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Childhood Acute Lymphoblastic Leukemia Treatment (PDQ®)

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.[1-3]

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:[1]

  • 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.[3]

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.[4] The factors described are grouped into the following three categories:

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.[5,6] 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

Age at diagnosis has strong prognostic significance, reflecting the different underlying biology of ALL in different age groups.[7]

  1. 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:[8-11]

    • 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.[10,12,13] 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.[10,14] Black infants with ALL are significantly less likely to have MLL translocations than white infants.[14] 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.[10,11] 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.[15]

    Blasts from infants with MLL translocations are typically CD10 negative and express high levels of FLT3.[10,11,13,16] 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.[10,11,13]

  2. 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.[1,7,17] 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).[7,18,19]

  3. 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.[20-22] Five-year survival rates for adolescents aged 15 to 19 years increased from 36% (1975–1984) to 72% (2003–2009).[23-25] Multiple retrospective studies have suggested that adolescents aged 16 to 21 years have a better outcome when treated on pediatric versus adult protocols.[26-28] (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,[1] 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.[6,29-35] 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.[36]

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.[37] Some studies have reported increased risk of CNS relapse and/or inferior event-free survival (EFS) in CNS2 patients, compared with CNS1 patients,[38,39] while others have not.[37,40-42]

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,[37,41,43] but not others.[38,40] 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.[37,40,41]

Some clinical trial groups have approached CNS2 and traumatic lumbar puncture by utilizing more intensive therapy, primarily additional doses of intrathecal therapy during induction.[37,44]; [40][Level of evidence: 2A] Other groups have not altered therapy based on CNS2 status.[38,45]

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.[46]

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.[47,48] 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.[48]

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.[47] 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.[49-53]

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.[49-52,54,55] 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.[54] 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.[55] 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.[56-60] 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.[60]

Gender

In some studies, the prognosis for girls with ALL is slightly better than it is for boys with ALL.[61-63] 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.[61-63] While some reports describe outcomes for boys as closely approaching those of girls,[44,64] larger clinical trial experiences and national data continue to show somewhat lower survival rates for boys.[23,24,65]

Race

Survival rates in black and Hispanic children with ALL have been somewhat lower than the rates in white children with ALL.[66,67] Asian children with ALL fare slightly better than white children.[67]

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.[68] Ancestry-related genomic variations may also contribute to racial/ethnic disparities in both the incidence and outcome of ALL.[69] 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.[70]

Leukemic cell characteristics affecting prognosis

Leukemic cell characteristics affecting prognosis include the following:

Morphology

In the past, ALL lymphoblasts were classified using the French-American-British (FAB) criteria as having L1 morphology, L2 morphology, or L3 morphology.[71] 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:[72]

  • 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.

  1. 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.[10,73] It is not clear whether CD10-negativity has any independent prognostic significance in the absence of an MLL gene rearrangement.[74]

    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).[75,76]

      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.[77]

      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.[77] (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.)

  2. 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:[17,29,64]

    • 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.[17,29,32,33,64]

    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.[6,29-35] 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.[78]

    Cytogenetic abnormalities common in B-lineage ALL (e.g., hyperdiploidy) are rare in T-cell ALL.[79,80]

    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.[79,81-85] 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).[79] 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.[81-83,85] 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,[83] although not in all studies.

    Notch pathway signaling is commonly activated by NOTCH1 and FBXW7 gene mutations in T-cell ALL.[86] 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.[87] 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,[88-91] while other studies have not shown prognostic significance for the presence of NOTCH1 and/or FBXW7 mutations.[87,92-94]

    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.[95-97] The fusion is cytogenetically cryptic and is seen in FISH on amplified episomes or more rarely, as a small homogeneous staining region.[97] T-cell ALL may also uncommonly show ABL1 fusion proteins with other gene partners (e.g., ETV6, BCR, and EML1).[97] ABL tyrosine kinase inhibitors, such as imatinib or dasatinib, may have therapeutic benefit in this T-cell ALL subtype,[95,96,98] although clinical experience with this strategy is very limited.[99-101]

    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.[36] 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.[102] 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.[102] Initial reports describing early T-cell precursor ALL suggested that this subset has a poorer prognosis than other cases of T-cell ALL.[36,103,104] 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%).[105] 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.[106,107] 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.

