves fusion of the E2A gene on chromosome 19 to the PBX1 gene on chromosome 1. The t(1;19) translocation may occur as either a balanced translocation or as an unbalanced translocation and is primarily associated with pre-B ALL immunophenotype (cytoplasmic Ig positive). Black children are more likely than white children to have pre-B ALL with the t(1;19).
    The t(1;19) translocation had been associated with inferior outcome in the context of antimetabolite-based therapy, but the adverse prognostic significance was largely negated by more aggressive multiagent therapies. However, in a trial conducted by SJCRH on which all patients were treated without cranial radiation, patients with the t(1;19) translocation had an overall outcome comparable to children lacking this translocation, with a higher risk of CNS relapse and a lower rate of bone marrow relapse, suggesting that more intensive CNS therapy may be needed for these patients.
  • Other genomic alterations
    Numerous new genetic lesions have been discovered by various array comparative hybridization and next-generation sequencing methods. Appreciation of these submicroscopic genomic abnormalities and mutations is redefining the subclassification of ALL:
      Intrachromosomal amplification of chromosome 21 (iAMP21): iAMP21 with multiple extra copies of the RUNX1 (AML1) gene occurs in approximately 2% of precursor B-cell ALL cases and is associated with older age (median, approximately 10 years), presenting WBC of less than 50 × 109/l, a slight female preponderance, and high end-induction minimal residual disease (MRD). The United Kingdom–ALL clinical trials group initially reported that the presence of iAMP21 conferred a poor prognosis in patients treated in the MRC ALL 97/99 trial (5-year EFS, 29%). In their subsequent trial (UKALL2003 [NCT00222612]), patients with iAMP21 were assigned to a more intensive chemotherapy regimen and had a markedly better outcome (5-year EFS, 78%). Similarly, the COG has reported that iAMP21 was associated with a significantly inferior outcome in NCI standard-risk patients (4-year EFS, 73% for iAMP21 vs. 92% in others), but not in NCI high-risk patients (4-year EFS, 73% vs 80%). On multivariate analysis, iAMP21 was an independent predictor of inferior outcome only in NCI standard-risk patients. The results of the UKALL2003 and COG studies suggest that treatment of iAMP21 patients with high-risk chemotherapy regimens abrogates its adverse prognostic significance.
    • IKZF1 deletions: IKZF1 deletions, including deletions of the entire gene and deletions of specific exons, are present in approximately 15% of precursor B-cell ALL cases. Cases with IKZF1 deletions tend to occur in older children, have a higher WBC count at diagnosis, and are therefore, more common among NCI high-risk patients compared with NCI standard-risk patients. A high proportion of BCR-ABL1 cases have a deletion of IKZF1, and ALL arising in children with Down syndrome appears to have elevated rates of IKZF1 deletions. IKZF1 deletions are also common in cases with CRLF2 genomic alterations and in Philadelphia chromosome–like (Ph-like) ALL (see below).
      Multiple reports have documented the adverse prognostic significance of an IKZF1 deletion, and most studies have reported that this deletion is an independent predictor of poor outcome on multivariate analyses.
    • ERG deletion: Approximately 4% of pediatric B-precursor ALL patients have a focal intragenic deletion in ERG, resulting in production of a truncated ERG protein. Patients with ERG deletion are significantly older than are other patients with pediatric B-precursor ALL; 40% of them show aberrant CD2 expression, and approximately 40% have the IKZF1 deletion. The ERG deletion connotes an excellent prognosis, with OS exceeding 90%; even when the IZKF1 deletion is present, prognosis remains highly favorable.
    • CRLF2 and JAK mutations: Genomic alterations in CRLF2, a cytokine receptor gene located on the pseudoautosomal regions of the sex chromosomes, have been identified in 5% to 10% of cases of B-precursor ALL. The chromosomal abnormalities that commonly lead to CRLF2 overexpression include translocations of the IgH locus (chromosome 14) to CRLF2 and interstitial deletions in pseudoautosomal regions of the sex chromosomes, resulting in a P2RY8-CRLF2 fusion. CRLF2 abnormalities are strongly associated with the presence of IKZF1 deletions and JAK mutations; they are also more common in children with Down syndrome. Point mutations in kinase genes other than JAK1 and JAK2 are uncommon in CRLF2-overexpressing cases.
      Although the results of several retrospective studies suggest that CRLF2 abnormalities may have adverse prognostic significance on univariate analyses, most do not find this abnormality to be an independent predictor of outcome. For example, in a large European study, increased expression of CRLF2 was not associated with unfavorable outcome in multivariate analysis, while IKZF1 deletion and BCR-ABL-like expression signatures were associated with unfavorable outcome. There is also controversy about whether the prognostic significance of CRLF2 abnormalities should be analyzed based on CRLF2 overexpression or on the presence of CRLF2 genomic alterations.
    • Ph-like ALL: BCR-ABL1–negative patients with a gene expression profile similar to BCR-ABL1–positive patients have been referred to as Ph-like ALL. This occurs in 10% to 15% of pediatric ALL patients, increasing in frequency with age, and is associated with a poor prognosis and with IKZF1 deletion/mutation. The hallmark of this entity is activated kinase signaling, with 50% containing CRLF2 genomic alterations and 25% concomitant JAK mutations. Many of the remaining cases have been noted to have a series of translocations with a common theme of involvement of either ABL1, JAK2, PDGFRB, or EPOR. Fusion proteins from these gene combinations have been noted in some cases to be transformative and have responded to tyrosine kinase inhibitors both in vitro and in vivo, suggesting potential therapeutic strategies for these patients. Point mutations in kinase genes, aside from those in JAK1 and JAK2, are uncommon in Ph-like ALL cases.
  • Gene polymorphisms in drug metabolic pathways
    A number of polymorphisms of genes involved in the metabolism of chemotherapeutic agents have been reported to have prognostic significance in childhood ALL. For example, patients with mutant phenotypes of thiopurine methyltransferase (a gene involved in the metabolism of thiopurines, such as 6-mercaptopurine), appear to have more favorable outcomes, although such patients may also be at higher risk of developing significant treatment-related toxicities, including myelosuppression and infection.
    Genome-wide polymorphism analysis has identified specific single nucleotide polymorphisms associated with high end-induction MRD and risk of relapse. Polymorphisms of IL-15, as well as genes associated with the metabolism of etoposide and methotrexate, were significantly associated with treatment response in two large cohorts of ALL patients treated on SJCRH and COG protocols. Polymorphic variants involving the reduced folate carrier and methotrexate metabolism have been linked to toxicity and outcome. While these associations suggest that individual variations in drug metabolism can affect outcome, few studies have attempted to adjust for these variations; whether individualized dose modification based on these findings will improve outcome is unknown.
  • Response to initial treatment affecting prognosis
    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.
  • Day 7 and day 14 bone marrow responses.
  • Peripheral blood response to steroid prophase.
  • Peripheral blood response to multiagent induction therapy.
  • Peripheral blood MRD before end of induction (day 8, day 15).
  • Induction failure.
  • 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 (e.g., day 8 and day 15 of induction) and later time points (e.g., week 12 of therapy) also predict outcome.
    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 B-precursor phenotype, NCI standard risk age/leukocyte count, CNS1 status, and favorable cytogenetic abnormalities (either high hyperdiploidy with favorable trisomies or the ETV6-RUNX1 fusion) who had less than 0.01% MRD levels at both day 8 (from peripheral blood) and end-induction (from bone marrow).
    Modifying therapy based on MRD determination has been shown to improve outcome in B-cell ALL. The UKALL2003 (NCT00222612) 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.[Level of evidence: 1iiDii] 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).
    There are fewer studies documenting the prognostic significance of MRD in T-cell ALL. In the AIEOP ALL-BFM-2000 (NCT00430118) 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 did just as well as patients who achieved MRD-negativity at the earlier end-induction time point. Thus, unlike in B-cell precursor ALL, end-induction MRD levels were irrelevant in those patients whose MRD was negative at day 78. A high MRD level at day 78 was associated with a significantly higher risk of relapse.
    There are few studies of MRD in the CSF. In one study, MRD was documented in about one-half of children at diagnosis. In this study, CSF MRD was not found to be prognostic when intensive chemotherapy was given.

    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 response to therapy 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.

    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 up to 5% 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).
    • B-precursor ALL with very high presenting leukocyte counts.
    • 11q23 rearrangement.
    • Older age.
    • Philadelphia chromosome.
    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 B-precursor ALL between the ages of 1 and 5 years without adverse cytogenetics (MLL translocation or BCR-ABL). 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 MLL 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 complete remission than those who received further treatment with chemotherapy alone.

    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 molecular characteristics 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 MLL translocations.
    • 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., <10-4) at both time points are classified as standard risk.
    • Intermediate risk: Patients who have positive MRD at week 5 and low MRD (<10-3) at week 12 are considered intermediate risk.
    • High risk: Patients with high MRD (≥10-3) at week 12 are high risk. Patients with a poor response to the prednisone prophase are also considered high risk, regardless of subsequent MRD.
    Phenotype, leukemic cell mass estimate, also known as BFM risk factor, and CNS status at diagnosis do not factor into the current risk classification schema. However, patients with either the t(9;22) or the t(4;11) are considered high risk, regardless of early response measures.

