Childhood Acute Lymphoblastic Leukemia Treatment (PDQ®)–Health Professional Version

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Childhood Acute Lymphoblastic Leukemia Treatment (PDQ®)–Health Professional Version

General Information About Childhood Acute Lymphoblastic Leukemia (ALL)

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Cancer in children and adolescents is rare, although the overall incidence of childhood cancer, including ALL, has slowly increased since 1975.[1] Dramatic improvements in survival have been achieved in children and adolescents with cancer.[1–3] Between 1975 and 2020, childhood cancer mortality decreased by more than 50%, although cancer remains the leading cause of death by disease past infancy among children in the United States.[1,2,4,5] For ALL, the 5-year survival rate increased over the same time, from 60% to approximately 90% for children younger than 15 years, and from 28% to more than 75% for adolescents aged 15 to 19 years.[2,3,6] Childhood and adolescent cancer survivors require close monitoring because cancer therapy side effects may persist or develop months or years after treatment. For specific information about the incidence, type, and monitoring of late effects in childhood and adolescent cancer survivors, see Late Effects of Treatment for Childhood Cancer.

Incidence

ALL, the most common cancer diagnosed in children, represents approximately 25% of cancer diagnoses among children younger than 15 years.[7] In the United States, ALL occurs at an annual rate of approximately 40 cases per 1 million people aged 0 to 14 years and approximately 20 cases per 1 million people aged 15 to 19 years.[3] Approximately 3,100 children and adolescents younger than 20 years are diagnosed with ALL each year in the United States.[8] Since 1975, there has been a gradual increase in the incidence of ALL.[2,9]

A sharp peak in ALL incidence is observed among children aged 1 to 4 years (76.3 cases per 1 million per year), with rates decreasing to 23.8 cases per 1 million by age 10 years.[3] The incidence of ALL among children aged 1 to 4 years is approximately fourfold greater than that for infants and for children aged 10 years and older.[3]

The incidence of ALL appears to be highest in American Indian or Alaska Native children and adolescents (43.9 cases per 1 million) and Hispanic children and adolescents (46.8 cases per 1 million).[3,10] The incidence is substantially higher in White children than in Black children, with a twofold higher incidence of ALL from age 1 to 4 years in White children than in Black children.[3]

Anatomy

Childhood ALL originates in the T and B lymphoblasts in tissues with hematopoietic progenitor cells, such as the bone marrow and thymus (see Figure 1).

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

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

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

Almost all patients with ALL present with an M3 marrow.

Morphology

In the past, ALL lymphoblasts were classified using the French-American-British (FAB) criteria as having L1, L2, or L3 morphology.[11] However, it is no longer used because of the lack of independent prognostic significance and the subjective nature of this classification system.

Most cases of ALL that show L3 morphology express surface immunoglobulin (Ig) and have a MYC gene translocation identical to those seen in Burkitt lymphoma (i.e., t(8;14)(q24;q32), t(2;8)) that join MYC to one of the Ig genes. Patients with this specific rare form of leukemia (mature B-cell or Burkitt leukemia) should be treated according to protocols for Burkitt lymphoma. For more information about the treatment of mature B-cell lymphoma/leukemia and Burkitt lymphoma/leukemia, see Childhood Non-Hodgkin Lymphoma Treatment. Rarely, blasts with L1/L2 (not L3) morphology will express surface Ig.[12] These patients should be treated in the same way as patients with B-ALL.[12]

Risk Factors for Developing ALL

The primary accepted risk factors for ALL and associated genes (when relevant) include the following:

  • Prenatal exposure to x-rays.
  • Postnatal exposure to high doses of radiation (e.g., therapeutic radiation previously used for conditions such as tinea capitis and thymus enlargement).
  • Previous treatment with chemotherapy.
  • Genetic conditions that include the following:
    • Down syndrome. For more information, see the Down syndrome section.
    • Neurofibromatosis (NF1).[13]
    • Bloom syndrome (BLM).[14]
    • Fanconi anemia (multiple genes; ALL is observed much less frequently than acute myeloid leukemia [AML]).[15]
    • Ataxia telangiectasia (ATM).[16,17]
    • Li-Fraumeni syndrome (TP53).[18–20]
    • Constitutional mismatch repair deficiency (biallelic variant of MLH1, MSH2, MSH6, and PMS2).[21,22]
  • Low- and high-penetrance inherited genetic variants.[23] For more information, see the Low- and high-penetrance inherited genetic variants section.
  • Carriers of a constitutional Robertsonian translocation that involves chromosomes 15 and 21 and carriers of constitutional ring chromosome 21 are specifically and highly predisposed to developing intrachromosomal amplification of chromosome 21 (iAMP21) ALL.[24,25]

Down syndrome

Children with Down syndrome have an increased risk of developing both ALL and AML,[26–28] with a cumulative risk of developing leukemia of approximately 2.1% by age 5 years and 2.7% by age 30 years.[26,28] These rates represent a 20- to 30-fold increased risk of ALL and over 100-fold increased risk of AML for children with Down syndrome.[27,28]

A genome-wide association study found that four susceptibility loci associated with B-ALL in the non-Down syndrome population (IKZF1, CDKN2A, ARID5B, and GATA3) were also associated with susceptibility to ALL in children with Down syndrome.[29] CDKN2A risk allele penetrance appeared to be higher for children with Down syndrome.

Approximately one-half to two-thirds of cases of acute leukemia in children with Down syndrome are ALL, and about 2% to 3% of childhood ALL cases occur in children with Down syndrome.[30–33] ALL in children with Down syndrome has an age distribution similar to that of ALL in children without Down syndrome, with a median age of 3 to 4 years.[30,31] In contrast, nearly all cases of AML in children with Down syndrome occur before the age of 4 years (median age, 1 year).[34]

Patients with ALL and Down syndrome have a lower incidence of both favorable (ETV6::RUNX1 fusion and hyperdiploidy [51–65 chromosomes]) and unfavorable (BCR::ABL1 or KMT2A::AFF1 fusions and hypodiploidy [<44 chromosomes]) genomic alterations and a near absence of T-cell phenotype.[30–32,34,35]

Approximately 50% to 60% of cases of ALL in children with Down syndrome have genomic alterations affecting CRLF2 that generally result in overexpression of the protein produced by this gene, which dimerizes with the interleukin-7 receptor alpha to form the receptor for the cytokine thymic stromal lymphopoietin.[36–38] The P2RY8::CRLF2 fusion occurs much more commonly than the IGH::CRLF2 fusion in children with Down syndrome, particularly in those of younger age.[38,39] CRLF2 genomic alterations are observed at a much lower frequency (<10%) in children with B-ALL who do not have Down syndrome; when they do occur, they are more often associated with the BCR::ABL1-like subtype.[38,40,41] In one retrospective study, the frequency of CRLF2 rearrangements was nine times higher in children with Down syndrome and ALL than in children with ALL but without Down syndrome (54.2% vs. 6.0%). In that study, only 25% of the cases with CRLF2 rearrangements and Down syndrome were classified as BCR::ABL1-like, compared with 54% of cases with CRLF2 rearrangements without Down syndrome.[42]

Based on the relatively small number of published series, it does not appear that genomic CRLF2 aberrations in patients with Down syndrome and ALL have prognostic relevance.[35,37] However, among patients with Down syndrome and CRLF2 rearrangements, those with the BCR::ABL1 signature appear to have a worse prognosis than those who do not have the BCR::ABL1 fusion.[42]

Approximately 20% to 30% of ALL cases arising in children with Down syndrome have somatically acquired JAK1 or JAK2 variants,[36,37,42–45] which are strongly associated with the presence of CRLF2 rearrangements.[36–38,42] JAK variants are uncommon among younger children with ALL who do not have Down syndrome but are observed more frequently in older children and adolescents with high-risk B-ALL, particularly in those with the BCR::ABL1-like subtype.[46] Preliminary evidence suggests no correlation between JAK2 variant status and 5-year event-free survival (EFS) in children with Down syndrome and ALL.[37,44]

IKZF1 gene deletions, observed in 20% to 35% of patients with Down syndrome and ALL, have been associated with a significantly worse outcome in this group of patients.[37,47,48]

Approximately 10% of patients with Down syndrome and ALL have genomic alterations leading to overexpression or abnormal activation of the CEBPD, CEBPA, and CEBPE genes.[42] Of the CEBP-activated cases with ALL and Down syndrome, approximately 40% also have FLT3 single nucleotide variants or insertions/deletions, compared with 4.1% in cases with Down syndrome and other ALL subtypes.

