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Childhood Acute Lymphoblastic Leukemia Treatment (Professional) (cont.)

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.[1,2,3]

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/mL and age 1 to younger than 10 years.
  • High risk—WBC count 50,000/mL or greater and 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.[1]

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:

  • 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.[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 in Recurrent 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:

  1. Age at diagnosis.
  2. WBC count at diagnosis.
  3. Central nervous system (CNS) involvement at diagnosis.
  4. Testicular involvement.
  5. Down syndrome (trisomy 21).
  6. Gender.
  7. Race.

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: [8,9,10,11]

    • Infants younger than 6 months (with an even poorer prognosis for those aged 60 to 90 days),
    • Infants with extremely high presenting leukocyte counts, and/or
    • Infants with a poor response to a prednisone prophase.

    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]

    Blasts from infants with MLL translocations are typically CD10 negative and express high levels of FLT3.[10,11,13,15] 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 infants with ALL characterized by MLL translocations.[10,11,13]

    A gene expression profile analysis in infants with MLL-rearranged ALL revealed significant differences between patients younger than 90 days compared with older infants. Younger infants had highly unfavorable outcomes, suggesting distinctive biological and clinical behaviors for MLL-translocation ALL, compared with older infants.[16]

  2. Young children (aged 1 to <10 years)

    Young children (aged 1 to <10 years) have a better disease-free survival (DFS) 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]

  3. Adolescents and young adults (=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.[19,20,21] Multiple retrospective studies have suggested that adolescents aged 16 to 21 years have a better outcome when treated on pediatric versus adult protocols.[22,23,24] (Refer to the Postinduction Treatment for Specifc ALL Subgroups section of this summary for more information about adolescents with ALL.)

WBC count at diagnosis

A WBC count of 50,000/無 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/無) than for B-precursor ALL (<10,000/無), and there is no consistent effect of WBC count at diagnosis on prognosis for T-cell ALL.[6,25,26,27,28,29,30,31] 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/無) than do other T-cell ALL patients.[32]

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/無 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/無 and cytospin positive for blasts.
  • CNS3 (CNS disease): CSF with 5 or more WBC/無 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 patients who are classified as CNS1 or CNS2.[33] The adverse prognostic significance associated with CNS2 status, if any, may be overcome by the application of more intensive intrathecal therapy, especially during the induction phase.[33,34]; [35][Level of evidence: 2A]

A traumatic lumbar puncture (=10 erythrocytes/無) that includes blasts at diagnosis appears to be associated with increased risk of CNS relapse and indicates an overall poorer outcome.[33,36] 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.[37]

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.[38,39] 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.[39]

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.[38] 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.[40,41,42,43]

The lower event-free survival (EFS) and OS of children with Down syndrome appear to be related to higher rates of treatment-related mortality and the absence of favorable biological features.[40,41,42,43,44] Patients with Down syndrome and ALL have a significantly lower incidence of favorable cytogenetic abnormalities such as ETV6-RUNX1 or trisomies of chromosomes 4 and 10.[44]

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.[44]

Gender

In some studies, the prognosis for girls with ALL is slightly better than it is for boys with ALL.[45,46,47] 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.[45,46,47] However, in clinical trials with high 5-year EFS rates (>80%), outcomes for boys are closely approaching those of girls.[34,48]

Race

Survival rates in black and Hispanic children with ALL have been somewhat lower than the rates in white children with ALL.[49,50] This difference may be therapy-dependent; a report from SJCRH found no difference in outcome by racial groups.[51]

Asian children with ALL fare slightly better than white children.[50] 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, blacks have a higher incidence of T-cell ALL and lower rates of favorable genetic subtypes of ALL. However, these differences do not completely explain the observed racial differences in outcome.[50]

Leukemic cell characteristics affecting prognosis

Leukemic cell characteristics affecting prognosis include the following:

  1. Morphology.
  2. Immunophenotype.
  3. Cytogenetics.

Morphology

In the past, ALL lymphoblasts were classified using the French-American-British (FAB) criteria as having L1 morphology, L2 morphology, or L3 morphology.[52] 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:[53]

  • B lymphoblastic leukemia.
  • T lymphoblastic leukemia.

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

  1. Precursor B-cell ALL (WHO B lymphoblastic leukemia)

    Prior to 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.[10,54] It is not clear whether CD10-negativity has any independent prognostic significance in the absence of an MLL gene rearrangement.[55]

    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 a t(4;11) translocation.

    • 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).[56,57]

      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.[58]

      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.[58] (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:[17,25,48]

    • Male gender.
    • Older age.
    • Leukocytosis.
    • Mediastinal mass.