    Prognostic (risk) groups under clinical evaluation
    COG AALL08B1 (Classification of Newly Diagnosed ALL): COG protocol AALL08B1 stratifies four risk groups for patients with B-precursor 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 B-precursor ALL:
    • Favorable genetics are defined as the presence of either hyperdiploidy with trisomies of chromosomes 4 and 10 (double trisomy) or the ETV6-RUNX1 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), MLL rearrangement, 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 BCR-ABL (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 B-precursor ALL are defined in Table 1.
    Table 1. Risk Groups for B-Precursor Acute Lymphoblastic Leukemiaa
    Low Risk Average RiskHigh RiskVery High RiskEFS = event-free survival; HR = age and WBC count risk group is high risk; MRD = minimal residual disease; NCI = National Cancer Institute; PB = peripheral blood; SR = age/WBC count risk group is standard risk; WBC = white blood cell.aFrom the Children's Oncology Group Classification of Newly Diagnosed ALL protocol.NCI Risk (Age/WBC) SR SR SRSR SRHR (age <13 y)SR HRHR (age ≥13 y) SR or HRFavorable GeneticsYesYes NoYes NoAnyNo AnyAnyAnyUnfavorable CharacteristicsNoneNone NoneNone None NoneNone None NoneYesDay 8 PB MRD<0.01%≥0.01% <1%Any Level ≥1%Any LevelAny Level Any LevelAny LevelAny Level Day 29 Marrow MRD<0.01%<0.01%<0.01%≥0.01% <0.01%<0.01%≥0.01% ≥0.01% <0.01%Any Level % of Patients (Estimated)15%36% 25% 24% Anticipated 5-year EFS>95%90%–95%88%–90%<80%
    NCI-2014-00712/AALL1231 (NCT02112916) (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:
      Standard risk
    • M1 marrow with MRD <0.01% on day 29.
    • CNS1 status and no testicular disease at diagnosis.
    • No steroid therapy pretreatment.
      Intermediate risk
    • M1 or M2 marrow at day 29 with MRD ≥0.01%.
    • MRD <0.1% at end of consolidation.
    • Any CNS status at diagnosis.
      Very high risk
    • M3 marrow at day 29 or MRD ≥0.1% at end of consolidation.
    • Any CNS status.
    DFCI-11-001 (NCT01574274) (SC-PEG Asparaginase vs. Oncaspar in Pediatric ALL and Lymphoblastic Lymphoma): On the current clinical trial conducted by the Dana-Farber Cancer Institute ALL Consortium, patients with B-precursor ALL are initially classified as either standard risk or high risk based on age, presenting leukocyte count, and the presence or absence of CNS disease (CNS3). At the completion of a five-drug remission induction regimen (4 weeks from diagnosis), the level of MRD is determined via PCR assay. Patients with high MRD (≥0.001) are classified as very high risk and receive a more intensive postremission consolidation. Patients with low MRD (<0.001) continue to receive treatment based on their initial risk group classification. The goal of this new classification schema is to determine whether intensification of therapy will improve the outcome of patients with high MRD at the end of remission induction. Patients with T-cell ALL are treated as high risk, regardless of MRD status. All patients with MLL translocations or hypodiploidy (<44 chromosomes) are classified as very high risk, regardless of MRD status or phenotype. Ph+ patients are removed from study midinduction and are eligible to enroll on the COG protocol for patients with Ph+ ALL.
    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 TOTXV study) are provided below.
      Criteria for low-risk ALL (approximately 48% of patients)
    • B-cell precursor ALL with DNA index ≥1.16, ETV6-RUNX1 fusion, or age 1 to 9.9 years and presenting WBC <50 × 109/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) or BCR-ABL1 fusion; t(1;19) with E2A-PBX1 fusion; rearranged MLL (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).
      Criteria for standard-risk ALL (approximately 44% of patients)
    • All cases of T-cell ALL and those of B-cell precursor ALL that do not meet the criteria for low-risk or high-risk ALL.
      Criteria for high-risk ALL (approximately 8% of patients)
    • t(9;22) or BCR-ABL fusion.
    • Infants with t(4;11) or MLL 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.

    Current Clinical Trials
    Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with childhood acute lymphoblastic leukemia. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.
    General information about clinical trials is also available from the NCI Web site.

    Treatment Option Overview for Childhood ALL
    Children with acute lymphoblastic leukemia (ALL) should be cared for at a center with specialized expertise in pediatric cancer. Treatment planning by a multidisciplinary team of pediatric cancer specialists with experience and expertise in treating leukemias of childhood is required to determine and implement optimum treatment.
    Treatment of childhood ALL typically involves chemotherapy given for 2 to 3 years. Since myelosuppression and generalized immunosuppression are anticipated consequences of leukemia and chemotherapy treatment, patients must be closely monitored at diagnosis and during 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.
    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 stronger 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:
  • Remission induction (at the time of diagnosis).
  • Postinduction therapy (after achieving complete remission).
      Consolidation/intensification therapy.
    • Maintenance or continuation therapy.

    Sanctuary Sites
    Historically, certain extramedullary sites have been considered sanctuary sites (i.e., anatomic spaces that are poorly penetrated by many of the systemically 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)
    Approximately 3% of patients have detectable CNS involvement by conventional criteria at diagnosis (cerebrospinal fluid specimen with ≥5 WBC/μL with lymphoblasts and/or the presence of cranial nerve palsies). However, unless specific therapy is directed toward the CNS, the majority of children will eventually develop overt CNS leukemia. 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 Acute Lymphoblastic Leukemia 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:
  • Chemotherapy.
  • 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 B-precursor ALL achieve CR by the end of this phase, with somewhat lower rates in patients with T-cell ALL or high presenting leukocyte counts.
    Induction chemotherapy consists of the following drugs, with or without an anthracycline:
    • Vincristine.
    • Corticosteroid (prednisone or dexamethasone).
    • L-asparaginase.
    The Children's Oncology Group (COG) protocols do not administer anthracycline during induction to patients with National Cancer Institute standard-risk precursor B-cell ALL.
    Patients treated by the following study groups receive an induction regimen with four or more drugs regardless of presenting features:
    • Berlin-Frankfurt-Münster Group in Europe.
    • St. Jude Children's Research Hospital.
    • Dana-Farber Cancer Institute ALL Consortium.
    The most common four-drug induction regimen is vincristine, corticosteroid (either dexamethasone or prednisone), L-asparaginase, and either doxorubicin or daunorubicin. In a randomized trial of doxorubicin and daunorubicin during induction, there were no differences between these two agents 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.[Level of evidence: 1iiDiv] Some studies have suggested that this more intensive induction regimen may result in improved event-free survival (EFS) in patients presenting with high-risk features, but it may not be necessary for favorable outcome provided that adequate postremission intensification therapy is administered. The COG reserves the use of a four-drug induction for patients with high-risk B-precursor ALL and T-cell ALL.
    Corticosteroid therapy
    Many current regimens utilize dexamethasone instead of prednisone during remission induction and later phases of therapy.
    Evidence (dexamethasone):
  • The Children's Cancer Group conducted a randomized trial that compared dexamethasone and prednisone in standard-risk ALL patients.
      The trial reported that dexamethasone was associated with a superior EFS.
  • Another randomized trial was conducted by the United Kingdom Medical Research Council.
      The trial demonstrated that dexamethasone was associated with a more favorable outcome than prednisolone in all patient subgroups.
    • Patients who received dexamethasone had a significantly lower incidence of both central nervous system (CNS) and non-CNS relapses than patients who received prednisolone.
  • Other randomized trials did not confirm an EFS advantage with dexamethasone.
  • 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.
    While dexamethasone may be more effective than prednisone, data also suggest that dexamethasone may be more toxic, especially in the context of more intensive induction regimens and in adolescents. Several reports indicate that dexamethasone may increase the frequency and severity of infections and/or other complications in patients receiving anthracycline-containing induction regimens. The increased risk of infection with dexamethasone during the induction phase has not been noted with three-drug induction regimens (vincristine, dexamethasone, and L-asparaginase). Dexamethasone appears to have a greater suppressive effect on short-term linear growth than prednisone and has been associated with a higher risk of osteonecrosis, especially in patients aged 10 years and older.

    L-asparaginase
    Several forms of L-asparaginase have been used in the treatment of children with ALL, including the following:
    • PEG-L-asparaginase.
    • Erwinia L-asparaginase.
    • Native E. coli L-asparaginase.
    Only PEG-L-asparaginase and Erwinia L-asparaginase are available in the United States. Native E. coli L-asparaginase remains available in other countries.
    PEG-L-asparaginase
    PEG-L-asparaginase, a form of L-asparaginase in which the Escherichia coli-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.
    PEG-L-asparaginase may be given either intramuscularly (IM) or intravenously (IV). Pharmacokinetics and toxicity profiles are similar for IM and IV PEG-L-asparaginase administration. There is no evidence that IV administration of PEG-L-asparaginase is more toxic than IM administration.
    PEG-L-asparaginase has a much longer serum half-life than native E. coli 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 PEG-L-asparaginase given either IM or IV as part of multiagent induction results in serum enzyme activity (>0.1 IU/mL) in nearly all patients for at least 2 to 3 weeks.
    Evidence (use of PEG-L-asparaginase instead of native E. coli L-asparaginase):
  • A randomized comparison of PEG-L-asparaginase versus native E. coli asparaginase was conducted. Each agent was administered for a 30-week period after the achievement of CR.
      Similar outcome and similar rates of asparaginase-related toxicities were observed for both groups of patients.
  • Another randomized trial of patients with standard-risk ALL assigned patients to receive either PEG-L-asparaginase or native E. coli asparaginase in induction and each of two delayed intensification courses.
      A single dose of PEG-L-asparaginase given in conjunction with vincristine and prednisone during induction therapy appeared to have similar activity and toxicity as nine doses of IM E. coli L-asparaginase (3 times a week for 3 weeks).
    • The use of PEG-L-asparaginase was associated with more rapid blast clearance and a lower incidence of neutralizing antibodies.
    Patients with an allergic reaction to PEG-L-asparaginase should be switched to Erwinia L-asparaginase.

    Erwinia L-asparaginase:
    Erwinia L-asparaginase is typically used in patients who have experienced allergy to native E. coli or PEG-L-asparaginase.
    The half-life of Erwinia L-asparaginase (0.65 days) is much shorter than that of native E. coli (1.2 days) or PEG-L-asparaginase (5.7 days). If Erwinia L-asparaginase is utilized, the shorter half-life of the Erwinia preparation requires more frequent administration to achieve adequate asparagine depletion.
    Evidence (increased dose frequency of Erwinia L-asparaginase needed to achieve goal therapeutic effect):
  • In two studies, newly diagnosed patients were randomly assigned to receive the same schedule and dosage of Erwinia L-asparaginase or E. coli L-asparaginase.
      Patients who received Erwinia L-asparaginase had a significantly worse EFS.
    • When administered more frequently (twice weekly), the use of Erwinia L-asparaginase did not adversely impact EFS in patients who had experienced an allergic reaction to E. coli L-asparaginase.
  • A COG trial demonstrated that IM Erwinia L-asparaginase given three times a week to patients with an allergy to PEG L-asparaginase leads to therapeutic serum asparaginase enzyme activity levels (defined as a level ≥0.1 IU/mL). On that trial, 96% of children achieved a level of 0.1 IU/mL or more at 2 days and 85% did so at 3 days.
  • 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 due to infection) and the other half will have resistant disease (persistent morphologic leukemia).; [Level of evidence: 3iA]
    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 overall survival 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 B-precursor patients younger than 6 years. B-precursor ALL patients who were aged 1 to 5 years at diagnosis and did not have any adverse cytogenetic abnormalities (MLL translocation, BCR-ABL) 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:
    • Morphologic persistence of marrow blasts at 7 and 14 days after starting multiagent remission induction therapy has been correlated with higher 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 under investigation by many groups.
    • 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.
    (Refer to the Response to initial treatment affecting prognosis section of this summary for more information.)
    (Refer to the CNS-Directed Therapy for Childhood Acute Lymphoblastic Leukemia section of this summary for specific information about CNS therapy to prevent CNS relapse in children with newly diagnosed ALL.)

    Current Clinical Trials
    Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with untreated childhood acute lymphoblastic leukemia. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.
    General information about clinical trials is also available from the NCI Web site.