Low- and high-penetrance inherited genetic variants

Genetic predisposition to ALL can be divided into several broad categories, as follows:

  • Association with genetic syndromes. Increased risk can be associated with the genetic syndromes listed above in which ALL is observed, although it is not the primary manifestation of the condition.
  • Common alleles. Another category for genetic predisposition includes common alleles with relatively small effect sizes that are identified by genome-wide association studies. Genome-wide association studies have identified a number of germline (inherited) genetic polymorphisms that are associated with the development of childhood ALL.[23] For example, the risk alleles of ARID5B are associated with the development of hyperdiploid (51–65 chromosomes) B-ALL. ARID5B is a gene that encodes a transcriptional factor important in embryonic development, cell type–specific gene expression, and cell growth regulation.[49,50] Other genes with polymorphisms associated with increased risk of ALL include GATA3,[51] IKZF1,[49,50,52] CDKN2A,[53] CDKN2B,[52,53] CEBPE,[49] PIP4K2A,[51,54] and TP63.[55]

    Genetic risk factors for T-ALL share some overlap with the genetic risk factors for B-ALL, but unique risk factors also exist. A genome-wide association study identified a risk allele near USP7 that was associated with an increased risk of developing T-ALL (odds ratio, 1.44) but not B-ALL. The risk allele was shown to be associated with reduced USP7 transcription, which is consistent with the finding that somatic loss-of-function variants in USP7 are observed in patients with T-ALL. USP7 germline and somatic variants are generally mutually exclusive and are most commonly observed in T-ALL patients with TAL1 alterations.[56]

    Genetic risk factors that have similar impact for developing both B-ALL and T-ALL include CDKN2A, CDKN2B, and 8q24.21 (cis distal enhancer region variants for MYC).[56]

  • Rare germline variants with high penetrance. Germline variants that cause pathogenic changes in genes associated with ALL and that are observed in kindreds with familial ALL (i.e., large effect sizes) comprise another category of genetic predisposition to ALL. Many of the genes associated with ALL risk play key roles in B-cell development (e.g., PAX5, ETV6, and IKZF1).[57]
    • PAX5. A germline pathogenic variant in PAX5 that substitutes serine for glycine at amino acid 183 and that reduces PAX5 activity has been identified in several families that experienced multiple cases of ALL.[58,59]
    • ETV6. Several germline ETV6 pathogenic variants that lead to loss of ETV6 function have been identified in kindreds affected by both thrombocytopenia and ALL.[60–64] Sequencing of ETV6 in remission (i.e., germline) specimens identified variants that were potentially related to ALL in approximately 1% of children with ALL that were evaluated.[60] Most of the germline pathogenic variants (approximately 75%) were shown to be deleterious for ETV6 function, and 70% of cases with a deleterious germline ETV6 pathogenic variant had a hyperdiploid karyotype. The remaining cases with a deleterious variant had diploid ALL, with a transcriptional profile similar to that of cases with ETV6::RUNX1 fusion–positive ALL.[64]
    • TP53. Germline TP53 pathogenic variants are associated with an increased risk of ALL.[65] A study of 3,801 children with ALL observed that 26 patients (0.7%) had a germline TP53 pathogenic variant, with an associated odds ratio of 5.2 for ALL development.[65] Compared with ALL in children with TP53 wild-type status or TP53 variants of unknown significance, ALL in children with germline TP53 pathogenic variants was associated with older age at diagnosis (15.5 years vs. 7.3 years), hypodiploidy (65% vs. 1%), inferior EFS and overall survival, and a higher risk of second cancers.
    • IKZF1. Germline IKZF1 pathogenic variants were identified in a kindred with familial ALL and in 43 of 4,963 (0.9%) children with sporadic ALL. Most (22 of 28) IKZF1 variants were shown to adversely affect IKZF1 gene function.[66] Germline pathogenic variants in IKZF1 have been identified in hereditary hypogammaglobulinemia. In one series, 2 of 29 affected patients developed B-ALL during childhood.[67]

Prenatal origin of childhood ALL

Development of ALL is a multistep process in most cases, with more than one genomic alteration required for frank leukemia to develop. In at least some cases of childhood ALL, the initial genomic alteration occurs in utero. Evidence to support this comes from the observation that the immunoglobulin or T-cell receptor antigen rearrangements that are unique to each patient’s leukemia cells can be detected in blood samples obtained at birth.[68,69] Similarly, in ALL characterized by specific chromosomal abnormalities, some patients have blood cells that carry at least one leukemic genomic abnormality at the time of birth, with additional cooperative genomic changes acquired postnatally.[68–70] Genomic studies of identical twins with concordant leukemia further support the prenatal origin of some leukemias.[68,71]

Evidence also exists that some children who never develop ALL are born with rare blood cells carrying a genomic alteration associated with ALL. Initial studies focused on the ETV6::RUNX1 translocation and used reverse transcriptase–polymerase chain reaction (PCR) to identify RNA transcripts indicating the presence of the gene fusion. For example, in one study, 1% of neonatal blood spots (Guthrie cards) tested positive for the ETV6::RUNX1 translocation.[72] While subsequent reports generally confirmed the presence of the ETV6::RUNX1 translocation at birth in some children, rates and extent of positivity varied widely.

To more definitively address this question, a highly sensitive and specific DNA-based approach (genomic inverse PCR for exploration of ligated breakpoints) was applied to DNA from 1,000 cord blood specimens and found that 5% of specimens had the ETV6::RUNX1 translocation.[73] When the same method was applied to 340 cord blood specimens to detect the TCF3::PBX1 fusion, two cord specimens (0.6%) were positive for its presence.[74] For both ETV6::RUNX1 and TCF3::PBX1, the percentage of cord blood specimens positive for one of the translocations far exceeds the percentage of children who will develop either type of ALL (<0.01%).

Clinical Presentation

The typical and atypical symptoms and clinical findings of childhood ALL have been published.[75–77]

Diagnosis

The evaluation needed to definitively diagnose childhood ALL has been published.[75–79]

Overall Prognosis

Among children with ALL, approximately 98% attain remission. Approximately 85% of patients aged 1 to 18 years with newly diagnosed ALL treated on current regimens are expected to be long-term event-free survivors, with more than 90% of patients alive at 5 years.[80–83] In one study of patients with newly diagnosed ALL, relapses were rare (occurring in fewer than 1% of patients) by 6 to 7 years after diagnosis.[84] In addition, the excess risk of death associated with the leukemia diagnosis had decreased such that the mortality rate of the surviving patients at 6 to 7 years after diagnosis was similar to that of the general population.

Cytogenetic and genomic findings combined with minimal residual disease (MRD) results can define subsets of ALL with EFS rates exceeding 95% and, conversely, subsets with EFS rates of 50% or lower. For more information, see the sections on Cytogenetics/Genomics of Childhood ALL and Prognostic Factors Affecting Risk-Based Treatment.

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

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

Current Clinical Trials

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

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  63. Rampersaud E, Ziegler DS, Iacobucci I, et al.: Germline deletion of ETV6 in familial acute lymphoblastic leukemia. Blood Adv 3 (7): 1039-1046, 2019. [PUBMED Abstract]
  64. Nishii R, Baskin-Doerfler R, Yang W, et al.: Molecular basis of ETV6-mediated predisposition to childhood acute lymphoblastic leukemia. Blood 137 (3): 364-373, 2021. [PUBMED Abstract]
  65. Qian M, Cao X, Devidas M, et al.: TP53 Germline Variations Influence the Predisposition and Prognosis of B-Cell Acute Lymphoblastic Leukemia in Children. J Clin Oncol 36 (6): 591-599, 2018. [PUBMED Abstract]
  66. Churchman ML, Qian M, Te Kronnie G, et al.: Germline Genetic IKZF1 Variation and Predisposition to Childhood Acute Lymphoblastic Leukemia. Cancer Cell 33 (5): 937-948.e8, 2018. [PUBMED Abstract]
  67. Kuehn HS, Boisson B, Cunningham-Rundles C, et al.: Loss of B Cells in Patients with Heterozygous Mutations in IKAROS. N Engl J Med 374 (11): 1032-1043, 2016. [PUBMED Abstract]
  68. Greaves MF, Wiemels J: Origins of chromosome translocations in childhood leukaemia. Nat Rev Cancer 3 (9): 639-49, 2003. [PUBMED Abstract]
  69. Taub JW, Konrad MA, Ge Y, et al.: High frequency of leukemic clones in newborn screening blood samples of children with B-precursor acute lymphoblastic leukemia. Blood 99 (8): 2992-6, 2002. [PUBMED Abstract]
  70. Bateman CM, Colman SM, Chaplin T, et al.: Acquisition of genome-wide copy number alterations in monozygotic twins with acute lymphoblastic leukemia. Blood 115 (17): 3553-8, 2010. [PUBMED Abstract]
  71. Greaves MF, Maia AT, Wiemels JL, et al.: Leukemia in twins: lessons in natural history. Blood 102 (7): 2321-33, 2003. [PUBMED Abstract]
  72. Mori H, Colman SM, Xiao Z, et al.: Chromosome translocations and covert leukemic clones are generated during normal fetal development. Proc Natl Acad Sci U S A 99 (12): 8242-7, 2002. [PUBMED Abstract]
  73. Schäfer D, Olsen M, Lähnemann D, et al.: Five percent of healthy newborns have an ETV6-RUNX1 fusion as revealed by DNA-based GIPFEL screening. Blood 131 (7): 821-826, 2018. [PUBMED Abstract]
  74. Hein D, Dreisig K, Metzler M, et al.: The preleukemic TCF3-PBX1 gene fusion can be generated in utero and is present in ≈0.6% of healthy newborns. Blood 134 (16): 1355-1358, 2019. [PUBMED Abstract]
  75. Gramatges MM, O’Brien MM, Rabin KR: Acute lymphoblastic leukemia. In: Blaney SM, Helman LJ, Adamson PC, eds.: Pizzo and Poplack’s Pediatric Oncology. 8th ed. Wolters Kluwer, 2020, pp 419-53.
  76. Chessells JM; haemostasis and thrombosis task force, British committee for standards in haematology: Pitfalls in the diagnosis of childhood leukaemia. Br J Haematol 114 (3): 506-11, 2001. [PUBMED Abstract]
  77. Onciu M: Acute lymphoblastic leukemia. Hematol Oncol Clin North Am 23 (4): 655-74, 2009. [PUBMED Abstract]
  78. Margolskee E, Waith Wertheim GB, Harvey RC: Pathology and molecular diagnosis of leukemias and lymphomas. In: Blaney SM, Helman LJ, Adamson PC, eds.: Pizzo and Poplack’s Pediatric Oncology. 8th ed. Wolters Kluwer, 2020, pp 117-30.
  79. Cheng J, Klairmont MM, Choi JK: Peripheral blood flow cytometry for the diagnosis of pediatric acute leukemia: Highly reliable with rare exceptions. Pediatr Blood Cancer 66 (1): e27453, 2019. [PUBMED Abstract]
  80. Möricke A, Zimmermann M, Valsecchi MG, et al.: Dexamethasone vs prednisone in induction treatment of pediatric ALL: results of the randomized trial AIEOP-BFM ALL 2000. Blood 127 (17): 2101-12, 2016. [PUBMED Abstract]
  81. Vora A, Goulden N, Wade R, et al.: Treatment reduction for children and young adults with low-risk acute lymphoblastic leukaemia defined by minimal residual disease (UKALL 2003): a randomised controlled trial. Lancet Oncol 14 (3): 199-209, 2013. [PUBMED Abstract]
  82. Place AE, Stevenson KE, Vrooman LM, et al.: Intravenous pegylated asparaginase versus intramuscular native Escherichia coli L-asparaginase in newly diagnosed childhood acute lymphoblastic leukaemia (DFCI 05-001): a randomised, open-label phase 3 trial. Lancet Oncol 16 (16): 1677-90, 2015. [PUBMED Abstract]
  83. Pieters R, de Groot-Kruseman H, Van der Velden V, et al.: Successful Therapy Reduction and Intensification for Childhood Acute Lymphoblastic Leukemia Based on Minimal Residual Disease Monitoring: Study ALL10 From the Dutch Childhood Oncology Group. J Clin Oncol 34 (22): 2591-601, 2016. [PUBMED Abstract]
  84. Moorman AV, Antony G, Wade R, et al.: Time to Cure for Childhood and Young Adult Acute Lymphoblastic Leukemia Is Independent of Early Risk Factors: Long-Term Follow-Up of the UKALL2003 Trial. J Clin Oncol 40 (36): 4228-4239, 2022. [PUBMED Abstract]