  3. 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.[108,109] No independent adverse prognostic significance exists for myeloid-surface antigen expression.[108,109]

    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.[110-112] 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.[113-115] 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:[110]

    • 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.[110] 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,[111,112,116] 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).[117]

Prognostically significant chromosomal abnormalities in childhood ALL include the following:

  1. 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.[118] 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.[19,118,119] 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.[19] Hyperdiploid leukemia cells are particularly susceptible to undergoing apoptosis and accumulate higher levels of methotrexate and its active polyglutamate metabolites,[120] 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.[121,122]

      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.[123] POG data suggest that NCI standard-risk patients with trisomies of 4 and 10, without regard to chromosome 17 status, have an excellent prognosis.[124]

      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,[125] 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).[126] 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.[126]

      Near triploidy (68–80 chromosomes) and near tetraploidy (>80 chromosomes) are much less common and appear to be biologically distinct from high hyperdiploidy.[127] Unlike high hyperdiploidy, a high proportion of near tetraploid cases harbor a cryptic ETV6-RUNX1 fusion.[127-129] 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.[127,129]

    • 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:[126]

      • 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.[126,130] Patients with fewer than 44 chromosomes have a worse outcome than do patients with 44 or 45 chromosomes in their leukemic cells.[126]

      The recurring genomic alterations of near-haploid and low-hypodiploid ALL appear to be distinctive from each other and from other types of ALL.[131] In near-haploid ALL, alterations targeting receptor tyrosine kinase signaling, Ras signaling, and IKZF3 are common.[132] 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.[131]

  2. 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.[128] The t(12;21) occurs most commonly in children aged 2 to 9 years.[133,134] Hispanic children with ALL have a lower incidence of t(12;21) than do white children.[135]

      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: [136-140]

      • 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.[136] 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.[140,141] There is a higher frequency of late relapses in patients with ETV6-RUNX1 fusion compared with other B-precursor ALL.[136,142] Patients with the ETV6-RUNX1 fusion who relapse seem to have a better outcome than other relapse patients,[143] with an especially favorable prognosis for patients who relapse more than 36 months from diagnosis.[144] 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).[145,146]

    • 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).

      Philadelphia chromosome; three-panel drawing shows a piece of chromosome 9 and a piece of chromosome 22 breaking off and trading places, creating a changed chromosome 22 called the Philadelphia chromosome. In the left panel, the drawing shows a normal chromosome 9 with the abl gene and a normal chromosome 22 with the bcr gene. In the center panel, the drawing shows chromosome 9 breaking apart in the abl gene and chromosome 22 breaking apart below the bcr gene. In the right panel, the drawing shows chromosome 9 with the piece from chromosome 22 attached and chromosome 22 with the piece from chromosome 9 containing part of the abl gene attached. The changed chromosome 22 with bcr-abl gene is called the Philadelphia chromosome.
      Figure 2. The Philadelphia chromosome is a translocation between the ABL-1 oncogene (on the long arm of chromosome 9) and the breakpoint cluster region (BCR) (on the long arm of chromosome 22), resulting in the fusion gene BCR-ABL. BCR-ABL encodes an oncogenic protein with tyrosine kinase activity.

      This subtype of ALL is more common in older children with precursor B-cell ALL and high WBC count.

      Historically, the Philadelphia chromosome t(9;22) was associated with an extremely poor prognosis (especially in those who presented with a high WBC count or had a slow early response to initial therapy), and its presence had been considered an indication for allogeneic hematopoietic stem cell transplantation (HSCT) in patients in first remission.[125,147-149] Inhibitors of the BCR-ABL tyrosine kinase, such as imatinib mesylate, are effective in patients with Ph+ ALL.[150] A study by the COG, which used intensive chemotherapy and concurrent imatinib mesylate given daily, demonstrated a 5-year EFS rate of 70% ± 12%, which was superior to the EFS rate of historical controls in the pre-tyrosine kinase inhibitor (imatinib mesylate) era.[150-152]

    • 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.[73,153-155] 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.[153]

      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.[10] 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.[73,153] 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.[73,153] Deletion of the MLL gene has not been associated with an adverse prognosis.[156]

      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.[157] 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.[157]

    • 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.[75,76] 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).[158]

      The t(1;19) translocation had been associated with inferior outcome in the context of antimetabolite-based therapy,[159] but the adverse prognostic significance was largely negated by more aggressive multiagent therapies.[76,160] 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.[44,161]