    Postinduction Treatment for Childhood ALL
    Standard Postinduction Treatment Options for Childhood ALL
    Standard treatment options for consolidation/intensification and maintenance therapy include the following:
  • Chemotherapy.
  • 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 Acute Lymphoblastic Leukemia 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:
  • An initial consolidation (sometimes referred to as “Induction IB”) immediately after the initial induction phase. This phase includes cyclophosphamide, low-dose cytarabine, and a thiopurine (mercaptopurine or thioguanine).
  • An interim maintenance phase, which includes multiple doses of either intermediate-dose or high-dose methotrexate (1–5 g/m2) with leucovorin rescue or escalating doses of methotrexate (starting dose 100 mg/m2) without leucovorin rescue.
  • Reinduction (or delayed intensification), which typically includes the same agents used during the induction and initial consolidation phases.
  • Maintenance, typically consisting of mercaptopurine, low-dose methotrexate, and sometimes, vincristine/steroid pulses.
  • 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 interim maintenance and/or reinduction phases and administering additional agents during some phases (e.g., vincristine and L-asparaginase added to interim maintenance 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:
    • Pediatric Oncology Group (POG): Protocols conducted by the former POG included intensification with high-dose antimetabolite therapy (e.g., multiple doses of intermediate-dose or high-dose methotrexate with leucovorin rescue), but no reinduction/delayed intensification phase.
    • DFCI: The DFCI ALL Consortium protocols include 20 to 30 weeks of L-asparaginase 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 do receive additional doses of doxorubicin (instead of methotrexate) during intensification.
    • SJCRH: SJCRH follows a BFM-backbone but intensifies maintenance for some patients using rotating drug pairs.
    Standard-risk ALL
    In children with standard-risk 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 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 L-asparaginase (20–30 weeks) as consolidation, without postinduction exposure to alkylating agents or anthracyclines.
    However, the effects of end-induction and/or consolidation minimal residual disease (MRD) on outcome 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):
  • Clinical trials conducted in the 1980s and early 1990s demonstrated that the use of a delayed intensification phase improved outcome for children with standard-risk ALL treated with regimens using a BFM backbone. The delayed intensification phase on such regimens, including those of the COG, consists of a 3-week reinduction (including anthracycline) and reconsolidation containing cyclophosphamide, cytarabine, and 6-thioguanine given approximately 3 months after remission is achieved.
  • A Children's Cancer Group study (CCG-1991/COG-1991) for standard-risk ALL utilized dexamethasone for induction and a second delayed intensification phase. This study also compared escalating intravenous (IV) methotrexate (without leucovorin rescue) in conjunction with vincristine versus a standard maintenance combination including oral methotrexate given during two interim maintenance phases.[Level of evidence: 1iiDi]
      A second delayed intensification phase provided no benefit in patients who were rapid early responders (M1 or M2 marrow by day 14 of induction).
    • Escalating IV methotrexate during the interim maintenance phases, compared with oral methotrexate during these phases, produced a significant improvement in event-free survival (EFS), which was because of a decreased incidence of isolated extramedullary relapses, particularly those involving the CNS.
  • In a randomized study conducted in the United Kingdom, children and young adults with ALL who lacked high-risk features (including adverse cytogenetics, and/or M3 marrow morphology at day 8 or day 15 of induction) were risk-stratified based on MRD level at the end of induction (week 4) and at week 11 of therapy. Patients with undetectable MRD at week 4 (or with low MRD at week 4 and undetectable by week 11) were considered low-risk, and were eligible to be randomly assigned to therapy with either one or two delayed intensification phases.[Level of evidence: 1iiDi]
      There was no significant difference in EFS between patients who received one and those who received two delayed intensification phases.
    • There was no significant difference in treatment-related deaths between the two arms; however, the second delayed intensification phase was associated with grade 3 or 4 toxic events in 17% of the 261 patients randomly assigned to that arm, and one patient experienced a treatment-related death during that phase.
  • Patients who are standard or intermediate risk at diagnosis, but have high levels of end-induction MRD, have been shown to have a poorer prognosis and should be treated as high-risk patients. The UKALL2003 (NCT00222612) study demonstrated in a randomized controlled trial that augmented postinduction therapy increases EFS to that comparable to patients with low levels of end-induction MRD. The augmented arm of this study included extra doses of pegylated asparaginase and vincristine and an escalated-dose of IV methotrexate without folinic acid rescue.
  • High-risk ALL
    In high-risk patients, a number of different approaches have been used with comparable efficacy.; [Level of evidence: 2Di] 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):
  • The former CCG developed an augmented BFM treatment regimen that included a second interim maintenance and delayed intensification phase. This regimen featured repeated courses of escalating-dose IV methotrexate (without leucovorin rescue) given with vincristine and L-asparaginase during interim maintenance and additional vincristine and L-asparaginase pulses during initial consolidation and delayed intensification. In the CCG-1882 trial, NCI high-risk patients with slow early response (M3 marrow on day 7 of induction) were randomly assigned to receive either standard- or augmented-BFM therapy.
      The augmented therapy regimen in the CCG-1882 trial produced a significantly better EFS than did standard CCG modified BFM therapy.
    • There was a significantly higher incidence of osteonecrosis in patients older than 10 years who received the augmented therapy (which included two 21-day postinduction dexamethasone courses), compared with those who were treated on the standard arm (one 21-day postinduction dexamethasone course).
  • In an Italian study, investigators showed that two applications of delayed intensification therapy (protocol II) significantly improved outcome for patients with a poor response to a prednisone prophase.
  • The CCG-1961 study used a 2 × 2 factorial design to compare both standard- versus augmented-intensity therapies and therapies of standard duration (one interim maintenance and delayed intensification phase) versus increased duration (two interim maintenance and delayed intensification phases) among NCI high-risk patients with a rapid early response. This trial also tested whether continuous versus alternate-week dexamethasone during delayed intensification phases affected rates of osteonecrosis.
      Augmented therapy was associated with an improvement in EFS; there was no EFS benefit associated with the administration of the second interim maintenance and delayed intensification phases.[Level of evidence: 1iiA]
    • The cumulative incidence of osteonecrosis of bone at 5 years was 9.9% for patients aged 10 to 15 years and 20.0% for patients aged 16 to 21 years, compared with 1.0% for patients aged 1 to 9 years (P = .0001). For patients aged 10 to 21 years, alternate-week dosing of dexamethasone during delayed intensification phases was associated with a significantly lower cumulative incidence of osteonecrosis, compared with continuous dosing (8.7% vs. 17.0%, P = .0005).[Level of evidence: 1iiC]
  • The use of the cardioprotectant agent dexrazoxane has been shown to prevent cardiac toxic effects without adversely impacting EFS in high-risk ALL patients. In a DFCI ALL Consortium trial, children with high-risk ALL were randomly assigned to receive doxorubicin alone (30 mg/m2/dose to a cumulative dose of 300 mg/m2) or the same dose of doxorubicin with dexrazoxane during the induction and intensification phases of multiagent chemotherapy.
      The use of the cardioprotectant dexrazoxane before doxorubicin resulted in better left ventricular fractional shortening and improved end-systolic dimension Z-scores without any adverse effect on EFS or increase in second malignancy risk, compared with the use of doxorubicin alone 5 years posttreatment.
    • A greater long-term protective effect was noted in girls than in boys.
    • The POG-9404 trial also demonstrated no difference in EFS between patients with T-cell ALL who were treated with dexrazoxane and patients who did not receive dexrazoxane.
  • A phase III clinical trial (POG-9406) was conducted in higher-risk pediatric B-precursor ALL patients. A total of 784 patients were randomly assigned to receive methotrexate, 1 g/m2 versus 2.5 g/m2.
      No differences in disease-free survival (DFS) or overall survival (OS) were observed between 1g/m2 and 2.5 g/m2 of methotrexate.

    Very high-risk ALL
    Approximately 10% to 20% of patients with ALL are classified as very high risk, including the following:
    • Infants.
    • Patients with adverse cytogenetic abnormalities, including t(9;22), MLL 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 remission, although it is not clear whether outcomes are better with transplantation.
    Evidence (allogeneic HSCT in first remission for very high-risk patients):
  • In a European cooperative group study, very high-risk patients (defined as one of the following: morphologically persistent disease after a four-drug induction, t(9;22) or t(4;11), or poor response to prednisone prophase in patients with either T-cell phenotype or presenting white blood cells [WBC] >100,000/μL) were assigned to receive either an allogeneic HSCT in first remission (based on the availability of a human lymphocyte antigen–matched related donor) or intensive chemotherapy.
      Using an intent-to-treat analysis, patients assigned to allogeneic HSCT (on the basis of donor availability) had a superior 5-year DFS compared with patients assigned to intensive chemotherapy (57% ± 7% for transplant versus 41% ± 3% for chemotherapy, P = .02)
    • There was no significant difference in OS (56% ± 6% for transplant versus 50% ± 3% for chemotherapy, P = .12).
    • For patients with T- cell ALL and a poor response to prednisone prophase, both DFS and OS rates were significantly better with allogeneic HSCT.
  • In another study of very high-risk patients that included children with extremely high presenting leukocyte counts and those with adverse cytogenetic abnormalities and/or initial induction failure (M2 marrow [between 5% and 25% blasts]), allogeneic HSCT in first remission was not associated with either a DFS or OS advantage.
  • In a large retrospective series of patients with initial induction failure, 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 with B-precursor ALL who were older than 6 years.
    • Patients with B-precursor ALL who were aged 1 to 5 years at diagnosis and did not have any adverse cytogenetic abnormalities (MLL translocation, BCR-ABL) had a relatively favorable prognosis, without any advantage in outcome with the utilization of HSCT compared with chemotherapy alone.
  • In a Dutch and Australian trial of 111 children with high-risk features or high MRD, patients received three novel intensive chemotherapy agents followed by allogeneic transplantation. Thirty of these patients were high risk by MRD and had a 5-year EFS of 64%.
  • The AIEOP ALL-BFM-2000 (NCT00430118) study allocated patients in first remission to allogeneic HSCT based on donor availability, investigator preference, and high-risk features that included poor prednisone response, high MRD levels, t(4;11), and no CR after induction therapy.[Level of evidence: 2Dii]
      No statistically significant difference was found for DFS in patients with these high-risk features who received a transplant versus patients who did not receive a transplant, after adjusting for waiting time to HSCT (5.7 months).