World Health Organization (WHO) Classification System for Childhood ALL

The 5th edition of the WHO Classification of Haematolymphoid Tumours lists the following entities for acute lymphoid leukemias:[1]

WHO 5th Edition Classification of B-Cell Lymphoblastic Leukemias/Lymphomas

  • B-lymphoblastic leukemia/lymphoma, not otherwise specified (NOS).
  • B-lymphoblastic leukemia/lymphoma with high hyperdiploidy.
  • B-lymphoblastic leukemia/lymphoma with iAMP21.
  • B-lymphoblastic leukemia/lymphoma with BCR::ABL1 fusion.
  • B-lymphoblastic leukemia/lymphoma with BCR::ABL1-like features.
  • B-lymphoblastic leukemia/lymphoma with KMT2A rearrangement.
  • B-lymphoblastic leukemia/lymphoma with ETV6::RUNX1 fusion.
  • B-lymphoblastic leukemia/lymphoma with ETV6::RUNX1-like features.
  • B-lymphoblastic leukemia/lymphoma with TCF3::PBX1 fusion.
  • B-lymphoblastic leukemia/lymphoma with IGH::IL3 fusion.
  • B-lymphoblastic leukemia/lymphoma with TCF3::HLF fusion.
  • B-lymphoblastic leukemia/lymphoma with other defined genetic abnormalities.

The category of B-ALL with other defined genetic abnormalities includes potential novel entities, including B-ALL with DUX4, MEF2D, ZNF384 or NUTM1 rearrangements; B-ALL with IG::MYC fusions; and B-ALL with PAX5alt or PAX5 p.P80R (NP_057953.1) abnormalities.

WHO 5th Edition Classification of T-Lymphoblastic Leukemia/Lymphoma

  • T-lymphoblastic leukemia/lymphoma, NOS.
  • Early T-precursor lymphoblastic leukemia/lymphoma.

2016 WHO Classification of Acute Leukemias of Ambiguous Lineage

For acute leukemias of ambiguous lineage, the group of acute leukemias that have characteristics of both acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL), the WHO classification system is summarized in Table 1.[2,3] The criteria for lineage assignment for a diagnosis of mixed phenotype acute leukemia (MPAL) are provided in Table 2.[4]

Table 1. Acute Leukemias of Ambiguous Lineage According to the World Health Organization Classification of Tumors of Hematopoietic and Lymphoid Tissuesa
Condition Definition
MPAL = mixed phenotype acute leukemia; NOS = not otherwise specified.
aAdapted from Béné MC: Biphenotypic, bilineal, ambiguous or mixed lineage: strange leukemias! Haematologica 94 (7): 891-3, 2009.[2] Obtained from Haematologica/the Hematology Journal website http://www.haematologica.org.
Acute undifferentiated leukemia Acute leukemia that does not express any marker considered specific for either lymphoid or myeloid lineage
MPAL with BCR::ABL1 (t(9;22)(q34;q11.2)) Acute leukemia meeting the diagnostic criteria for mixed phenotype acute leukemia in which the blasts also have the (9;22) translocation or the BCR::ABL1 rearrangement
MPAL with KMT2A rearranged (t(v;11q23)) Acute leukemia meeting the diagnostic criteria for mixed phenotype acute leukemia in which the blasts also have a translocation involving the KMT2A gene
MPAL, B/myeloid, NOS (B/M MPAL) Acute leukemia meeting the diagnostic criteria for assignment to both B and myeloid lineage, in which the blasts lack genetic abnormalities involving BCR::ABL1 or KMT2A
MPAL, T/myeloid, NOS (T/M MPAL) Acute leukemia meeting the diagnostic criteria for assignment to both T and myeloid lineage, in which the blasts lack genetic abnormalities involving BCR::ABL1 or KMT2A
MPAL, B/myeloid, NOS—rare types Acute leukemia meeting the diagnostic criteria for assignment to both B and T lineage
Other ambiguous lineage leukemias Natural killer–cell lymphoblastic leukemia/lymphoma
Table 2. Lineage Assignment Criteria for Mixed Phenotype Acute Leukemia According to the 2016 Revision to the World Health Organization Classification of Myeloid Neoplasms and Acute Leukemiaa
Lineage Criteria
aAdapted from Arber et al.[4]
bStrong defined as equal to or brighter than the normal B or T cells in the sample.
Myeloid lineage Myeloperoxidase (flow cytometry, immunohistochemistry, or cytochemistry); or monocytic differentiation (at least two of the following: nonspecific esterase cytochemistry, CD11c, CD14, CD64, lysozyme)
T lineage Strongb cytoplasmic CD3 (with antibodies to CD3 epsilon chain); or surface CD3
B lineage Strongb CD19 with at least one of the following strongly expressed: CD79a, cytoplasmic CD22, or CD10; or weak CD19 with at least two of the following strongly expressed: CD79a, cytoplasmic CD22, or CD10

Leukemias of mixed phenotype may be seen in various presentations, including the following:

  1. Bilineal leukemias in which there are two distinct populations of cells, usually one lymphoid and one myeloid.
  2. Biphenotypic leukemias in which individual blast cells display features of both lymphoid and myeloid lineage.

Biphenotypic cases represent most of the mixed phenotype leukemias.[5] Patients with B-myeloid biphenotypic leukemias lacking the ETV6::RUNX1 fusion have lower rates of complete remission (CR) and significantly worse event-free survival (EFS) rates compared with patients with B-ALL.[5] Cases of MPAL (B/myeloid) that have ZNF384 gene fusions have been reported,[6,7] and a genomic evaluation of MPAL found that ZNF384 gene fusions were present in approximately one-half of B/myeloid cases.[8]

Some studies suggest that patients with biphenotypic leukemia may fare better with a lymphoid, as opposed to a myeloid, treatment regimen.[9–12]; [13][Level of evidence C1] A large retrospective study from the international Berlin-Frankfurt-Münster group demonstrated that initial therapy with an ALL-type regimen was associated with a superior outcome compared with AML-type or combined ALL/AML regimens, particularly in cases with CD19 positivity or other lymphoid antigen expression. In this study, hematopoietic stem cell transplant in first CR was not beneficial, with the possible exception of cases with morphological evidence of persistent marrow disease (≥5% blasts) after the first month of treatment.[12]

For more information about key clinical and biological characteristics, as well as the prognostic significance for these entities, see the Cytogenetics/Genomics of Childhood ALL section.