    With appropriately intensive therapy, children with T-cell ALL have an outcome similar to that of children with B-lineage ALL.[17,25,48]

    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] 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.[59]

    Cytogenetic abnormalities common in B-lineage ALL (e.g., hyperdiploidy) are rare in T-cell ALL.[60,61]

    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.[60,62,63,64,65,66] 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).[60] 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.[62,63,64,66] Overexpression of TLX3/HOX11L2 resulting from the 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,[64] although not in all studies.

    NOTCH1 gene mutations occur in approximately 50% of T-cell ALL cases, but their prognostic significance has not been established.[67,68,69,70,71,72]

    A NUP214–ABL1 fusion has been noted in 4% to 6% of adults with T-cell ALL. The fusion is usually not detectable by standard cytogenetics. Tyrosine kinase inhibitors may have therapeutic benefit in this type of T-cell ALL.[73,74,75]

    Early precursor T-cell ALL, a distinct subset of childhood T-cell ALL, was identified by gene expression profiling, flow cytometry, and single nucleotide polymorphism array analyses.[32] This subset, identified in 13% of T-cell ALL cases, is characterized by a distinctive immunophenotype (CD1a and CD8 negativity, with weak expression of CD5 and co-expression 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 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.[76] A retrospective analysis suggested that this subset may have a poorer prognosis than other cases of T-cell ALL.[32]

    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.[77,78] 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.[79,80] No independent adverse prognostic significance exists for myeloid-surface antigen expression.[79,80]

    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.[81,82,83] 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.[84,85,86] 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:[81]

    • 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.[81] Patients with B-myeloid biphenotypic leukemias lacking the ETV6-RUNX1 fusion have a lower rate of complete remission and a significantly worse EFS than 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,[82,83,87] although the optimal treatment for patients remains unclear.

Cytogenetics

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 are 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).[88]

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.[89] Hyperdiploidy can be evaluated by measuring the DNA content of cells (DNA index) or by karyotyping. Interphase FISH may detect hidden hyperdiploidy in cases with a normal karyotype or in which standard cytogenetic analysis was unsuccessful. 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.[89,90] Hyperdiploid leukemia cells are particularly susceptible to undergoing apoptosis and accumulate higher levels of methotrexate and its active polyglutamate metabolites,[91] 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, the following factors have been shown to modify its prognostic significance:[92]

      • Age.
      • Gender.
      • WBC count.
      • Specific trisomies.

      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 (CCG) analyses of NCI standard-risk ALL.[93] POG data suggest that NCI standard-risk patients with trisomies of 4 and 10, without regard to chromosome 17 status, have an excellent prognosis.[94]

      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,[95] 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).[96] 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.[96]

      Near triploidy (68–80 chromosomes) and near tetraploidy (>80 chromosomes) are much less common and appear to be biologically distinct from high hyperdiploidy.[97] Unlike high hyperdiploidy, a high proportion of near tetraploid cases harbor a cryptic ETV6-RUNX1 fusion.[97,98,99] 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.[97,99]

    • Hypodiploidy (<44 chromosomes)

      A significant trend is observed for a progressively worse outcome with a decreasing chromosome number. Cases with 24 to 28 chromosomes (near haploidy) have the worst outcome.[96] Patients with fewer than 44 chromosomes have a worse outcome than patients with 44 or 45 chromosomes in their leukemic cells.[96]

  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.[96] The t(12;21) occurs most commonly in children aged 2 to 9 years.[100,101] Hispanic children with ALL have a lower incidence of t(12;21) than white children.[102]

      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: [103,104,105]

      • Early response to treatment.
      • NCI risk category.
      • 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.[103] There is a higher frequency of late relapses in patients with ETV6-RUNX1 fusion compared with other B-precursor ALL.[103,106] Patients with the ETV6-RUNX1 fusion who relapse seem to have a better outcome than other relapse patients.[107] 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).[108]

    • 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 stem cell transplantation (SCT) in patients in first remission.[95,109,110,111] Inhibitors of the BCR-ABL tyrosine kinase, such as imatinib mesylate, are effective in patients with Ph+ ALL. A study by the COG, which used intensive chemotherapy and concurrent imatinib mesylate given daily, demonstrated a 3-year EFS rate of 80.5%, which was superior to the EFS rate of historical controls in the pre-tyrosine kinase inhibitor (imatinib mesylate) era.[112] Longer follow-up is necessary to determine whether this treatment improves the cure rate or merely prolongs DFS.