    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 trials generally call for the administration of oral mercaptopurine in the evening, which is supported by evidence 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. Nonadherence to treatment with 6-mercaptopurine (6-MP) in the maintenance phase is associated with a significant increase in the risk of relapse.
    Treating physicians must also recognize that some patients may develop severe hematopoietic toxicity when receiving conventional dosages of mercaptopurine because of an inherited deficiency (homozygous mutant) of thiopurine S-methyltransferase, an enzyme that inactivates mercaptopurine. 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 hematopoietic toxicity than do patients who are homozygous for the normal allele.
    Evidence (maintenance therapy):
  • In a meta-analysis of randomized trials that compared thiopurines, 6-thioguanine (6-TG) did not improve the overall EFS, although particular subgroups may benefit from its use. The use of continuous 6-TG instead of 6-MP during the maintenance phase is associated with an increased risk of hepatic complications, including veno-occlusive disease and portal hypertension. Because of the increased toxicity of 6-TG, 6-MP remains the standard drug of choice.
  • Another approach is an intensified maintenance phase that consists of rotating pairs of agents, including cyclophosphamide and epipodophyllotoxins, along with more standard maintenance agents.
      The intensified maintenance with rotating pairs of agents has been associated with more episodes of febrile neutropenia and a higher risk of secondary acute myelogenous leukemia, especially when epipodophyllotoxins are included.
      SJCRH has modified the agents used in the rotating pair schedule during the maintenance phase. On the Total XV study, standard-risk and high-risk patients received three rotating pairs (mercaptopurine plus methotrexate, cyclophosphamide plus cytarabine, and dexamethasone plus vincristine) throughout this treatment phase; low-risk patients received more standard maintenance (without cyclophosphamide and cytarabine).
  • A randomized study from Argentina demonstrated no benefit from this intensified approach compared with a more standard maintenance regimen for patients who receive induction and consolidation phases based on a BFM backbone.
  • 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 intensive, multiagent regimens remains controversial.
    Evidence (vincristine/corticosteroid pulses):
  • A CCG randomized trial conducted in the 1980s demonstrated improved outcome in patients receiving monthly vincristine/prednisone pulses. A meta-analysis combining data from six clinical trials from the same treatment era showed an EFS advantage for vincristine/prednisone pulses.
  • A systematic review of the impact of vincristine plus steroid pulses from more recent clinical trials raised the question of whether such pulses are of value in current ALL treatment, which includes more intensive early therapy.
  • In a multicenter randomized trial in children with intermediate-risk ALL being treated on a BFM regimen, there was no benefit associated with the addition of six pulses of vincristine/dexamethasone during the continuation phase, although the pulses were administered less frequently than in other trials in which a benefit had been demonstrated.
  • A small multicenter trial of average-risk patients demonstrated superior EFS in patients receiving vincristine plus corticosteroid pulses. In this study, there was no difference in outcome based on type of steroid (prednisone vs. dexamethasone).[Level of evidence: 1iiA]
  • 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):
  • In a CCG study, dexamethasone was compared with prednisone for children aged 1 to younger than 10 years with lower-risk ALL.
      Patients randomly assigned to receive dexamethasone had significantly fewer CNS relapses and a significantly better EFS rate.
  • In a Medical Research Council trial, dexamethasone was compared with prednisolone during induction and maintenance therapies in both standard-risk and high-risk patients.
      The EFS and incidence of both CNS and non-CNS relapses improved with the use of dexamethasone.
    • Dexamethasone was associated with an increased risk of steroid-associated toxicities, including behavioral problems, myopathy, and osteopenia.
  • In a DFCI ALL Consortium trial, patients were randomly assigned to receive either dexamethasone or prednisone during all postinduction treatment phases.
      Dexamethasone was associated with a superior EFS, but also with a higher frequency of infections (primarily episodes of bacteremia) and, in patients aged 10 years or older, an increased incidence of osteonecrosis and fracture.
    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 gender. It is not clear whether longer duration of maintenance therapy reduces relapse in boys, especially in the context of current therapies.[Level of evidence: 2Di] Extending the duration of maintenance therapy beyond 3 years does not improve outcome.

    Adherence to maintenance therapy
    Nonadherence to treatment with 6-MP in maintenance is associated with a significant increase in the risk of relapse.
    Evidence (adherence to treatment):
  • The COG studied the impact of non-adherence to 6-MP during maintenance in 327 children and adolescents of different ethnic backgrounds.
      Adherence declined from 95% to 90% over the 6-month observation period.
    • Adherence was significantly lower among Hispanics, patients older than 12 years, and patients from single-mother households.
    • Lower adherence to 6-MP was associated with a significantly higher risk of relapse. After adjusting for other prognostic factors (including NCI risk group and chromosomal abnormalities), a progressive increase in relapse was observed with decreasing adherence.

    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 B-precursor ALL
    Standard-risk ALL
  • COG-AALL0932 (Risk-Adapted Chemotherapy in Younger Patients With Newly Diagnosed Standard-Risk ALL):
    This trial subdivides standard-risk patients into two groups: low risk and average risk. Low risk is defined as the presence of all of the following: NCI-standard risk age/WBC, favorable genetics (e.g., double trisomies or ETV6-RUNX1), CNS1 at presentation, and low MRD (<0.01% by flow cytometry) at day 8 (peripheral blood) and day 29 (marrow). Average risk includes other NCI standard-risk patients excluding those with high day 29 MRD morphologic induction failure or other unfavorable presenting features (e.g., CNS3, iAMP21, low hypodiploidy, MLL translocations, and BCR-ABL).
    All patients will receive a three-drug induction (dexamethasone, vincristine, and IV PEG-L-asparaginase) with intrathecal chemotherapy. For postinduction therapy, low-risk patients will be randomly assigned to receive one of the following:
      A regimen based on POG-9904, including six courses of intermediate-dose methotrexate (1 g/m2) but without any alkylating agents or anthracyclines.
    • A modified BFM backbone including two interim maintenance phases with escalating doses of IV methotrexate (no leucovorin) and one delayed intensification phase.
    The objective is not to prove superiority of either regimen, but rather, to determine whether excellent outcomes (at least 95% 5-year DFS) can be achieved.
    All average-risk patients will receive a modified BFM-backbone as postinduction treatment. For these patients, the study is comparing, in a randomized fashion, two doses of weekly oral methotrexate during the maintenance phase (20 mg/m2 and 40 mg/m2) to determine whether the higher dose favorably impacts DFS. Average-risk patients are also eligible to participate in a randomized comparison of two schedules of vincristine/dexamethasone pulses during maintenance (delivered every 4 weeks or every 12 weeks). The objective of this randomization is to determine whether vincristine/dexamethasone pulses can be delivered less frequently without adversely impacting outcome.

    High-risk ALL
  • COG-AALL1131 (Combination Chemotherapy in Treating Young Patients With Newly Diagnosed High-Risk ALL):
    This protocol is open to patients aged 12 years or younger. Patients treated on this trial are classified as high risk who lack very high-risk features and two groups of NCI standard-risk patients who otherwise lack very high-risk features: (1) those without favorable genetics (no ETV6-RUNX1 or double trisomies 4 and 10) and with day 8 peripheral blood MRD greater than 1%; and (2) those with favorable cytogenetics and high marrow MRD at day 29. Patients with BCR-ABL (Philadelphia chromosome–positive) are treated on a separate clinical trial.
    Patients on this trial will receive a four-drug induction (vincristine, corticosteroid, daunorubicin, and IV PEG-L-asparaginase) with intrathecal chemotherapy. Patients younger than 10 years receive dexamethasone during induction, and those aged 10 years and older receive prednisone. Postinduction therapy consists of a modified BFM backbone, including an interim maintenance phase with high-dose methotrexate and one delayed intensification phase.
    For high-risk patients, the study will compare, in a randomized fashion, triple intrathecal chemotherapy (methotrexate, cytarabine, and hydrocortisone) with intrathecal methotrexate to determine whether triple intrathecal chemotherapy reduces CNS relapse rates and improves EFS.
    Patients with very high-risk features are currently not eligible for enrollment on COG-AALL1131. The presence of any of the following features classify a patient as very high risk.
      Age 13 years and older.
    • CNS3 at diagnosis.
    • M3 marrow at day 29.
    • Unfavorable genetics (e.g., iAMP21, low hypodiploidy, MLL gene rearrangements).
    • High marrow MRD (>0.01% by flow cytometry) at day 29 (with the exception of NCI standard-risk patients with favorable genetics).

    Other studies
  • Total XVI study (TOTXVI) (Total Therapy Study XVI for Newly Diagnosed Patients With ALL): A study at SJCRH is randomly assigning patients to receive either standard-dose (2,500 u/m2) or high-dose (3,500 u/m2) PEG-L-asparaginase during postremission therapy.
  • DFCI-11-001 (NCT01574274) (SC-PEG Asparaginase versus Oncaspar in Pediatric ALL and Lymphoblastic Lymphoma): A DFCI ALL Consortium protocol is comparing the pharmacokinetics and toxicity of two forms of IV PEG-L-asparaginase (pegaspargase [Oncaspar] and calaspargase pegol [SC-PEG]). Patients will be randomly assigned to receive a single dose of one of these preparations during multiagent induction, and then either pegaspargase every 2 weeks (15 doses total) or calaspargase pegol every 3 weeks (10 doses total) during the 30-week consolidation phase.
    This protocol is also examining the following:
      Whether an intensified consolidation including high-dose cytarabine and etoposide improves the outcome for very high-risk patients (patients with high MRD at the end of remission induction, MLL translocations, or hypodiploidy [<44 chromosomes]).
    • Whether antibiotic prophylaxis (with fluoroquinolones) reduces rates of bacteremia and other serious bacterial infections during the remission induction phase.

    Current Clinical Trials
    Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with childhood acute lymphoblastic leukemia in remission. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.
    General information about clinical trials is also available from the NCI Web site.

    CNS-Directed Therapy for Childhood ALL
    Approximately 3% of patients have detectable central nervous system (CNS) involvement by conventional criteria at diagnosis (cerebrospinal fluid [CSF] specimen with ≥5 white blood cell [WBC]/μL with lymphoblasts and/or the presence of cranial nerve palsies). However, unless specific therapy is directed toward the CNS, the majority of children will eventually develop overt CNS leukemia. 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 sanctuary site (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:
  • Intrathecal chemotherapy.
  • CNS-directed systemic chemotherapy.
  • Cranial radiation.
  • 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 five 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:
    Table 2. CNS-Directed Treatment Regimens for Newly Diagnosed Childhood ALL
    Disease StatusStandard Treatment OptionsALL = acute lymphoblastic leukemia; CNS = central nervous system; CNS3 = cerebrospinal fluid with five or more white blood cells/µL, cytospin positive for blasts, or cranial nerve palsies.aThe drug itself is not CNS-penetrant, but leads to cerebrospinal fluid asparagine depletion.Standard-risk ALLIntrathecal chemotherapyMethotrexate aloneMethotrexate with cytarabine and hydrocortisoneCNS-directed systemic chemotherapyDexamethasoneL-asparaginaseaHigh-dose methotrexate with leucovorin rescueEscalating-dose intravenous methotrexate (no leucovorin rescue)High-risk ALLIntrathecal chemotherapyMethotrexate aloneMethotrexate with cytarabine and hydrocortisoneCNS-directed systemic chemotherapyDexamethasoneL-asparaginaseaHigh-dose methotrexate with leucovorin rescueCranial radiation
    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:
  • Methotrexate alone.
  • Methotrexate with cytarabine and hydrocortisone (triple intrathecal chemotherapy).
  • 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):
  • In a randomized Children's Cancer Group (CCG) study of standard-risk patients who all received the same dose and schedule of intrathecal methotrexate without cranial irradiation, oral dexamethasone was associated with a 50% decrease in the rate of CNS relapse compared with oral prednisone.
  • In another standard-risk ALL trial (COG-1991), escalating dose IV methotrexate without rescue significantly reduced the CNS relapse rate compared with standard, low-dose, oral methotrexate given during each of two interim maintenance phases.
  • In a randomized clinical trial conducted by the former Pediatric Oncology Group, T-cell ALL patients who received high-dose methotrexate experienced a significantly lower CNS relapse rate than patients who did not receive high-dose methotrexate.
  • 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 cranial radiation, the dose has been significantly reduced.
    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.[Level of evidence: 1iDi]