References
  1. Alaggio R, Amador C, Anagnostopoulos I, et al.: The 5th edition of the World Health Organization Classification of Haematolymphoid Tumours: Lymphoid Neoplasms. Leukemia 36 (7): 1720-1748, 2022. [PUBMED Abstract]
  2. Béné MC: Biphenotypic, bilineal, ambiguous or mixed lineage: strange leukemias! Haematologica 94 (7): 891-3, 2009. [PUBMED Abstract]
  3. Borowitz MJ, Béné MC, Harris NL: Acute leukaemias of ambiguous lineage. In: Swerdlow SH, Campo E, Harris NL, et al., eds.: WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. 4th ed. International Agency for Research on Cancer, 2008, pp 150-5.
  4. Arber DA, Orazi A, Hasserjian R, et al.: The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia. Blood 127 (20): 2391-405, 2016. [PUBMED Abstract]
  5. Gerr H, Zimmermann M, Schrappe M, et al.: Acute leukaemias of ambiguous lineage in children: characterization, prognosis and therapy recommendations. Br J Haematol 149 (1): 84-92, 2010. [PUBMED Abstract]
  6. Shago M, Abla O, Hitzler J, et al.: Frequency and outcome of pediatric acute lymphoblastic leukemia with ZNF384 gene rearrangements including a novel translocation resulting in an ARID1B/ZNF384 gene fusion. Pediatr Blood Cancer 63 (11): 1915-21, 2016. [PUBMED Abstract]
  7. Yao L, Cen J, Pan J, et al.: TAF15-ZNF384 fusion gene in childhood mixed phenotype acute leukemia. Cancer Genet 211: 1-4, 2017. [PUBMED Abstract]
  8. Alexander TB, Gu Z, Iacobucci I, et al.: The genetic basis and cell of origin of mixed phenotype acute leukaemia. Nature 562 (7727): 373-379, 2018. [PUBMED Abstract]
  9. Rubnitz JE, Onciu M, Pounds S, et al.: Acute mixed lineage leukemia in children: the experience of St Jude Children’s Research Hospital. Blood 113 (21): 5083-9, 2009. [PUBMED Abstract]
  10. Al-Seraihy AS, Owaidah TM, Ayas M, et al.: Clinical characteristics and outcome of children with biphenotypic acute leukemia. Haematologica 94 (12): 1682-90, 2009. [PUBMED Abstract]
  11. Matutes E, Pickl WF, Van’t Veer M, et al.: Mixed-phenotype acute leukemia: clinical and laboratory features and outcome in 100 patients defined according to the WHO 2008 classification. Blood 117 (11): 3163-71, 2011. [PUBMED Abstract]
  12. Hrusak O, de Haas V, Stancikova J, et al.: International cooperative study identifies treatment strategy in childhood ambiguous lineage leukemia. Blood 132 (3): 264-276, 2018. [PUBMED Abstract]
  13. Orgel E, Alexander TB, Wood BL, et al.: Mixed-phenotype acute leukemia: A cohort and consensus research strategy from the Children’s Oncology Group Acute Leukemia of Ambiguous Lineage Task Force. Cancer 126 (3): 593-601, 2020. [PUBMED Abstract]

Cytogenetics/Genomics of Childhood ALL

Genomics of childhood ALL

The genomics of childhood acute lymphoblastic leukemia (ALL) has been extensively investigated, and multiple distinctive subtypes have been defined on the basis of cytogenetic and molecular characterizations, each with its own pattern of clinical and prognostic characteristics.[1,2] The discussion of the genomics of childhood ALL below is divided into three sections: the genomic alterations associated with B-ALL, followed by the genomic alterations associated with T-ALL and mixed phenotype acute leukemia (MPAL). Figures 2, 3, and 5 illustrate the distribution of B-ALL (stratified by National Cancer Institute [NCI] standard- and high-risk B-ALL) and T-ALL cases by cytogenetic/molecular subtypes.[1]

Throughout this section, the percentages of genomic subtypes from among all B-ALL and T-ALL cases are derived primarily from a report describing the genomic characterization of patients treated on several Children’s Oncology Group (COG) and St. Jude Children’s Research Hospital (SJCRH) clinical trials. Percentages by subtype are presented for NCI standard-risk and NCI high-risk patients with B-ALL (up to age 18 years).[1]

B-ALL cytogenetics/genomics

B-ALL is typified by genomic alterations that include: 1) gene fusions that lead to aberrant activity of transcription factors, 2) chromosomal gains and losses (e.g., hyperdiploidy or hypodiploidy), and 3) alterations leading to activation of tyrosine kinase genes.[1] Figures 2 and 3 illustrate the distribution of NCI standard-risk and high-risk B-ALL cases by 23 cytogenetic/molecular subtypes.[1] The two most common subtypes (hyperdiploid and ETV6::RUNX1 fusion) together account for approximately 60% of NCI standard-risk B-ALL cases, but only approximately 25% of NCI high-risk cases. Most other subtypes are much less common, with most occurring at frequencies less than 2% to 3% of B-ALL cases. The molecular and clinical characteristics of some of the subtypes are discussed below.

EnlargePie chart showing genomic subtypes and frequencies of NCI standard-risk B-ALL.
Figure 2. Genomic subtypes and frequencies of NCI standard-risk B-ALL. The figure represents data from 1,126 children diagnosed with NCI standard-risk B-ALL (aged 1–9 years and WBC <50,000/µL) and enrolled in St. Jude Children’s Research Hospital or Children’s Oncology Group clinical trials. Adapted from Supplemental Table 2 of Brady SW, Roberts KG, Gu Z, et al.: The genomic landscape of pediatric acute lymphoblastic leukemia. Nature Genetics 54: 1376-1389, 2022.
EnlargePie chart showing genomic subtypes and frequencies of NCI high-risk B-ALL.
Figure 3. Genomic subtypes and frequencies of NCI high-risk B-ALL. The figure represents data from 1,084 children diagnosed with NCI high-risk B-ALL (aged 1–18 years and WBC >50,000/µL) and enrolled in St. Jude Children’s Research Hospital or Children’s Oncology Group clinical trials. Adapted from Supplemental Table 2 of Brady SW, Roberts KG, Gu Z, et al.: The genomic landscape of pediatric acute lymphoblastic leukemia. Nature Genetics 54: 1376-1389, 2022.

The genomic landscape of B-ALL is characterized by a range of genomic alterations that disrupt normal B-cell development and, in some cases, by variants in genes that provide a proliferation signal (e.g., activating variants in RAS family genes or variants/translocations leading to kinase pathway signaling). Genomic alterations leading to blockage of B-cell development include translocations (e.g., TCF3::PBX1 and ETV6::RUNX1 fusions), single nucleotide variants (e.g., IKZF1 and PAX5), and intragenic/intergenic deletions (e.g., IKZF1, PAX5, EBF, and ERG).[3]

The genomic alterations in B-ALL tend not to occur at random, but rather to cluster within subtypes that can be delineated by biological characteristics such as their gene expression profiles. Cases with recurring chromosomal translocations (e.g., TCF3::PBX1 and ETV6::RUNX1 fusions and KMT2A-rearranged ALL) have distinctive biological features and illustrate this point, as do the examples below of specific genomic alterations within unique biological subtypes:

  • IKZF1 deletions and variants are most commonly observed within cases of BCR::ABL1 ALL and BCR::ABL1-like ALL.[4,5]
  • Intragenic ERG deletions occur within a distinctive subtype characterized by gene rearrangements involving DUX4.[6,7]
  • TP53 variants, often germline and pathogenic, occur at high frequency in patients with low hypodiploid ALL with 32 to 39 chromosomes.[8] TP53 variants are uncommon in other patients with B-ALL.

Activating single nucleotide variants in kinase genes are uncommon in high-risk B-ALL. JAK genes are the primary kinases that are found to be altered. These variants are generally observed in patients with BCR::ABL1-like ALL who have CRLF2 abnormalities, although JAK2 variants are also observed in approximately 25% of children with Down syndrome and ALL, occurring exclusively in cases with CRLF2 gene rearrangements.[5,9–11] Several kinase genes and cytokine receptor genes are activated by translocations, as described below in the discussion of BCR::ABL1 ALL and BCR::ABL1-like ALL. FLT3 variants occur in a minority of cases (approximately 10%) of hyperdiploid ALL and KMT2A-rearranged ALL, and are rare in other subtypes.[12]

Understanding of the genomics of B-ALL at relapse is less advanced than the understanding of ALL genomics at diagnosis. Childhood ALL is often polyclonal at diagnosis and under the selective influence of therapy, some clones may be extinguished and new clones with distinctive genomic profiles may arise.[13] However, molecular subtype–defining lesions such as translocations and aneuploidy are almost always retained at relapse.[1,13] Of particular importance are new variants that arise at relapse that may be selected by specific components of therapy. As an example, variants in NT5C2 are not found at diagnosis, whereas specific variants in NT5C2 were observed in 7 of 44 (16%) and 9 of 20 (45%) cases of B-ALL with early relapse that were evaluated for this variant in two studies.[13,14] NT5C2 variants are uncommon in patients with late relapse, and they appear to induce resistance to mercaptopurine and thioguanine.[14] Another gene that is found altered only at relapse is PRSP1, a gene involved in purine biosynthesis.[15] Variants were observed in 13.0% of a Chinese cohort and 2.7% of a German cohort, and were observed in patients with on-treatment relapses. The PRSP1 variants observed in relapsed cases induce resistance to thiopurines in leukemia cell lines. CREBBP variants are also enriched at relapse and appear to be associated with increased resistance to glucocorticoids.[13,16] With increased understanding of the genomics of relapse, it may be possible to tailor upfront therapy to avoid relapse or detect resistance-inducing variants early and intervene before a frank relapse.

Several recurrent chromosomal abnormalities have been shown to have prognostic significance, especially in B-ALL. Some chromosomal alterations are associated with more favorable outcomes, such as favorable trisomies (51–65 chromosomes) and the ETV6::RUNX1 fusion.[17][Level of evidence B4] Other alterations historically have been associated with a poorer prognosis, including the BCR::ABL1 fusion (Philadelphia chromosome–positive [Ph+]; t(9;22)(q34;q11.2)), rearrangements of the KMT2A gene, hypodiploidy, and intrachromosomal amplification of the RUNX1 gene (iAMP21).[18]

In recognition of the clinical significance of many of these genomic alterations, the 5th edition revision of the World Health Organization Classification of Haematolymphoid Tumours lists the following entities for B-ALL:[19]

  • B-lymphoblastic leukemia/lymphoma, NOS.
  • B-lymphoblastic leukemia/lymphoma with high hyperdiploidy.
  • B-lymphoblastic leukemia/lymphoma with hypodiploidy.
  • B-lymphoblastic leukemia/lymphoma with iAMP21.
  • B-lymphoblastic leukemia/lymphoma with BCR::ABL1 fusion.
  • B-lymphoblastic leukemia/lymphoma with BCR::ABL1-like features.
  • B-lymphoblastic leukemia/lymphoma with KMT2A rearrangement.
  • B-lymphoblastic leukemia/lymphoma with ETV6::RUNX1 fusion.
  • B-lymphoblastic leukemia/lymphoma with ETV6::RUNX1-like features.
  • B-lymphoblastic leukemia/lymphoma with TCF3::PBX1 fusion.
  • B-lymphoblastic leukemia/lymphoma with IGH::IL3 fusion.
  • B-lymphoblastic leukemia/lymphoma with TCF3::HLF fusion.
  • B-lymphoblastic leukemia/lymphoma with other defined genetic abnormalities.