    • 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.[54,113,114,115] 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.[113]

      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.[54,113] Irrespective of the type of 11q23 abnormality, infants with leukemia cells that have 11q23 abnormalities have a worse treatment outcome than older patients whose leukemia cells have an 11q23 abnormality.[54,113]

      Of interest, the t(11;19) translocation occurs in approximately 1% of cases and occurs in both early B-lineage and T-cell ALL.[116] 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.[116]

    • 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.[56,57] 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).[51]

      The t(1;19) translocation had been associated with inferior outcome in the context of antimetabolite-based therapy,[117] but the adverse prognostic significance was largely negated by more aggressive multi-agent therapies.[57] However, in a trial conducted by SJCRH on which all patients were treated without cranial radiation, the t(1;19) translocation was associated with a higher risk of CNS relapse.[34]

  3. Other genetic abnormalities
    • Intrachromosomal amplification of chromosome 21 (iAMP21): iAMP21 with multiple extra copies of the RUNX1 (AML1) gene occurs in 1% to 2% of precursor B-cell ALL cases and may be associated with an inferior outcome.[118,119]
    • IKZF1 deletions: Recent application of microarray-based genome-wide analysis of gene expression and DNA copy number, complemented by transcriptional profiling, resequencing, and epigenetic approaches, has identified a specific subset of patients with high-risk B-precursor ALL with a very poor prognosis. These patients have a gene-expression signature similar to patients with BCR-ABL-positive ALL, but lack that translocation. IKZF1 deletions were identified in about 30% of high-risk B-precursor ALL and were significantly associated with a very poor outcome.[120,121,122] A subset of patients with IKZF1 deletions were found to have JAK kinase mutations (about 10% of all high-risk cases), suggesting a possible future therapeutic target.[123]
    • CRLF2 and JAK mutation: Overexpression of CRLF2, a cytokine receptor gene located on the pseudoautosomal regions of the sex chromosomes, has been identified in 5% to 10% of cases of B-precursor ALL.[124,125] Chromosomal abnormalities described in cases with 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 PDRY8-CRLF2 fusion.[124,125,126]CRLF2 abnormalities are strongly associated with the presence of IKZF1 deletions and JAK mutations;[125,126] they are also more common in children with Down syndrome.[125] The results of several retrospective studies suggest that CRLF2 abnormalities may have adverse prognostic significance, although none have established it as an independent predictor of outcome.[124,125,126]
  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.[127,128,129] 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,[130] although such patients may also be at higher risk of developing significant treatment-related toxicities, including myelosuppression and infection.[131,132]

    Genome-wide polymorphism analysis has identified specific single nucleotide polymorphisms associated with high end-induction minimal residual disease (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.[133] Polymorphic variants involving the reduced folate carrier have been linked to methotrexate metabolism, toxicity, and outcome.[134] 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 following onset 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,[135] early response has strong prognostic significance. Various ways of evaluating the leukemia cell response to treatment have been utilized, including the following:

  1. MRD determination.
  2. Day 7 and day 14 bone marrow responses.
  3. Peripheral blood response to steroid prophase.
  4. Peripheral blood response to multiagent induction therapy.
  5. 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.[136]

Multiple studies have demonstrated that end-induction MRD is an important, independent predictor of outcome in children and adolescents with B-lineage ALL.[104,137,138,139] MRD response discriminates outcome in subsets of patients defined by age, leukocyte count, and cytogenetic abnormalities.[140] Patients with higher levels of end-induction MRD have a poorer prognosis than those with lower or undetectable levels.[104,136,137,138,141] 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.[104,136,138,140,141,142,143,144,145]

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).[104]

There are fewer studies documenting the prognostic significance of MRD in T-cell ALL. In the AIEOP-BFM ALL 2000 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.[145]

There are few studies of MRD in the CSF. In one study, MRD was documented in about one-half of children at diagnosis.[146] In this study, CSF MRD was not found to be prognostic when intensive chemotherapy was given.

Although MRD is the most important prognostic factor in determining outcome, there are no data to conclusively show that modifying therapy based on MRD determination significantly improves outcome in newly diagnosed ALL.[140]

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 following initiation of multiagent chemotherapy have a more favorable prognosis than do patients who have slower clearance of leukemia cells from the bone marrow.[147]

Peripheral blood response to steroid prophase

Patients with a reduction in peripheral blast count to less than 1,000/無 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/無 (a poor prednisone response).[17] Poor prednisone response is observed in fewer than 10% of patients.[17,148] 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 prior to the initiation of multiagent remission induction).

Patients with no circulating blasts on day 7 have a better outcome than those patients whose circulating blast level is between 1 and 999/無.[149,150]

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.[151] Rate of clearance of peripheral blasts has been found to be of prognostic significance in both T-cell and B-lineage ALL.[151]

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.[152] Patients at highest risk of induction failure have one or more of the following features:[153,154]

  • 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%.[152] 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 SCT 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 SCT after achieving complete remission than those who received further treatment with chemotherapy alone.