    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 does not appear to be a necessary component of CNS-directed therapy for these patients.
    Evidence (triple intrathecal chemotherapy vs. intrathecal methotrexate):
  • The CCG-1952 study for National Cancer Institute (NCI) standard-risk patients compared the relative efficacy and toxicity of triple intrathecal chemotherapy (methotrexate, hydrocortisone, and cytarabine) with methotrexate as the sole intrathecal agent in nonirradiated patients. There was no significant difference in either CNS or non-CNS toxicities.
  • Although triple intrathecal chemotherapy was associated with a lower rate of isolated CNS relapse (3.4% ± 1.0% compared with 5.9% ± 1.2% for intrathecal methotrexate; P = .004), there was no difference in event-free survival (EFS).
      This effect was especially notable in patients with CNS2 status at diagnosis (lymphoblasts seen in CSF cytospin, but with <5 WBC/high-power field [hpf] on CSF cell count); the isolated CNS relapse rate was 7.7% ± 5.3% for CNS2 patients who received triple intrathecal chemotherapy compared with 23.0% ± 9.5% for those who received intrathecal methotrexate alone (P = .04).
    • There were more bone marrow relapses in the group that received the triple intrathecal chemotherapy, leading to a worse overall survival (OS) (90.3% ± 1.5%) compared with the intrathecal methotrexate group (94.4% ± 1.1%; P = .01).
    • When the analysis was restricted to patients with precursor B-cell ALL and rapid early response (M1 marrow on day 14), there was no difference between triple and single intrathecal chemotherapy in terms of rates of CNS relapse rate, OS, or EFS.
    • The findings of this trial need to be interpreted within the context of other therapy administered to patients. Dexamethasone, which has been associated with lower CNS relapse rates and improved EFS in standard-risk patients in other trials, was not used in CCG-1952 (prednisone was the only steroid administered to patients). It is not clear whether the results of the CCG-1952 trial are generalizable to protocols that include the use of dexamethasone and/or other CNS-directed systemic therapies.
  • In a follow-up study of neurocognitive functioning in the two groups, there were no clinically significant differences.[Level of evidence: 1iiC]
  • CNS Therapy for High-risk Patients
    Controversy exists as to which 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):
  • In a trial conducted between 1990 and 1995, the Berlin-Frankfurt-Münster (BFM) group demonstrated that a reduced dose of prophylactic radiation (12 Gy instead of 18 Gy) provided effective CNS prophylaxis in high-risk patients.
  • In the follow-up trial conducted by the BFM group between 1995 and 2000 (BFM-95), cranial radiation was administered to approximately 20% of patients (compared with 70% on the previous trial), including patients with T-cell phenotype, a slow early response (as measured by peripheral blood blast count after a 1-week steroid prophase), and/or adverse cytogenetic abnormalities.
      While the rate of isolated CNS relapses was higher in the nonirradiated higher-risk patients compared with historic (irradiated) cohorts, their overall EFS rate was not significantly different.
  • Several groups, including the St. Jude Children's Research Hospital (SJCRH), the Dutch Childhood Oncology Group (DCOG), and the European Organization for Research and Treatment of Cancer (EORTC), have published results of trials that omitted cranial radiation for all patients, including high-risk subsets. Most of these trials have included at least four doses of high-dose methotrexate during postinduction consolidation and an increased frequency of intrathecal chemotherapy. The SJCRH and DCOG studies also included frequent vincristine/dexamethasone pulses and intensified dosing of L-asparaginase, while the EORTC trials included additional high-dose methotrexate and multiple doses of high-dose cytarabine during postinduction treatment phases for CNS3 (CSF with ≥5 WBC/µL and cytospin positive for blasts) patients.
      The 5-year cumulative incidence of isolated CNS relapse on those trials was between 2% and 4%, although some patient subsets had a significantly higher rate of CNS relapse. On the SJCRH study, clinical features associated with a significantly higher risk of isolated CNS relapse included T-cell phenotype, the t(1;19) translocation, or the presence of blasts in the CSF at diagnosis.
    • The overall EFS for the SJCRH study was 85.6% and 81% for the DCOG study, both in line with outcomes achieved by contemporaneously conducted clinical trials on which some patients received prophylactic radiation, but was lower on the EORTC trial (8-year EFS, 69.6%).
    • Of note, on the SJCRH study, 33 of 498 (6.6%) patients in first remission with high-risk features (including 26 with high minimal residual disease, six with Philadelphia chromosome-positive ALL, and one with near haploidy) received an allogeneic hematopoietic stem cell transplant , which included total-body irradiation.

    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):
  • SJCRH, DCOG, and the EORTC have published results of trials that omitted cranial radiation for all patients, including high-risk subsets. These trials have included at least four doses of high-dose methotrexate during postinduction consolidation and an increased frequency of intrathecal chemotherapy. The SJCRH study also included higher cumulative doses of anthracycline than on Children’s Oncology Group (COG) trials, and frequent vincristine/dexamethasone pulses and intensified dosing of L-asparaginase, while the EORTC trials included additional high-dose methotrexate and multiple doses of high-dose cytarabine, during postinduction treatment phases for CNS3 (CSF with ≥5 WBC/µL and cytospin positive for blasts) patients.
      On the SJCRH Total XV (TOTXV) study, patients with CNS3 status (N = 9) were treated without cranial radiation (observed 5-year EFS, 43% ± 23%). On this study, CNS leukemia at diagnosis (defined as CNS3 status or traumatic lumbar puncture with blasts) was an independent predictor of inferior EFS.
    • On the DCOG-9 trial, the 5-year EFS of CNS3 patients (n = 21) treated without cranial radiation was 67% ± 10%.
    • On the EORTC trial, the 8-year EFS of CNS3 patients (n = 49) treated without cranial radiation was 68%. The cumulative incidence of isolated CNS relapse for those patients was 9.4%.[Level of evidence: 2A]
    Larger 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:
  • NCI-2014-00712/AALL1231 (NCT02112916) (Combination Chemotherapy With or Without Bortezomib in Treating Younger Patients With Newly Diagnosed T-Cell ALL or Stage II–IV T-Cell Lymphoblastic Lymphoma): This trial is for patients with T-cell ALL and is testing, in a nonrandomized fashion, reduction in the proportion of T-cell ALL patients who receive prophylactic cranial radiation. In this study, only very high-risk patients (those with M3 marrow at day 29 or MRD >0.1% at end of consolidation, regardless of initial CNS status) and any other patient who is CNS3 at diagnosis receive cranial radiation therapy. CNS3 patients receive 18 Gy of cranial radiation, while the other patients allocated to cranial radiation receive 12 Gy. It is estimated that 10% to 15% of T-cell ALL patients will receive cranial radiation on AALL1231, compared with 85% to 90% of T-cell ALL patients on predecessor COG trials.
  • COG-AALL1131 (Combination Chemotherapy in Treating Young Patients With Newly Diagnosed High-Risk ALL): The COG-AALL1131 protocol for patients with high-risk B-precursor ALL includes a randomized comparison of triple intrathecal chemotherapy (methotrexate, cytarabine, and hydrocortisone) with intrathecal methotrexate, with the objective of determining whether triple intrathecal chemotherapy reduces CNS-relapse rates and improves overall EFS. Only patients with CNS3 status at diagnosis will receive cranial radiation (18 Gy).
  • SJCRH Total XVI (TOTXVI) (Total Therapy Study XVI for Newly Diagnosed Patients With ALL): Patients receive both intrathecal chemotherapy and high-dose methotrexate without radiation therapy. Certain patients with high-risk features, including those with a t(1;19) translocation, receive intensified intrathecal therapy.
  • Toxicity of CNS-Directed Therapy
    Toxic effects of CNS-directed therapy for childhood ALL can be divided into the following two broad groups:
  • Acute/subacute toxicities (e.g., seizures, stroke, somnolence syndrome, and ascending paralysis).
  • Late-developing toxicities (e.g., meningiomas and other second neoplasms; leukoencephalopathy; and a range of neurocognitive, behavioral, and neuroendocrine disturbances).
  • Acute/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.
    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
    In general, patients who receive intrathecal chemotherapy without cranial radiation appear to 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. This modest decline is primarily seen in young children and girls.
    A comparison of neurocognitive outcomes of patients treated with methotrexate versus triple intrathecal chemotherapy showed no clinically meaningful difference.[Level of evidence: 3iiiC]
    Controversy exists about whether patients who receive dexamethasone have a higher risk of neurocognitive disturbances. 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.
    Long-term deleterious effects of cranial radiation, particularly at doses higher than 18 Gy, have been recognized for years. Children receiving these higher doses of cranial radiation are at significant risk of neurocognitive and neuroendocrine sequelae. At doses of 18 Gy, it does not appear that irradiated patients have more severe neurocognitive impairments than ALL survivors who were treated without radiation. On current clinical trials, many patients who receive prophylactic or presymptomatic cranial radiation are treated with an even lower dose. Longer follow-up is needed to determine whether 12 Gy will be associated with a lower incidence of late effects.
    The following groups have been associated with neurocognitive and neuroendocrine sequelae after cranial radiation:
    • Young children (i.e., younger than 4 years) are at increased risk of neurocognitive decline and other sequelae after cranial radiation.
    • Girls may be at a higher risk than boys of radiation-induced neuropsychologic and neuroendocrine sequelae.
    • Long-term survivors treated with 18 Gy radiation appear to have less severe neurocognitive sequelae than those who had received higher doses of radiation (24–28 Gy) on clinical trials conducted in the 1970s and 1980s.
    Evidence (toxicity of cranial radiation):
  • In a randomized trial, hyperfractionated radiation (at a dose of 18 Gy) did not decrease neurologic late effects when compared with conventionally fractionated radiation; cognitive function for both groups was not significantly impaired.
  • In another randomized trial comparing irradiated (at a dose of 18 Gy) and nonirradiated standard-risk ALL patients, cognitive function for both groups (assessed at a median of 6 years postdiagnosis) was in the average range, with only subtle differences noted between the groups in cognitive skills.[Level of evidence: 1iiC]
  • Cranial radiation has also been associated with an increased risk of second neoplasms, many of which are benign or of low malignant potential, such as meningiomas, although high-grade lesions may occur. Leukoencephalopathy has been observed after cranial radiation in children with ALL but appears to be more common with higher doses than are currently administered. In general, systemic methotrexate doses greater than 1 g/m2 should not be given after cranial radiation because of the increased risk of neurologic sequelae, including leukoencephalopathy.