  3. 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:[162-168]

    • 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).[169-171] 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%).[117] 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%).[170] 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%).[169] On multivariate analysis, iAMP21 was an independent predictor of inferior outcome only in NCI standard-risk patients.[169] The results of the UKALL2003 and COG studies suggest that treatment of iAMP21 patients with high-risk chemotherapy regimens abrogates its adverse prognostic significance.[171]
    • 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.[172,173] A high proportion of BCR-ABL1 cases have a deletion of IKZF1,[173,174] and ALL arising in children with Down syndrome appears to have elevated rates of IKZF1 deletions.[60] IKZF1 deletions are also common in cases with CRLF2 genomic alterations and in Philadelphia chromosome–like (Ph-like) ALL (see below).[162,173,175]

      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.[162,173,175-181]

    • 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.[162,182,183] 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.[162,182,183]
    • 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.[184,185] 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.[184-187] CRLF2 abnormalities are strongly associated with the presence of IKZF1 deletions and JAK mutations;[56,173,185-187] they are also more common in children with Down syndrome.[185] Point mutations in kinase genes other than JAK1 and JAK2 are uncommon in CRLF2-overexpressing cases.[187]

      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.[165,184-186,188] 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.[180] 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.[165,188]

    • 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.[175,176] 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.[167,175,176,180,187] The hallmark of this entity is activated kinase signaling, with 50% containing CRLF2 genomic alterations [186] and 25% concomitant JAK mutations.[56] 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.[167] 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,[167] 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.[187]
  4. 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.[189-191] 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,[192] although such patients may also be at higher risk of developing significant treatment-related toxicities, including myelosuppression and infection.[193,194]

    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.[195] Polymorphic variants involving the reduced folate carrier and methotrexate metabolism have been linked to toxicity and outcome.[196,197] 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,[198] early response has strong prognostic significance. Various ways of evaluating the leukemia cell response to treatment have been utilized, including the following:

MRD determination

Morphologic assessment of residual leukemia in blood or bone marrow is often difficult and is relatively insensitive. Traditionally, a cutoff of 5% blasts in the bone marrow (detected by light microscopy) has been used to determine remission status. This corresponds to a level of 1 in 20 malignant cells. If one wishes to detect lower levels of leukemic cells in either blood or marrow, specialized techniques such as PCR assays, which determine unique Ig/T-cell receptor gene rearrangements, fusion transcripts produced by chromosome translocations, or flow cytometric assays, which detect leukemia-specific immunophenotypes, are required. With these techniques, detection of as few as 1 leukemia cell in 100,000 normal cells is possible, and MRD at the level of 1 in 10,000 cells can be detected routinely.[199]

Multiple studies have demonstrated that end-induction MRD is an important, independent predictor of outcome in children and adolescents with B-lineage ALL.[137,200-203] MRD response discriminates outcome in subsets of patients defined by age, leukocyte count, and cytogenetic abnormalities.[204] Patients with higher levels of end-induction MRD have a poorer prognosis than those with lower or undetectable levels.[137,199-201,205] 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.[137,199,201,204-209]

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).[137]

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.[210][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).[211]

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.[209]

There are few studies of MRD in the CSF. In one study, MRD was documented in about one-half of children at diagnosis.[212] 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.[213] 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.[137,214]

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).[17] Poor prednisone response is observed in fewer than 10% of patients.[17,215] 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.[216] Rate of clearance of peripheral blasts has been found to be of prognostic significance in both T-cell and B-lineage ALL.[216]

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.[137] 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.[217] 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.[218] Patients at highest risk of induction failure have one or more of the following features:[219,220]

  • 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%.[218] 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%.[3,44,215,221,222] 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%.[3,137]

Patients who are at very high risk of treatment failure include the following: [9,223-225]

  • 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:[204]

  • 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).[1]
  • 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 RiskAverage RiskHigh RiskVery High Risk
EFS = 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) SRSRSRSRSRHR (age <13 y)SRHRHR (age ≥13 y)SR or HR
Favorable Genetics YesYesNoYesNoAnyNoAnyAnyAny
Unfavorable Characteristics NoneNoneNoneNoneNoneNoneNoneNoneNoneYes
Day 8 PB MRD <0.01%≥0.01%<1%Any Level≥1%Any LevelAny LevelAny 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.[36] 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.

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  • Updated: December 17, 2014