The category of B-ALL with other defined genetic abnormalities includes potential novel entities, including B-ALL with DUX4, MEF2D, ZNF384 or NUTM1 rearrangements; B-ALL with IG::MYC fusions; and B-ALL with PAX5alt or PAX5 p.P80R (NP_057953.1) abnormalities.

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

  1. Chromosome number.
    • High hyperdiploidy (51–65 chromosomes).

      High hyperdiploidy, defined as 51 to 65 chromosomes per cell or a DNA index greater than 1.16, occurs in approximately 33% of NCI standard-risk and 14% of NCI high-risk pediatric B-ALL cases.[1,20] 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 fluorescence in situ hybridization (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 white blood cell [WBC] count) and is an independent favorable prognostic factor.[20–22] Within the hyperdiploid range of 51 to 65 chromosomes, patients with higher modal numbers (58–66) appeared to have a better prognosis in one study.[22] Hyperdiploid leukemia cells are particularly susceptible to undergoing apoptosis and accumulate higher levels of methotrexate and its active polyglutamate metabolites,[23] 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.[24–26]

      Multiple reports have described the prognostic significance of specific chromosome trisomies among children with hyperdiploid B-ALL.

      • A study combining experience from the Children’s Cancer Group and the Pediatric Oncology Group (POG) found that patients with trisomies of chromosomes 4, 10, and 17 (triple trisomies) have a particularly favorable outcome.[27]; [17][Level of evidence B4]
      • A report using POG data found that NCI standard-risk patients with trisomies of 4 and 10, without regard to chromosome 17 status, have an excellent prognosis.[28] COG protocols currently use double trisomies of chromosomes 4 and 10 to define favorable hyperdiploidy.
      • A retrospective analysis evaluated patients treated on two consecutive UKALL trials to identify and validate a profile to predict outcome in high hyperdiploid B-ALL. The investigators defined a good-risk group (approximately 80% of high hyperdiploidy patients) that was associated with a more favorable prognosis. Good-risk patients had either trisomies of both chromosomes 17 and 18 or trisomy of one of these two chromosomes along with absence of trisomies of chromosomes 5 and 20. All other patients were defined as poor risk and had a less favorable outcome. End-induction MRD and copy number alterations (such as IKZF1 deletion) were prognostically significant within each hyperdiploid risk group.[29]

      Chromosomal translocations may be seen with high hyperdiploidy, and in those cases, patients are more appropriately risk-classified on the basis of the prognostic significance of the translocation. For instance, in one study, 8% of patients with the BCR::ABL1 fusion also had high hyperdiploidy,[30] and the outcome of these patients (treated without tyrosine kinase inhibitors) was inferior to that observed in non-BCR::ABL1 high hyperdiploid patients.

      Certain patients with hyperdiploid ALL may have a hypodiploid clone that has doubled (masked hypodiploidy).[31] Molecular technologies, such as single nucleotide polymorphism microarrays to detect widespread loss of heterozygosity, can be used to identify patients with masked hypodiploidy.[31] These cases may be interpretable based on the pattern of gains and losses of specific chromosomes (hyperdiploidy with two and four copies of chromosomes rather than three copies). These patients have an unfavorable outcome, similar to those with hypodiploidy.[32]

      Near triploidy (68–80 chromosomes) and near tetraploidy (>80 chromosomes) are much less common and appear to be biologically distinct from high hyperdiploidy.[33] Unlike high hyperdiploidy, a high proportion of near tetraploid cases harbor a cryptic ETV6::RUNX1 fusion.[33–35] 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.[33,35]

      The genomic landscape of hyperdiploid ALL is characterized by variants in genes of the receptor tyrosine kinase (RTK)/RAS pathway in approximately one-half of cases. Genes encoding histone modifiers are also present in a recurring manner in a minority of cases. Analysis of variant profiles demonstrates that chromosomal gains are early events in the pathogenesis of hyperdiploid ALL and may occur in utero, while variants in RTK/RAS pathway genes are late events in leukemogenesis and are often subclonal.[1,36]

    • Hypodiploidy (<44 chromosomes).

      B-ALL cases with fewer than the normal number of chromosomes have been subdivided in various ways, with one report stratifying on the basis of modal chromosome number into the following four groups:[32]

      • 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).

      Near-haploid cases represent approximately 2% of NCI standard-risk and 2% of NCI high-risk pediatric B-ALL.[1]

      Low-hypodiploid cases represent approximately 0.5% of NCI standard-risk and 2.6% of NCI high-risk pediatric B-ALL cases.[1]

      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.[32,37] Patients with fewer than 44 chromosomes have a worse outcome than do patients with 44 or 45 chromosomes in their leukemic cells.[32] Several studies have shown that patients with high minimal residual disease (MRD) (≥0.01%) after induction do very poorly, with 5-year event-free survival (EFS) rates ranging from 25% to 47%. Although hypodiploid patients with low MRD after induction fare better (5-year EFS rates, 64%–75%), their outcomes are still inferior to most children with other types of ALL.[38–40]

      The recurring genomic alterations of near-haploid and low-hypodiploid ALL appear to be distinctive from each other and from other types of ALL.[8] In near-haploid ALL, alterations targeting RTK signaling, RAS signaling, and IKZF3 are common.[41] 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 variants are germline pathogenic and that low-hypodiploid ALL represents, in some cases, a manifestation of Li-Fraumeni syndrome.[8] Approximately two-thirds of patients with ALL and germline TP53 pathogenic variants have hypodiploid ALL.[42]

  2. Chromosomal translocations and gains/deletions of chromosomal segments.
    • ETV6::RUNX1 fusion (t(12;21)(p13.2;q22.1)).

      Fusion of the ETV6 gene on chromosome 12 to the RUNX1 gene on chromosome 21 is present in approximately 27% of NCI standard-risk and 10% of NCI high-risk pediatric B-ALL cases.[1,34]

      The ETV6::RUNX1 fusion produces a cryptic translocation that is detected by methods such as FISH, rather than conventional cytogenetics, and it occurs most commonly in children aged 2 to 9 years.[43,44] Hispanic children with ALL have a lower incidence of ETV6::RUNX1 fusions than do White children.[45]

      Reports generally indicate favorable EFS and overall survival (OS) rates in children with the ETV6::RUNX1 fusion; however, the prognostic impact of this genetic feature is modified by the following factors:[26,46–50]; [17][Level of evidence B4]

      • 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 fusion status, to be independent prognostic factors.[46] However, another large trial only enrolled patients classified as having favorable-risk B-ALL, with low-risk clinical features, either trisomies of 4, 10, and 17 or ETV6::RUNX1 fusion, and end induction MRD less than 0.01%. Patients had a 5-year continuous complete remission rate of 93.7% and a 6-year OS rate of 98.2% for patients with ETV6::RUNX1.[17] 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.[50,51]

      There is a higher frequency of late relapses in patients with ETV6::RUNX1 fusions compared with other relapsed B-ALL patients.[46,52] Patients with the ETV6::RUNX1 fusion who relapse seem to have a better outcome than other relapse patients,[53] with an especially favorable prognosis for patients who relapse more than 36 months from diagnosis.[54] Some relapses in patients with ETV6::RUNX1 fusions may represent a new independent second hit in a persistent preleukemic clone (with the first hit being the ETV6::RUNX1 translocation).[55,56]

    • BCR::ABL1 fusion (t(9;22)(q34.1;q11.2); Ph+).

      The BCR::ABL1 fusion leads to production of a BCR::ABL1 fusion protein with tyrosine kinase activity (see Figure 4).[1] The BCR::ABL1 fusion occurs in approximately 2% of NCI standard-risk and 5% of NCI high-risk pediatric B-ALL cases.[1] The BCR::ABL1 fusion is also the leukemogenic driver for chronic myeloid leukemia (CML). The most common BCR breakpoint in CML is different from the most common BCR breakpoint in ALL. The breakpoint that typifies CML produces a larger fusion protein (termed p210) than the breakpoint most commonly observed for ALL (termed p190, a smaller fusion protein).

      EnlargePhiladelphia 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 ABL1 gene and a normal chromosome 22 with the BCR gene. In the center panel, the drawing shows part of the ABL1 gene breaking off from chromosome 9 and a piece of chromosome 22 breaking off, below the BCR gene. In the right panel, the drawing shows chromosome 9 with the piece from chromosome 22 attached. It also shows a shortened version of chromosome 22 with the piece from chromosome 9 containing part of the ABL1 gene attached. The ABL1 gene joins to the BCR gene on chromosome 22 to form the BCR::ABL1 fusion gene. The changed chromosome 22 with the BCR::ABL1 fusion gene on it is called the Philadelphia chromosome.
      Figure 4. The Philadelphia chromosome is a translocation between the ABL1 oncogene (on the long arm of chromosome 9) and the BCR gene (on the long arm of chromosome 22), resulting in the fusion gene BCR::ABL1. BCR::ABL1 encodes an oncogenic protein with tyrosine kinase activity.