    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. 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) DFCI-95001 (NCT00004034) trial was 90.1% compared with 88.7% for patients with B-cell disease. However, 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.
    Treatment options
  • Protocols of the former Pediatric Oncology Group (POG) treated children with T-cell ALL differently from children with B-lineage ALL. The POG-9404 protocol for patients with T-cell ALL was designed to evaluate the role of high-dose methotrexate. The multiagent chemotherapy regimen for this protocol was based on the DFCI-87001 regimen.
      Results of the POG-9404 study indicated that the addition of high-dose methotrexate to the DFCI-based chemotherapy regimen resulted in significantly improved event-free survival (EFS) in patients with T-cell ALL (10-year EFS, 78% for those randomly assigned to high-dose methotrexate versus 68% for those randomly assigned to therapy without high-dose methotrexate, P = .05).
    • High-dose methotrexate was associated with a lower incidence of relapses involving the central nervous system (CNS). This POG study was the first clinical trial to provide evidence that high-dose methotrexate can improve outcome for children with T-cell ALL. High-dose asparaginase, doxorubicin, and prophylactic cranial irradiation were also important components of this regimen.
  • Protocols of the former Children’s Cancer Group (CCG) treated children with T-cell ALL on the same treatment regimens as children with precursor B-cell ALL, basing protocol and treatment assignment on the patients' clinical characteristics (e.g., age and white blood cell [WBC] count) and the disease response to initial therapy. Most children with T-cell ALL meet National Cancer Institute (NCI) high-risk criteria.
      Results from CCG-1961 for high-risk ALL including T-cell ALL showed that an augmented Berlin-Frankfurt-Münster (BFM) regimen with a single delayed intensification course produced the best results for patients with morphologic rapid response to initial induction therapy (estimated 5-year EFS, 83%). Almost 60% of events in this group, however, were isolated CNS relapses.
    • Overall results from POG-9404 and CCG-1961 were similar, although POG-9404 used cranial radiation for every patient, while CCG-1961 used cranial radiation only for patients with slow morphologic response.
    • Among children with NCI standard-risk T-cell ALL, the EFS for those treated on CCG-1952 and COG-1991 studies was inferior to the EFS for those treated on the POG-9404 study.
  • In the COG, children with T-cell ALL are not treated on the same protocols as children with precursor B-cell ALL. Pilot studies from the COG have demonstrated the feasibility of incorporating nelarabine (a nucleoside analog with demonstrated activity in patients with relapsed and refractory T-cell lymphoblastic disease) in the context of a BFM regimen for patients with newly diagnosed T-cell ALL. The pilot study showed a 5-year EFS rate of 73% for all patients receiving nelarabine and 69% for those patients with a slow early response.
  • The role of prophylactic cranial radiation in the treatment of T-cell ALL is controversial. Some groups, such as St. Jude Children's Research Hospital (SJCRH) and the Dutch Childhood Oncology Group (DCOG), do not use cranial radiation in first-line treatment of ALL, while other groups, such as DFCI, COG, and BFM, use radiation for the majority of patients with T-cell ALL.
  • Treatment options under clinical evaluation for T-cell ALL
    Treatment options under clinical evaluation for T-cell ALL include the following:
  • NCI-2014-00712/AALL1231 (NCT02112916) (Combination Chemotherapy With or Without Bortezomib in Treating Younger Patients With Newly Diagnosed T-Cell ALL or Stage II–IV T-Cell Lymphoblastic Lymphoma): This phase III trial is utilizing a modified augmented BFM regimen for patients aged 1 to 30 years with T-cell ALL. Patients are classified into one of three risk groups (standard, intermediate, or very high) based on morphologic response at day 29, minimal residual disease (MRD) status at day 29 and end of consolidation, and CNS status at diagnosis. Age and presenting leukocyte count are not used to stratify patients. The objectives of the trial include the following:
      To compare EFS in patients who are randomly assigned to receive or not to receive bortezomib on a modified augmented BFM backbone. For those randomly assigned to receive bortezomib, it is given during the induction phase (four doses) and again during the delayed intensification phase (four doses).
    • To determine the safety and feasibility of modifying standard COG therapy for T-cell ALL by using dexamethasone instead of prednisone during the induction and maintenance phases and additional doses of PEG-asparaginase during the induction and delayed intensification phases.
    • To determine whether prophylactic cranial radiation can be omitted in 85% to 90% of T-cell ALL patients (non–very high risk, non-CNS3) without an increase in relapse risk, compared with historic controls.
    • To determine the proportion of patients with end consolidation MRD >0.1% who become MRD-negative after intensification therapy using three high-risk BFM blocks that include high-dose cytarabine, high-dose methotrexate, ifosfamide, and etoposide.
  • DFCI-11-001 (NCT01574274) (SC-PEG Asparaginase versus Oncaspar in Pediatric ALL and Lymphoblastic Lymphoma):
    Patients with T-cell ALL are eligible to enroll on a DFCI ALL Consortium protocol that is comparing the pharmacokinetics and toxicity of two forms of intravenous PEG-L-asparaginase (pegaspargase [Oncaspar] and calaspargase pegol [SC-PEG]). Patients will be randomly assigned to receive a single dose of one of these preparations during multiagent induction, and then either pegaspargase every 2 weeks (15 doses total) or calaspargase pegol every 3 weeks (10 doses total) during the 30-week consolidation phase.
    This protocol is also testing whether antibiotic prophylaxis (with fluoroquinolones) reduces rates of bacteremia and other serious bacterial infections during the remission induction phase. All T-cell patients are treated on the high-risk arm of this trial, regardless of other presenting characteristics.
  • Current Clinical Trials
    Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with T-cell childhood acute lymphoblastic leukemia. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.
    General information about clinical trials is also available from the NCI Web site.

    Infants With 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. Despite intensification of therapy, long-term EFS rates remain below 50%. Infants with congenital leukemia (diagnosed within 1 month of birth) have a particularly poor outcome (17% OS).[Level of evidence: 2A]
    For infants with MLL gene rearrangement, the EFS rates continue to be in the 17% to 40% range.[Level of evidence: 2A] Factors predicting poor outcome for infants with MLL translocations include the following:; [Level of evidence: 3iDii]
    • A very young age (<6 months).
    • Extremely high presenting leukocyte count (≥200,000–300,000/μL).
    • High levels of MRD at the end of induction and consolidation phases of treatment.
    Treatment options for infants with MLL translocations
    Infants with MLL gene translocations 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 MLL translocations):
  • The international Interfant clinical trials consortium utilized a cytarabine-intensive chemotherapy regimen, with increased exposure to both low- and high-dose cytarabine during the first few months of therapy, resulting in a 5-year EFS of 37% for infants with MLL translocations.
  • The COG tested intensification of therapy with a regimen including multiple doses of high-dose methotrexate, cyclophosphamide, and etoposide, resulting in a 5-year EFS of 34%.
  • The role of allogeneic hematopoietic stem cell transplant (HSCT) during first remission in infants with MLL gene translocations remains controversial.
    Evidence (allogeneic HSCT in first remission for infants with MLL translocations):
  • On a Japanese clinical trial conducted between 1998 and 2002, all infants with MLL-rearrangement were intended to proceed to allogeneic HSCT from the best available donor (related, unrelated, or umbilical cord) 3 to 5 months after diagnosis.
      The 3-year EFS for all enrolled infants was 44%. This result was due, in part, to the high frequency of early relapses, even with intensive chemotherapy; of the 41 infants with MLL-rearrangement on that study who achieved complete remission (CR), 11 infants (27%) relapsed before proceeding to transplant.
  • In a COG report that included 189 infants treated on CCG or POG infant ALL protocols between 1996 and 2000, there was no difference in EFS between patients who underwent HSCT in first CR and those who received chemotherapy alone.
  • The Interfant clinical trials group, after adjusting for waiting time to transplantation, also did not observe any difference in disease-free survival (DFS) in high-risk infants (defined by prednisone response) with MLL translocations treated on the Interfant-99 trial with either allogeneic HSCT in first CR or chemotherapy alone.
      In a subset analysis from the same trial, allogeneic HSCT in first remission was associated with a significantly better DFS for infants with MLL translocations who were younger than 6 months at diagnosis and had either a poor response to steroids at day 8 or leukocyte counts of at least 300,000/µL. In this subset, HSCT in first remission was associated with a 64% reduction in the risk of failure resulting from relapse or death compared with chemotherapy alone.

    Treatment options for infants without MLL translocations
    The optimal treatment for infants without MLL translocations also remains unclear.

    Treatment options under clinical evaluation for infants with ALL
    Treatment options under clinical evaluation include the following:
  • Interfant-06 Study Group trial (DCOG-INTERFANT-06) (Different Therapies in Treating Infants With Newly Diagnosed Acute Leukemia): The Interfant-06 Study Group is conducting an international collaborative randomized trial (including sites in the United States) to test whether an ALL/acute myeloid leukemia hybrid regimen might improve outcomes for infants with MLL-rearranged ALL. The role of allogeneic transplantation in first remission is also being assessed in high-risk patients (defined as infants with MLL-rearranged ALL, younger than 6 months, and WBC >300,000 /µL) or poor peripheral blood response to steroid prophase. Infants with MLL-rearranged ALL with high MRD at end of consolidation phase are also eligible for allogeneic HSCT in first remission regardless of other presenting features.
  • 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+).
    • 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.; [Level of evidence: 2A] 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 (pediatric treatment regimen):
  • Investigators reported on 197 patients aged 16 to 21 years treated on the CCG study (a pediatric ALL regimen) who showed a 7-year EFS of 63% compared with 124 adolescents and young adults treated on the Cancer and Leukemia Group B (CALGB) study (an adult ALL regimen) with a 7-year EFS of 34%.
  • A study from France of patients aged 15 to 20 years and diagnosed between 1993 and 1999 demonstrated superior outcome for patients treated on a pediatric trial (67%; 5-year EFS) compared with patients treated on an adult trial (41%; 5-year EFS).
  • In the COG high-risk study (CCG-1961), the 5-year EFS rate for 262 patients aged 16 to 21 years was 71.5%.[Level of evidence: 1iiDi] For rapid responders randomly assigned to early intensive postinduction therapy on the augmented intensity arms of this study, the 5-year EFS rate was 82% (n = 88).
  • The DFCI ALL Consortium reported that a study of 51 adolescents aged 15 to 18 years in a pediatric trial had a 5-year EFS of 78%.
  • In an SJCRH study, 44 adolescents aged 15 to 18 years had an EFS of approximately 85% ± 5%.
  • In a Spanish study, 35 adolescents (aged 15–18 years) and 46 young adults (aged 19–30 years) with standard-risk ALL were treated with a pediatric-based regimen.[Level of evidence: 2A]
      EFS rate was 61%.
    • The OS rate was 69%.
    • There were no differences in outcome between adolescents and young adults.
    Other studies have confirmed that older adolescent patients and young adults fare better on pediatric rather than adult regimens (see Table 3).; [Level of evidence: 2A]
    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.
    Table 3. Outcome According to Treatment Protocol for Adolescents and Young Adults with ALL
    Site and Study GroupAdolescent and Young Adult Patients (No.)Median age (y)Survival (%)ALL = acute lymphoblastic leukemia; EFS = event-free survival; OS = overall survival.AEIOP = Associazione Italiana Ematologia Oncologia Pediatrica; CALGB = Cancer and Leukemia Group B; CCG = Children's Cancer Group; DCOG = Dutch Childhood Oncology Group; FRALLE = French Acute Lymphoblastic Leukaemia; GIMEMA = Gruppo Italiano Malattie e Matologiche dell'Adulto; HOVON = Dutch-Belgian Hemato-Oncology Cooperative Group; LALA = France-Belgium Group for Lymphoblastic Acute Leukemia in Adults; MRC = Medical Research Council (United Kingdom); NOPHO = Nordic Society for Pediatric Hematology and Oncology; UKALL = United Kingdom Acute Lymphoblastic Leukaemia.United States CCG (Pediatric)1971667, OS 7 yCALGB (Adult)1241946France FRALLE 93 (Pediatric)771667 EFSLALA 941001841Italy AEIOP (Pediatric)1501580, OS 2 yGIMEMA (Adult)951671Netherlands DCOG (Pediatric)471271 EFSHOVON442038Sweden NOPHO 92 (Pediatric)361674, OS 5 yAdult ALL991839United Kingdom MRC ALL (Pediatric)6115–1771, OS 5 yUKALL XII (Adult)6715–1756
    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):
  • In the CCG-1961 high-risk ALL study, alternate-week dosing of dexamethasone was compared with standard continuous dexamethasone during delayed intensification to see if the osteonecrosis risk could be reduced.
      The median age at symptom onset was 16 years.
    • The cumulative incidence was higher in adolescents and young adults aged 16 to 21 years (20% at 5 years) than in those aged 10 to 15 years (9.9%) or in patients aged 1 to 9 years (1%).
    • Operative interventions are needed for management of symptoms and impaired mobility in more than 40% of cases.
    • The use of alternate-week dosing of dexamethasone as compared with standard continuous dexamethasone during delayed intensification in CCG-1961 reduced the risk of osteonecrosis. The greatest impact was seen in females aged 16 to 21 years, who showed the highest incidence of osteonecrosis with standard therapy containing continuous dexamethasone; osteonecrosis was reduced with alternate-week dexamethasone postinduction (57.6% to 5.6%).