Prognostic (Risk) Groups

Children's Cancer Group (CCG)/Pediatric Oncology Group (POG) risk groups

Former CCG studies made an initial risk assignment of patients older than 1 year as standard risk or high risk based on the NCI consensus age and WBC criteria, regardless of phenotype.[1] The standard-risk category included patients aged 1 to younger than 10 years who had a WBC count at diagnosis less than 50,000/無. The remaining patients were classified as high risk. Final treatment assignment for CCG protocols was based on early response to therapy with slow early responders being treated as high-risk patients.

Former POG studies defined the low-risk group based on the NCI consensus age and WBC criteria and required the absence of adverse translocations, absence of CNS disease and testicular disease, and the presence of either the ETV6-RUNX1 translocation or trisomy of chromosomes 4 and 10. The high-risk group required the absence of favorable translocations and the presence of CNS or testicular involvement, or the presence of MLL gene rearrangement, or unfavorable age and WBC count.[104] The standard-risk category included patients not meeting the criteria for inclusion in any of the other risk group categories. In POG studies, patients with T-cell ALL were treated on different protocols than patients with precursor B-cell ALL. The very high-risk category for CCG and POG was defined by one of the following factors taking precedence over all other considerations: presence of the t(9;22), M3 marrow on day 29 or M2 or M3 marrow on day 43, or hypodiploidy (DNA index <0.95).[96]

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.
  • Presence of extramedullary disease.

EFS rates exceed 85% in children meeting good-risk criteria (aged 1 to <10 years, WBC count <50,000/無, and precursor B-cell immunophenotype); in children meeting high-risk criteria, EFS rates are approximately 70%.[3,34,148,155,156] Additional factors, including cytogenetic abnormalities and measures of early response to therapy (e.g., day 7 and/or day 14 marrow blast percentage and MRD levels at the end of induction), considered in conjunction with presenting age, WBC count, and immunophenotype, can identify patient groups with expected EFS rates ranging from less than 40% to more than 95%.[3,104]

Subgroups of patients who have a poor prognosis with current risk-adapted, multiagent chemotherapy regimens may require different therapeutic approaches. For example, infants with ALL are at much higher risk for treatment failure than older children.[10,157] Infants with ALL are generally treated on separate protocols using more intensified regimens, although the likelihood of long-term EFS appears to be no better than 50% for infants with MLL translocations even with a more intensive therapeutic approach.[9,10,11,157] (Refer to the Infants with ALL section of this summary for information about infants with ALL.)

The following subgroups of patients are sometimes considered candidates for allogeneic SCT in first complete remission (CR1): [9,158,159,160]

  • Infants with MLL translocations.
  • Patients with hypodiploidy.
  • Patients with initial induction failure.
  • Other subsets of patients who have a less than 50% chance of long-term remission with current therapies.

However, because of small numbers, possible patient selection bias, and center preference, studies to definitively show whether transplantation in CR1 is superior to intensive chemotherapy for these very high-risk patients have not been feasible. The use of allogeneic SCT in CR1 for patients with Ph+ ALL is less clear in the era of tyrosine kinase inhibitors.[112]

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:[140]

  • Standard risk: Patients who are MRD-negative 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]
  • Initial CNS status.
  • Genetic abnormalities.
  • Day 8 peripheral blood MRD.
  • Day 29 bone marrow morphologic response and MRD.

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), older than 13 years, and the following unfavorable genetic abnormalities: hypodiploidy (<44 chromosomes), 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. Patients with BCR-ABL (Ph+ ALL) are treated on a separate clinical trial.
  • MRD is assessed by flow cytometry. At day 29, a level of less than 0.01% is considered low risk.

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.
a From the Children's Oncology GroupClassification of Newly Diagnosed ALL protocol.
NCI Risk (Age/WBC)SRSRSRSRSRHR (age <13 y)SRHRHR (age =13 y)SR or HR
Favorable GeneticsYesYesNoYesNoYes or NoNoYes or NoYes or NoYes or No
Unfavorable CharacteristicsNoneNoneNoneNoneNoneNoneNoneNoneNoneYes
Day 8 PB MRD<0.01%=0.01%<1%Any Level=1%Any LevelAny LevelAny LevelAny LevelAny Level
Day 29 Marrow MRDLowLowLowHighLowLowHighHigh<0.01%Any Level
% of Patients (Estimated)15%36%25%24%
Anticipated 5-year EFS>95%90%–95%88%–90%<80%

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: Risk classification is based mainly on MRD level (assessed by flow cytometry) after 6 weeks of remission induction therapy as follows: low risk (<0.01%), standard risk (0.01% – <1%), and high risk (=1%). Patients with early T-cell precursor ALL are also considered to be high risk.[32]

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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