      Ph+ ALL is more common in older children with B-ALL and high WBC counts, with the incidence of the BCR::ABL1 fusions increasing to about 25% in young adults with ALL.

      Historically, the BCR::ABL1 fusion 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 transplant (HSCT) in patients in first remission.[30,57–59] Inhibitors of the BCR::ABL1 tyrosine kinase, such as imatinib mesylate, are effective in patients with BCR::ABL1 ALL.[60] A study by the Children’s Oncology Group (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. This result eliminated the recommendation of HSCT for patients with a good early response to chemotherapy using a tyrosine kinase inhibitor.[61,62]

      The International Consensus Classification of acute lymphoblastic leukemia/lymphoma from 2022 divides BCR::ABL1–positive B-ALL into two subtypes: cases with lymphoid-only involvement and cases with multilineage involvement.[63] These subtypes differ in the timing of their transformation event. A multipotent progenitor serves as the target cell of origin for BCR::ABL1–positive B-ALL with multilineage involvement, and a later progenitor is the target cell of origin for BCR::ABL1–positive B-ALL with lymphoid-only involvement.

      • BCR::ABL1–positive B-ALL with lymphoid-only involvement is the predominate subtype. Only a minority of cases in children and adults have multilineage involvement (estimated at 15%–30%).[64]
      • BCR::ABL1–positive B-ALL cases with lymphoid-only involvement and cases with multilineage involvement have similar clinical presentations and immunophenotypes. In addition, both subtypes commonly have the p190 fusion protein.[64,65]
      • One way of distinguishing between patients with lymphoid-only and multilineage involvement is to detect the BCR::ABL1 fusion in normal non-ALL B cells, T cells, and myeloid cells.[65]
      • A second way of distinguishing between patients with lymphoid-only and multilineage involvement is to detect quantitative differences in MRD levels (typically 1 log) using measures that quantify BCR::ABL1 DNA or RNA, compared with measures based on flow cytometry, real-time quantitative polymerase chain reaction (PCR), or next-generation sequencing (NGS) quantitation of leukemia-specific immunoglobulin (IG) or T-cell receptor (TCR) rearrangements.[64–66]
        • For patients with lymphoid-only BCR::ABL1–positive B-ALL, MRD estimates for these methods will be correlated with each other.
        • For patients with multilineage involvement BCR::ABL1–positive B-ALL, posttreatment MRD estimates based on detection of BCR::ABL1 DNA or RNA will often be higher than estimates based on flow cytometry or quantitation of leukemia-specific IG/TCR rearrangements.
      • For patients with BCR::ABL1–positive B-ALL and multilineage involvement, levels of BCR::ABL1 transcripts and DNA may remain stable over time despite continued treatment with chemotherapy and tyrosine kinase inhibitors. In these situations, the persisting BCR::ABL1 DNA or RNA likely represents evidence of a residual preleukemic clone and not leukemia cells. Therefore, the term MRD is a misnomer.
      • A corollary of the difference in MRD detection by methods based on BCR::ABL1 DNA or RNA detection versus MRD detection based on flow cytometry or IG/TCR rearrangements is that the latter methods provide more reliable prognostication.[64,66,67] For example, the presence of MRD by BCR::ABL1 DNA or RNA detection in the absence of MRD detection by IG/TCR rearrangements does not confer inferior prognosis.
      • Based on the limited numbers of patients studied to date, prognosis appears similar in both adults and children with lymphoid-only versus multilineage involvement BCR::ABL1–positive B-ALL.[64,66]
      • There are case reports of patients with multilineage involvement BCR::ABL1–positive B-ALL who relapse years from their initial diagnosis. In addition, their relapsed leukemia has the same BCR::ABL1 breakpoint as their initial leukemia, but it has a different IG/TCR rearrangement.[66] These case reports suggest that patients with multilineage BCR::ABL1–positive B-ALL are at risk of a second leukemogenic event, leading to a second BCR::ABL1 leukemia.
      • There is no evidence that a specific monitoring schedule or prolonged treatment with a tyrosine kinase inhibitor provides clinical benefit for patients with multilineage involvement BCR::ABL1–positive B-ALL who have maintained presence of BCR::ABL1 transcripts or DNA at the completion of a standard-duration course of leukemia therapy.
    • KMT2A-rearranged ALL (t(v;11q23.3)).

      Rearrangements involving the KMT2A gene with more than 100 translocation partner genes result in the production of fusion oncoproteins. KMT2A gene rearrangements occur in up to 80% of infants with ALL. Beyond infancy, approximately 1% of NCI standard-risk and 4% of NCI high-risk pediatric B-ALL cases have KMT2A rearrangements.[1]

      These rearrangements are generally associated with an increased risk of treatment failure, particularly in infants.[68–71] The KMT2A::AFF1 fusion (t(4;11)(q21;q23)) is the most common rearrangement involving the KMT2A gene in children with ALL and occurs in approximately 1% to 2% of childhood ALL.[69,72]

      Patients with KMT2A::AFF1 fusions are usually infants with high WBC counts. These patients are more likely than other children with ALL to have central nervous system (CNS) disease and to have a poor response to initial therapy.[73] While both infants and adults with the KMT2A::AFF1 fusion are at high risk of treatment failure, children with the KMT2A::AFF1 fusion appear to have a better outcome.[68,69,74] Irrespective of the type of KMT2A gene rearrangement, infants with KMT2A-rearranged ALL have much worse event-free survival rates than non-infant pediatric patients with KMT2A-rearranged ALL.[68,69,74]

      Whole-genome sequencing has determined that cases of infant ALL with KMT2A gene rearrangements have frequent subclonal NRAS or KRAS variants and few additional genomic alterations, none of which have clear clinical significance.[12,75] Deletion of the KMT2A gene has not been associated with an adverse prognosis.[76]

      Of interest, the KMT2A::MLLT1 fusion (t(11;19)(q23;p13.3)) occurs in approximately 1% of ALL cases and occurs in both early B-lineage ALL and T-ALL.[77] Outcome for infants with the KMT2A::MLLT1 fusion is poor, but outcome appears relatively favorable in older children with T-ALL and the KMT2A::MLLT1 fusion.[77]

    • TCF3::PBX1 fusion (t(1;19)(q23;p13.3)) and TCF3::HLF fusion (t(17;19)(q22;p13)).

      Fusion of the TCF3 gene on chromosome 19 to the PBX1 gene on chromosome 1 is present in approximately 4% of NCI standard-risk and 5% of NCI high-risk pediatric B-ALL cases.[1,78,79] The TCF3::PBX1 fusion may occur as either a balanced translocation or as an unbalanced translocation and is the primary recurring genomic alteration of the pre-B–ALL immunophenotype (cytoplasmic immunoglobulin positive).[80] Black children are relatively more likely than White children to have pre-B–ALL with the TCF3::PBX1 fusion.[81]

      The TCF3::PBX1 fusion had been associated with inferior outcome in the context of antimetabolite-based therapy,[82] but the adverse prognostic significance was largely negated by more aggressive multiagent therapies.[79,83] More specifically, in a trial conducted by St. Jude Children’s Research Hospital (SJCRH) in which all patients were treated without cranial radiation, patients with the TCF3::PBX1 fusion had an overall outcome comparable to children lacking this translocation, but 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.[84,85]

      The TCF3::HLF fusion occurs in less than 1% of pediatric ALL cases. ALL with the TCF3::HLF fusion is associated with disseminated intravascular coagulation and hypercalcemia at diagnosis. Outcome is very poor for children with the TCF3::HLF fusion, with a literature review noting mortality for 20 of 21 cases reported.[86] In addition to the TCF3::HLF fusion, the genomic landscape of this ALL subtype was characterized by deletions in genes involved in B-cell development (PAX5, BTG1, and VPREB1) and by variants in RAS pathway genes (NRAS, KRAS, and PTPN11).[80]

    • DUX4-rearranged ALL with frequent ERG deletions.

      Approximately 3% of NCI standard-risk and 6% of NCI high-risk pediatric B-ALL patients have a rearrangement involving DUX4 that leads to its overexpression.[1,6,7] East Asian ancestry was linked to an increased prevalence of DUX4-rearranged ALL (favorable).[87] The most common rearrangement produces IGH::DUX4 fusions, with ERG::DUX4 fusions also observed.[88] DUX4-rearranged cases show a distinctive gene expression pattern that was initially identified as being associated with focal deletions in ERG,[88–91] and one-half to more than two-thirds of these cases have focal intragenic deletions involving ERG that are not observed in other ALL subtypes.[6,88] ERG deletions often appear to be clonal, but using sensitive detection methodology, it appears that most cases are polyclonal.[88] IKZF1 alterations are observed in 20% to 40% of DUX4-rearranged ALL.[6,7]

      ERG deletion connotes an excellent prognosis, with OS rates exceeding 90%. Even when the IZKF1 deletion is present, prognosis remains highly favorable.[89–92] While patients with DUX4-rearranged ALL have an overall favorable prognosis, there is uncertainty as to whether this applies to both ERG-deleted and ERG-intact cases. In a study of 50 patients with DUX4-rearranged ALL, patients with an ERG deletion detected by genomic PCR (n = 33) had a more favorable EFS rate of approximately 90% than did patients with intact ERG (n = 17), with an EFS rate of approximately 70%.[90]

    • MEF2D-rearranged ALL.