    Treatment options under clinical evaluation for adolescent and young adult patients with ALL
    Treatment options under clinical evaluation include the following:
  • NCI-2014-00712/AALL1231 (NCT02112916) (Combination Chemotherapy With or Without Bortezomib in Treating Younger Patients With Newly Diagnosed T-Cell ALL or Stage II–IV T-Cell Lymphoblastic Lymphoma): This phase III trial for patients aged 1 to 30 years with T-cell ALL is utilizing a modified augmented BFM regimen. Patients are classified into one of three risk groups (standard, intermediate, or very high) based on morphologic response at day 29, MRD status at day 29 and end of consolidation, and CNS status at diagnosis. Age and presenting leukocyte count are not used to stratify patients. The objectives of the trial include the following:
      To compare EFS in patients who are randomly assigned to receive or not to receive bortezomib on a modified augmented BFM backbone.
    • To determine the safety and feasibility of modifying standard COG therapy for T-ALL by using dexamethasone instead of prednisone during the induction and maintenance phases and additional doses of PEG-asparaginase during the induction and delayed intensification phases.
    • To determine whether prophylactic cranial radiation can be omitted in 85% to 90% of T-ALL patients (non-very high risk, non-CNS3) without an increase in relapse risk, compared with historic controls.
    • To determine the proportion of patients with end consolidation MRD >0.1% who become MRD-negative after intensification therapy using three high-risk BFM blocks that include high-dose cytarabine, high-dose methotrexate, ifosfamide, and etoposide.

    Philadelphia Chromosome–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 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 (P = .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 BCR-ABL 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. Preliminary outcome of results for Ph+ ALL demonstrated a better outcome after HSCT if imatinib was given before or after transplant.
    Evidence (tyrosine kinase inhibitor):
  • A retrospective study of 30 pediatric patients with Ph+ ALL (19 patients treated between 1991–2004 without a tyrosine kinase inhibitor, and 11 patients treated between 2004–2012 with either imatinib or dasatinib) indicated that tyrosine kinase inhibitors, when started mid-induction, are associated with lower end-induction MRD.
  • The COG-AALL0031 study evaluated whether imatinib mesylate could be incorporated into an intensive chemotherapy regimen for children with Ph+ ALL. Patients received imatinib mesylate in conjunction with chemotherapy during postinduction therapy. Some children proceeded to allogeneic HSCT after two cycles of consolidation chemotherapy with imatinib mesylate, while other patients received imatinib mesylate in combination with chemotherapy throughout all treatment phases.
      The 5-year EFS for the 25 patients who received intensive chemotherapy with continuous dosing of imatinib mesylate is 70% ± 12%. These patients fared better than historic controls treated with chemotherapy alone (without imatinib mesylate), and at least as well as the other patients on the trial who underwent allogeneic transplantation. Longer follow-up is necessary to determine whether this novel treatment improves cure rate or merely prolongs DFS.
  • A nonrandomized study reported the outcome in 16 pediatric patients with Ph+ ALL who were treated with chemotherapy, imatinib, and allogeneic HSCT.
      With a median follow-up of 65 months, the 5-year EFS was 81% for patients who received imatinib compared with 30% (P = .01) for a historic control group treated similarly, but without imatinib. Of note, only one of the 16 patients received prophylactic imatinib posttransplant.
  • The EsPhALL trial tested whether imatinib (administered discontinuously) given in the context of intensive chemotherapy improves outcome for pediatric Ph+ ALL patients, most of whom (80%) received an allogeneic HSCT in first CR. Patients were classified as either good risk or poor risk based on early response measures and remission status at the end of induction. Good- risk patients (N = 90) were randomly assigned to receive imatinib or not; poor-risk patients (N = 70) were directly assigned to imatinib. Interpretation of this study is limited due to the high noncompliance rate with randomized assignment in good-risk patients and early closure before reaching goal accrual due to publication of the results of the COG AALL0031 trial on which imatinib had been given continuously with chemotherapy. The overall DFS of patients treated on this trial appeared to be better than historic controls, and when analyzed as-treated (and not by intent-to-treat), good-risk patients who received imatinib had a superior DFS. The EsPhALL trial has since been amended to test continuous dosing of imatinib; results are pending.
  • 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
    Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with Philadelphia chromosome positive childhood precursor acute lymphoblastic leukemia. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.
    General information about clinical trials is also available from the NCI Web site.

    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.; [Level of evidence: 3iiDi]
    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 have a better prognosis than those with a marrow relapse.

    Time from diagnosis to relapse
    For patients with relapsed B-precursor 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 has been reported as an independent predictor 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%; P = .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 had inferior outcomes as reported in a BFM report before 2000, primarily due to increased induction deaths and treatment-related mortality. However, since 2000, with improvements in supportive care, there have been no differences in outcome between patients with and without Down syndrome. 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 indicated that hematopoietic recovery, graft-versus-host disease (GVHD), and transplant-related mortality were within the expected range for non–Down syndrome ALL patients. In that series, relapse rather than transplant toxicity was the primary cause of treatment failure.[Level of evidence: 3iiiA]

    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 (CR2).[Level of evidence: 2Di]; [Level of evidence: 3iiiA] Several studies have demonstrated that minimal residual disease (MRD) levels after the achievement of CR2 are of prognostic significance in relapsed ALL.; [Level of evidence: 3iiiDi] 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
    TP53 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% TP53 alteration vs. 12.5% TP53 wild-type) and poor event-free survival (EFS) (9% TP53 alteration vs. 49% TP53 wild-type). Approximately one-half of the TP53 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 B-precursor ALL in first bone marrow relapse is IKZF1 deletion. The frequency of IKZF1 deletion in B-precursor 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.
    Patients with ETV6-RUNX1-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%, SE) was observed for patients with ETV6-RUNX1 ALL with bone marrow relapse. In this study, 94% of patients with ETV6-RUNX1 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 ETV6-RUNX1) was an independent predictor of outcome. Similarly, the 5-year OS for ETV6-RUNX1 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 ETV6-RUNX1 was associated with a favorable survival outcome compared with other late relapsing patients. However, the 3-year OS of ETV6-RUNX1 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.
  • Postreinduction therapy for patients achieving a CR2.
  • Reinduction chemotherapy
    Initial treatment of relapse consists of reinduction therapy to achieve a CR2. 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 CR2 at the end of the first month of treatment.; [Level of evidence: 2A]; [Level of evidence: 2Di] Patients with early marrow relapses have a lower rate of achieving a morphologic CR2 (approximately 70%) than do those with late marrow relapses (approximately 95%).
    Evidence (chemotherapy):
  • A COG study used three blocks of intensive reinduction therapy with an initial four-drug combination including doxorubicin followed by two intensive consolidation blocks before either HSCT or chemotherapy continuation.
      Second remission was achieved after block 1 in 68% of patients with early relapse (<36 months from initial diagnosis) and in 96% of those with later relapse.
    • Blocks 2 and 3 reduced MRD in 40 of 56 patients who were MRD-positive after block 1.
  • A United Kingdom–based randomized trial of ALL patients in first relapse compared reinduction with a four-drug combination using idarubicin versus mitoxantrone.[Level of evidence: 1iiA]
      There was no difference in CR2 rates or end-reinduction MRD levels between the two study arms.
    • A significant improvement in OS in the mitoxantrone arm (69% vs. 45%, P = .007) due to decreased relapse after transplantation was reported.
    The potential benefit of mitoxantrone in relapsed ALL regimens requires further investigation.
  • Investigators from the ALL-REZ BFM group used a six-drug reinduction approach, including high-dose methotrexate. A randomized comparison of 1 g/m2 of methotrexate versus 5 g/m2 of methotrexate with reinduction showed no advantage at the higher dose.
  • The combination of clofarabine, cyclophosphamide, and etoposide was reported to induce remission in 42% to 56% of patients with refractory or multiply relapsed disease.; [Level of evidence: 2A]
  • The combination of bortezomib plus vincristine, dexamethasone, PEG-L-asparaginase, and doxorubicin was reported to induce complete response (with or without platelet recovery) in 80% of multiply relapsed patients with B-precursor ALL.[Level of evidence: 3iiiDiv] Notably, this trial did not include patients who were refractory to reinduction.
  • In a study of induction therapy comprising intensive asparaginase (weekly PEG-L-asparaginase or 12 doses of E.coli asparaginase) with prednisone, vincristine, and doxorubicin for patients with first relapse, the CR2 rate was 86% for those receiving PEG-L-asparaginase and 81% for those receiving E.coli asparaginase.[Level of evidence: 2Di]
  • T-cell ALL
    Patients with relapsed T-cell ALL have much lower rates of achieving CR2 with standard reinduction regimens than do patients with B-precursor 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.

    Postreinduction therapy for patients achieving a second complete remission
    Early-relapsing B-precursor ALL
    For B-precursor 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 B-precursor ALL
    For patients with a late marrow relapse of B-precursor ALL, a primary chemotherapy approach after achievement of CR2 has resulted in survival rates of approximately 50%, and it is not clear whether allogeneic transplantation is associated with superior cure rate.; [Level of evidence: 3iiA] End-reinduction MRD levels may help to identify patients with a high risk of subsequent relapse if treated with chemotherapy alone (no HSCT) in CR2. 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 CR2.
    Evidence (MRD-based risk stratification for late-relapse of B-precursor ALL):
  • In a St. Jude Children's Research Hospital study, which included 23 patients with late relapses treated with chemotherapy in CR2, the 2-year cumulative incidence of relapse was 49% for the 12 patients who were MRD-positive at the end of reinduction and 0% for the 11 patients who were MRD-negative.
  • In BFM studies, patients are considered to be intermediate risk if they have a late isolated marrow relapse or an early or late combined marrow/extramedullary relapse. In the ALL-REZ BFM P95/96 study from this group, end-reinduction MRD (assessed by a polymerase chain reaction–based assay) significantly predicted outcomes of children with intermediate-risk relapsed B-cell ALL treated with chemotherapy alone in CR2 (no HSCT).
      Patients with low MRD (<10-3) had a 10-year EFS of 73%, while those with high MRD (>10-3) had a 10-year EFS of 10%. On multivariate analysis, end-reinduction MRD was the strongest independent prognostic factor.

    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 CR2, regardless of time to relapse.

    Standard Treatment 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.[Level of evidence: 3iiA]

    Hematopoietic Stem Cell Transplantation for First and Subsequent Bone Marrow Relapse
    Components of the transplantation process
    An updated expert panel review of indications for HSCT has been published. 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:
  • Total-body irradiation (TBI)-containing transplant preparative regimens.
  • MRD detection just before transplant.
  • Donor type and HLA match.
  • Role of GVHD/graft-versus-leukemia (GVL) in ALL and immune modulation after transplant to prevent relapse.
  • 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 1.32 and 1.4 Gy. On the other hand, when cyclophosphamide and etoposide were used with TBI, doses above 1.2 Gy resulted in worse survival due to excessive toxicity.

    MRD detection just before transplant
    Disease 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.[Level of evidence: 3iiA]; [Level of evidence: 3iiB] 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.

    Donor type and HLA match
    Survival rates after matched unrelated donor and umbilical cord blood transplantations have improved significantly over the past decade and offer an outcome similar to that obtained with matched sibling donor transplants.; [Level of evidence: 2A]; [Level of evidence: 3iiiA]; [Level of evidence: 3iiiDii] 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.; [Level of evidence: 3iiA]
    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. For T cell-depleted CD34-selected haploidentical transplants in which a parent is the donor, patients receiving maternal stem cells may have a better outcome than those who receive paternal stem cells.[Level of evidence: 3iiA]

    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; P = .04) and better EFS (multivariate analysis, HR, 0.5; P = .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; P = .003), while grades I to III acute GVHD had no statistically detectable effect on transplant-related mortality (HR, 0.6; P = .42).
    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 (P < .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% may achieve long-term EFS.; [Level of evidence: 3iiA] 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.[Level of evidence: 2A] Donor leukocyte infusion has limited benefit for patients with ALL who relapse after allogeneic HSCT.; [Level of evidence: 3iiiA]
    Whether a second allogeneic transplant is necessary to treat isolated CNS and testicular relapse is unknown, and a small series has shown survival in selected patients using chemotherapy alone or chemotherapy followed by a second transplant.[Level of evidence: 3iA]

    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 diagnosis was noted to be an adverse prognostic factor for patients with an isolated extramedullary relapse in one study. 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%).
    CNS relapse
    Standard treatment options for childhood ALL that has recurred in the CNS include the following:
  • Systemic and intrathecal chemotherapy.
  • Cranial or craniospinal radiation.
  • 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):
  • In a Pediatric Oncology Group (POG) study using this strategy, children who had not previously received radiation therapy and whose initial remission was 18 months or longer had a 4-year EFS rate of approximately 80%, compared with EFS rates of approximately 45% for children with CNS relapse within 18 months of diagnosis.
  • In a follow-up POG study, children who had not previously received radiation therapy and who had initial remission of 18 months or more were treated with intensive systemic and intrathecal chemotherapy for 1 year followed by 18 Gy of cranial radiation only. The 4-year EFS was 78%. Children with an initial remission of less than 18 months also received the same chemotherapy but had craniospinal radiation (24 Gy cranial/15 Gy spinal) as in the first POG study and achieved a 4-year EFS of 52%.
  • A number of case series describing HSCT in the treatment of isolated CNS relapse have been published. 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):
  • In a study comparing outcome of patients treated with either HLA-matched sibling transplants or chemoradiation therapy as in the POG studies above, 8-year probabilities of leukemia-free survival adjusted for age and duration of first remission were similar (58% and 66%, respectively).[Level of evidence: 3iiiDii] This retrospective, registry-based study included transplantation of both early (<18 months from diagnosis) and late relapses.
      Because of the relatively good outcome of patients with isolated CNS relapse more than 18 months from diagnosis treated with chemoradiation therapy alone (>75%), transplantation is generally not recommended for this group.

    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:
  • Chemotherapy.
  • Radiation therapy.
  • 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]):
  • Dutch investigators treated five boys with a late testicular relapse with high-dose methotrexate during induction (12 g/m2) and at regular intervals during the remainder of therapy (6 g/m2) without testicular radiation. All five boys were long-term survivors.
  • In a small series of boys who had an isolated testicular relapse after a HSCT for a prior systemic relapse of ALL, five of seven boys had extended EFS without a second HSCT.[Level of evidence: 3iA]
  • Treatment Options Under Clinical Evaluation for Relapsed Childhood ALL
    Trials for ALL in first relapse
    Treatment options under clinical evaluation include the following:
  • TACL 2008-002 (NCT00981799) (Trial of Nelarabine, Etoposide, and Cyclophosphamide in Relapsed T-cell ALL and T-cell Lymphoblastic Lymphoma): This trial, conducted by the Therapeutic Advances in Childhood Leukemia & Lymphoma clinical trials group, is testing the feasibility of administering nelarabine in combination with cyclophosphamide and etoposide as reinduction for patients with T-cell ALL in first relapse (as well as those who failed primary induction therapy). Doses of nelarabine and cyclophosphamide will be escalated in successive cohorts of patients to determine the maximum tolerated doses of these drugs when given in combination.
  • DFCI-11-237 (NCT01523977) (Everolimus With Multiagent Reinduction Chemotherapy in Pediatric Patients With ALL): Patients in first relapse are eligible to enroll on a Dana-Farber Cancer Institute ALL Consortium trial testing the feasibility of administering everolimus, an oral mTOR inhibitor, in combination with multiagent reinduction (vincristine, prednisone, doxorubicin, intravenous PEG-L-asparaginase, and intrathecal chemotherapy).
  • Trials for ALL in second or subsequent relapse
    Treatment options under clinical evaluation include the following:
  • NCT01471782 (Clinical Study With Blinatumomab in Pediatric and Adolescent Patients With Relapsed/Refractory B-Precursor ALL): This is a phase I and II trial evaluating the safety and efficacy of blinatumomab, the CD3-CD19–binding molecule, in recruiting autologous T-cells to treat relapsed B-cell ALL.
  • COG-ADVL1114 (NCT01403415) (Temsirolimus, Dexamethasone, Mitoxantrone Hydrochloride, Vincristine Sulfate, and Pegaspargase in Treating Young Patients With Relapsed ALL or Non-Hodgkin Lymphoma [NHL]): This is a phase I trial to determine the feasibility and safety of adding three doses of temsirolimus (intravenously) to the United Kingdom ALL R3 induction regimen for patients with relapsed ALL and NHL.
  • 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
    Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with recurrent childhood acute lymphoblastic leukemia. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.
    General information about clinical trials is also available from the NCI Web site.

    Changes to this Summary (12/22/2014)
    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 Lundin et al. as reference 53, Chilton et al. as reference 122, and Irving et al. as reference 132.
    Revised text to state that a study by the Children's Oncology Group, which used intensive chemotherapy and concurrent imatinib mesylate given daily, demonstrated a 5-year event-free survival (EFS) rate of 70% ± 12%, which was superior to the EFS rate of historical controls in the pre-tyrosine kinase inhibitor (imatinib mesylate) era (cited Schultz et al. as reference 152).
    Added text to state that modifying therapy based on minimal residual disease (MRD) determination has been shown to improve outcome in B-cell ALL. Also added text to state that 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% (cited Vora et al. as reference 211).
    Postinduction Treatment for Childhood ALL
    Added text to state that the effects of end-induction and/or consolidation MRD on outcome has influenced the treatment of patients originally diagnosed as National Cancer Institute standard risk; multiple studies have demonstrated that higher levels of end-induction MRD are associated with poorer prognosis (cited Borowitz et al, van Dongen et al., Zhou et al., Coustan-Smith et al., and Stow et al. as references 13, 14, 15, 16, and 17, respectively). Also added text to state that augmenting therapy has been shown to improve the outcome in standard-risk patients with elevated MRD levels at the end of induction (cited Vora et al. as reference 18).
    Added text to state that patients who are standard or intermediate risk at diagnosis, but have high levels of end-induction MRD, have been shown to have a poorer prognosis and should be treated as high-risk patients. The UKALL2003 study demonstrated in a randomized controlled trial that augmented postinduction therapy increases EFS to that comparable to patients with low levels of end-induction MRD.
    Added text to state that a phase III clinical trial (POG-9406) was conducted in higher-risk pediatric B-precursor ALL patients. A total of 784 patients were randomly assigned to receive methotrexate, 1 g/m2 versus 2.5 g/m2; no differences in disease-free survival or overall survival were observed between 1 g/m2 and 2.5 g/m2 of methotrexate (cited Tower et al. as reference 34).
    Revised text about the COG-AALL1131 trial to state that patients with very high-risk features are currently not eligible for enrollment on this study.
    Postinduction Treatment for Specific ALL Subgroups
    Added text to state that a retrospective study of 30 pediatric patients with Philadelphia chromosome–positive ALL indicated that tyrosine kinase inhibitors, when started mid-induction, are associated with lower end-induction MRD (cited Jeha et al. as reference 58).
    Revised text to state that the 5-year EFS for the 25 patients who received intensive chemotherapy with continuous dosing of imatinib mesylate is 70% ± 12% (cited Schultz et al. as reference 59).
    Treatment of Relapsed Childhood ALL
    Added text to state that 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 hematopoietic stem cell transplantation in second complete remission (cited Eckert et al. as reference 53).
    The Role of GVHD/GVL in ALL and immune modulation after transplant to prevent relapse subsection was extensively revised.
    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:
    • Robert J. Arceci, MD, PhD (Phoenix Children's Hospital)
    • Karen J. Marcus, MD (Dana-Farber Cancer Institute/Boston Children's Hospital)
    • Michael A. Pulsipher, MD (Primary Children's Medical Center)
    • 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 Web site's Contact Form. 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.

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    National Cancer Institute: PDQ® Childhood Acute Lymphoblastic Leukemia Treatment. Bethesda, MD: National Cancer Institute. Date last modified <MM/DD/YYYY>. Available at: http://cancer.gov/cancertopics/pdq/treatment/childALL/HealthProfessional. Accessed <MM/DD/YYYY>.
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