      Gene fusions involving MEF2D, a transcription factor that is expressed during B-cell development, are observed in approximately 0.3% of NCI standard-risk and 3% of NCI high-risk pediatric B-ALL cases.[1,93,94]

      Although multiple fusion partners may occur, most cases involve BCL9, which is located on chromosome 1q21, as is MEF2D.[93,95] The interstitial deletion producing the MEF2D::BCL9 fusion is too small to be detected by conventional cytogenetic methods. Cases with MEF2D gene fusions show a distinctive gene expression profile, except for rare cases with MEF2D::CSFR1 that have a BCR::ABL1-like gene expression profile.[93,96]

      The median age at diagnosis for cases of MEF2D-rearranged ALL in studies that included both adult and pediatric patients was 12 to 14 years.[93,94] For 22 children with MEF2D-rearranged ALL enrolled in a high-risk ALL clinical trial, the 5-year EFS rate was 72% (standard error, ± 10%), which was inferior to that for other patients.[93]

    • ZNF384-rearranged ALL.

      ZNF384 is a transcription factor that is rearranged in approximately 0.3% of NCI standard-risk and 2.7% of NCI high-risk pediatric B-ALL cases.[1,93,97,98]

      East Asian ancestry was associated with an increased prevalence of ZNF384.[87] Multiple fusion partners for ZNF384 have been reported, including ARID1B, CREBBP, EP300, SMARCA2, TAF15, and TCF3. Regardless of the fusion partner, ZNF384-rearranged ALL cases show a distinctive gene expression profile.[93,97,98] ZNF384 rearrangement does not appear to confer independent prognostic significance.[93,97,98] However, within the subset of patients with ZNF384 rearrangements, patients with EP300::ZNF384 fusions have lower relapse rates than patients with other ZNF384 fusion partners.[99] The immunophenotype of B-ALL with ZNF384 rearrangement is characterized by weak or negative CD10 expression, with expression of CD13 and/or CD33 commonly observed.[97,98] Cases of mixed phenotype acute leukemia (MPAL) (B/myeloid) that have ZNF384 gene fusions have been reported,[100,101] and a genomic evaluation of MPAL found that ZNF384 gene fusions were present in approximately one-half of B/myeloid cases.[102]

    • NUTM1-rearranged B-ALL.

      NUTM1-rearranged B-ALL is most commonly observed in infants, representing 3% to 5% of overall cases of B-ALL in this age group and approximately 20% of infant B-ALL cases lacking the KMT2A rearrangement.[103] The frequency of NUTM1 rearrangement is lower in children after infancy (<1% of cases).[1,103]

      The NUTM1 gene is located on chromosome 15q14, and some cases of B-ALL with NUTM1 rearrangements show chromosome 15q aberrations, but other cases are cryptic and have no cytogenetic abnormalities.[104] RNA sequencing, as well as break-apart FISH, can be used to detect the presence of the NUTM1 rearrangement.[103]

      The NUTM1 rearrangement appears to be associated with a favorable outcome.[103,105] Among 35 infants with NUTM1-rearranged B-ALL who were treated on Interfant protocols, all patients achieved remission and no relapses were observed.[103] For the 32 children older than 12 months with NUTM1-rearranged B-ALL, the 4-year EFS and OS rates were 92% and 100%, respectively.

    • IGH::IL3 fusion (t(5;14)(q31.1;q32.3)).

      This entity is included in the 2016 revision of the World Health Organization (WHO) classification of tumors of the hematopoietic and lymphoid tissues.[106] The finding of t(5;14)(q31.1;q32.3) in patients with ALL and hypereosinophilia in the 1980s was followed by the identification of the IGH::IL3 fusion as the underlying genetic basis for the condition.[107,108] The joining of the IGH locus to the promoter region of the IL3 gene leads to dysregulation of IL3 expression.[109] Cytogenetic abnormalities in children with ALL and eosinophilia are variable, with only a subset resulting from the IGH::IL3 fusion.[110]

      The number of cases of IGH::IL3 ALL described in the published literature is too small to assess the prognostic significance of the IGH::IL3 fusion. Diagnosis of cases of IGH::IL3 ALL may be delayed because the ALL clone in the bone marrow may be small, and because it can present with hypereosinophilia in the absence of cytopenias and circulating blasts.[106]

    • Intrachromosomal amplification of chromosome 21 (iAMP21).

      iAMP21 occurs in approximately 5% of NCI standard-risk and 7% of NCI high-risk pediatric B-ALL cases.[1] iAMP21 is generally diagnosed using FISH and is defined by the presence of greater than or equal to five RUNX1 signals per cell (or ≥3 extra copies of RUNX1 on a single abnormal chromosome).[106] iAMP21 can also be identified by chromosomal microarray analysis. Uncommonly, iAMP21 with an atypical genomic pattern (e.g., amplification of the genomic region but with less than 5 RUNX1 signals or having at least 5 RUNX1 signals with some located apart from the abnormal iAMP21-chromosome) is identified by microarray but not RUNX1 FISH.[111] The prognostic significance of iAMP21 defined only by microarray has not been characterized.

      iAMP21 is associated with older age (median, approximately 10 years), presenting WBC count of less than 50 × 109/L, a slight female preponderance, and high end-induction MRD.[112–114] Analysis of variant signatures indicates that gene amplifications in iAMP21 occur later in leukemogenesis, which is in contrast to those of hyperdiploid ALL that can arise early in life and even in utero.[1]

      The United Kingdom Acute Lymphoblastic Leukaemia (UKALL) 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 rate, 29%).[18] 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 rate, 78%).[113] Similarly, the COG has reported that iAMP21 was associated with a significantly inferior outcome in NCI standard-risk patients (4-year EFS rate, 73% for iAMP21 vs. 92% in others), but not in NCI high-risk patients (4-year EFS rate, 73% vs. 80%).[112] On multivariate analysis, iAMP21 was an independent predictor of inferior outcome only in NCI standard-risk patients.[112] The results of the UKALL2003 and COG studies suggest that treatment of iAMP21 patients with high-risk chemotherapy regimens abrogates its adverse prognostic significance and obviates the need for HSCT in first remission.[114]

    • PAX5 alterations.

      Gene expression analysis identified two distinctive ALL subsets with PAX5 genomic alterations, called PAX5alt and PAX5 p.P80R (NP_057953.1).[115] The alterations in the PAX5alt subtype included rearrangements, sequence variants, and focal intragenic amplifications.

      PAX5alt. PAX5 rearrangements have been reported to represent approximately 3% of NCI standard-risk and 11% of NCI high-risk pediatric B-ALL cases.[1] More than 20 partner genes for PAX5 have been described,[115] with PAX5::ETV6, the primary genomic alteration in dic(9;12)(p13;p13),[116] being the most common gene fusion.[115]

      Intragenic amplification of PAX5 was identified in approximately 1% of B-ALL cases, and it was usually detected in cases lacking known leukemia-driver genomic alterations.[117] Cases with PAX5 amplification show male predominance (66%), with most (55%) having NCI high-risk status. For a cohort of patients with PAX5 amplification diagnosed between 1993 and 2015, the 5-year EFS rate was 49% (95% confidence interval [CI], 36%–61%), and the OS rate was 67% (95% CI, 54%–77%), suggesting a relatively poor prognosis for patients with this B-ALL subtype.

      PAX5 p.P80R (NP_057953.1). PAX5 with a p.P80R variant shows a gene expression profile distinctive from that of other cases with PAX5 alterations.[115] Cases with PAX5 p.P80R represent approximately 0.3% of NCI standard-risk and 1.8% of NCI high-risk pediatric B-ALL.[1] PAX5 p.P80R B-ALL appears to occur more frequently in the adolescent and young adult (AYA) and adult populations (3.1% and 4.2%, respectively).[115]

      Outcome for the pediatric patients with PAX5 p.P80R and PAX5alt treated in a COG clinical trial appears to be intermediate (5-year EFS rate, approximately 75%).[115] PAX5alt rearrangements have also been detected in infant patients with ALL, with a reported outcome similar to KMT2A-rearranged infant ALL.[105]

    • BCR::ABL1-like (Ph-like).

      BCR::ABL1-negative patients with a gene expression profile similar to BCR::ABL1-positive patients have been referred to as Ph-like,[118–120] and are now referred to as BCR::ABL1-like.[19] This occurs in 10% to 20% of pediatric B-ALL patients, increasing in frequency with age, and has been associated with an IKZF1 deletion or variant.[1,9,118,119,121,122]

      Retrospective analyses have indicated that patients with BCR::ABL1-like ALL have a poor prognosis.[5,118] In one series, the 5-year EFS rate for NCI high-risk children and adolescents with BCR::ABL1-like ALL was 58% and 41%, respectively.[5] While it is more frequent in older and higher-risk patients, the BCR::ABL1-like subtype has also been identified in NCI standard-risk patients. In a COG study, 13.6% of 1,023 NCI standard-risk B-ALL patients were found to have BCR::ABL1-like ALL; these patients had an inferior EFS rate compared with non–BCR::ABL1-like standard-risk patients (82% vs. 91%), although no difference in OS rate (93% vs. 96%) was noted.[123] In one study of 40 BCR::ABL1-like patients, the adverse prognostic significance of this subtype appeared to be abrogated when patients were treated with risk-directed therapy on the basis of MRD levels.[124]

      The hallmark of BCR::ABL1-like ALL is activated kinase signaling, with approximately 35% to 50% containing CRLF2 genomic alterations [1,120,125] and half of those cases containing concomitant JAK variants.[126]

      Many of the remaining cases of BCR::ABL1-like ALL have been noted to have a series of translocations involving tyrosine-kinase encoding ABL-class fusion genes, including ABL1, ABL2, CSF1R, and PDGFRB.[5,121,127] 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,[121,128] suggesting potential therapeutic strategies for these patients. Preclinical drug sensitivity assays have suggested that sensitivity to different tyrosine kinase inhibitors (TKIs) may vary by the specific ABL-class gene involved in the fusion. In one study of ex vivo TKI sensitivity, samples from patients with PDGFRB fusions were sensitive to imatinib. However, these samples were less sensitive to dasatinib and bosutinib than samples from patients with ABL1 fusions (including BCR::ABL1).[128] Clinical studies have not yet confirmed the differing responses to various TKIs by type of ABL-class fusion.

      BCR::ABL1-like ALL cases with non-CRLF2 genomic alterations represent approximately 3% of NCI standard-risk and 8% of NCI high-risk pediatric B-ALL cases.[1] In a retrospective study of 122 pediatric patients (aged 1–18 years) with ABL-class fusions (all treated without tyrosine kinase inhibitors), the 5-year EFS rate was 59%, and the OS rate was 76%.[129]

      Approximately 9% of BCR::ABL1-like ALL cases result from rearrangements that lead to overexpression of a truncated erythropoietin receptor (EPOR).[130] The C-terminal region of the receptor that is lost is the region that is altered in primary familial congenital polycythemia and that controls stability of the EPOR. The portion of the EPOR remaining is sufficient for JAK-STAT activation and for driving leukemia development. Single nucleotide variants in kinase genes, aside from those in JAK1 and JAK2, are uncommon in patients with BCR::ABL1-like ALL.[9]

      CRLF2. 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-ALL. These alterations represent approximately 50% of cases of BCR::ABL1-like ALL.[131–133] 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.[9,125,131,132] These two genomic alterations are associated with distinctive clinical and biological characteristics.

      BCR::ABL1-like B-ALL with CRLF2 genomic alterations is observed in approximately 2% of NCI standard-risk and 5% of NCI high-risk pediatric B-ALL cases.[1]

      ALL with genomic alterations in CRLF2 occurs at a higher incidence in children with Hispanic or Latino genetic ancestry [125,134,135] and American Indian genetic ancestry.[87] In a study of 205 children with high-risk B-ALL, 18 of 51 (35.3%) Hispanic or Latino patients had CRLF2 rearrangements, compared with 11 of 154 (7.1%) cases of other declared ethnicity.[125] In a second study, the frequency of IGH::CRLF2 fusions was increased in Hispanic or Latino children compared with non-Hispanic or non-Latino children with B-ALL (13.2% vs. 3.6%).[134,135] In this study, the percentage of B-ALL with P2RY8::CRLF2 fusions was approximately 6% and was not affected by ethnicity.

      The P2RY8::CRLF2 fusion is observed in 70% to 75% of pediatric patients with CRLF2 genomic alterations, and it occurs in younger patients (median age, approximately 4 years vs. 14 years for patients with IGH::CRLF2).[136,137] P2RY8::CRLF2 occurs not infrequently with established chromosomal abnormalities (e.g., hyperdiploidy, iAMP21, dic(9;20)), while IGH::CRLF2 is generally mutually exclusive with known cytogenetic subgroups. CRLF2 genomic alterations are observed in approximately 60% of patients with Down syndrome and ALL, with P2RY8::CRLF2 fusions being more common than IGH::CRLF2 (approximately 80%–85% vs. 15%–20%).[132,136]

      IGH::CRLF2 and P2RY8::CRLF2 commonly occur as an early event in B-ALL development and show clonal prevalence.[138] However, in some cases they appear to be a late event and show subclonal prevalence.[138] Loss of the CRLF2 genomic abnormality in some cases at relapse confirms the subclonal nature of the alteration in these cases.[136,139]

      CRLF2 abnormalities are strongly associated with the presence of IKZF1 deletions. Deletions of IKZF1 are more common in cases with IGH::CRLF2 fusions than in cases with P2RY8::CRLF2 fusions.[137] Hispanic and Latino children have a higher frequency of CRLF2 rearrangements with IKZF1 deletions than non-Hispanic children.[135]

      Other recurring genomic alterations found in association with CRLF2 alterations include deletions in genes associated with B-cell differentiation (e.g., PAX5, BTG1, EBF1, etc.) and cell cycle control (CDKN2A), as well as genomic alterations activating JAK-STAT pathway signaling (e.g., IL7R and JAK variants).[5,125,126,132,140]

      Although the results of several retrospective studies suggest that CRLF2 abnormalities may have adverse prognostic significance in univariate analyses, most do not find this abnormality to be an independent predictor of outcome.[125,131,132,141,142] 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::ABL1-like expression signatures were associated with unfavorable outcome.[122] Controversy exists about whether the prognostic significance of CRLF2 abnormalities should be analyzed on the basis of CRLF2 overexpression or on the presence of CRLF2 genomic alterations.[141,142]

    • IKZF1 deletions.

      IKZF1 deletions, including deletions of the entire gene and deletions of specific exons, are present in approximately 15% of B-ALL cases. Less commonly, IKZF1 can be inactivated by deleterious single nucleotide variants.[119]

      Cases with IKZF1 deletions tend to occur in older children, have a higher WBC count at diagnosis, and are therefore more common in NCI high-risk patients than in NCI standard-risk patients.[3,119,140,143,144] A high proportion of BCR::ABL1-positive cases have a deletion of IKZF1,[4,140] and ALL arising in children with Down syndrome appears to have elevated rates of IKZF1 deletions.[145] IKZF1 deletions are also common in cases with CRLF2 genomic alterations and in BCR::ABL1-like ALL cases.[89,118,140] IKZF1 deletions also occur more commonly in Hispanic children. In one study from a single cancer center, IKZF1 deletions were observed in 29% of Hispanic children, compared with 11% of non-Hispanic children (P = .001).[135]

      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 in multivariate analyses.[89,118,119,122,140,146–153]; [154][Level of evidence B4] However, the prognostic significance of IKZF1 may not apply equally across ALL biological subtypes, as illustrated by the apparent lack of prognostic significance in patients with ERG deletions.[89–91] Similarly, the prognostic significance of the IKZF1 deletion also appeared to be minimized in a cohort of COG patients with DUX4-rearranged ALL and with ERG transcriptional dysregulation that frequently occurred by ERG deletion.[7] The Associazione Italiana di Ematologia e Oncologia Pediatrica–Berlin-Frankfurt-Münster group reported that IKZF1 deletions were significant adverse prognostic factors only in B-ALL patients with high end-induction MRD and in whom co-occurrence of deletions of CDKN2A, CDKN2B, PAX5, or PAR1 (in the absence of ERG deletion) were identified.[155] This combination of IKZF1 deletion with accompanying deletion of select other genes is termed IKZF1PLUS.[155] In a single-center study, the IKZF1PLUS profile was more commonly observed in Hispanic children than in non-Hispanic children (20% vs. 5%, P = .001).[135]

      The poor prognosis associated with IKZF1 alterations appears to be enhanced by the concomitant finding of deletion of 22q11.22. In a study of 1,310 patients with B-ALL, approximately one-half of the patients with IKZF1 alterations also had deletion of 22q11.22. The 5-year EFS rate was 43.3% for those with both abnormalities, compared with 68.5% for patients with IKZF1 alterations and wild-type 22q11.22 (P < .001).[156]

      There are few published results of changing therapy on the basis of IKZF1 gene status. The Malaysia-Singapore group published results of two consecutive trials. In the first trial (MS2003), IKZF1 status was not considered in risk stratification, while in the subsequent trial (MS2010), IKZF1-deleted patients were excluded from the standard-risk group. Thus, more IKZF1-deleted patients in the MS2010 trial received intensified therapy. Patients with IKZF1-deleted ALL had improved outcomes in MS2010 compared with patients in MS2003, but interpretation of this observation is limited by other changes in risk stratification and therapeutic differences between the two trials.[157][Level of evidence B4]

      In the Dutch ALL11 study, patients with IKZF1 deletions had maintenance therapy extended by 1 year, with the goal of improving outcomes.[158] The landmark analysis demonstrated an almost threefold reduction in relapse rate and an improvement in the 2-year EFS rate (from 74.4% to 91.2%), compared with historical controls.

    • MYC-rearranged ALL (8q24).

      MYC gene rearrangements are a rare but recurrent finding in pediatric patients with B-ALL. Patients with rearrangements of the MYC gene and the IGH2, IGK, and IGL genes at 14q32, 2p12, and 22q11.2, respectively, have been reported.[159–161] The lymphoblasts typically exhibit a precursor B-cell immunophenotype, with a French-American-British (FAB) L2 or L3 morphology, with no expression of surface immunoglobulin and kappa or lambda light chains. Concurrent MYC gene rearrangements have been observed along with additional cytogenetic rearrangements such as IGH::BCL2 or KMT2A.[161] Patients reported in the literature have been variably treated with ALL therapy or with mature B leukemia/lymphoma treatment protocols, and the optimal treatment for this patient group remains uncertain.[161]

Genomics of ALL in children with Down syndrome

The largest study that examined the genomic landscape of ALL arising in children with Down syndrome included 295 patients enrolled in COG clinical trials.[11]

  • Almost all cases of ALL in children with Down syndrome are B-ALL. T-ALL is uncommon.
  • The common recurring genomic alterations found in non-Down syndrome ALL (e.g., high hyperdiploidy and ETV6::RUNX1) occur much less often in children with Down syndrome and ALL. Other alterations occur more often in children with Down syndrome and ALL.
  • Fifty percent to 60% of children with Down syndrome and ALL have CRLF2 rearrangements involving either IGH or P2RY8, with most cases (85%) involving P2RY8.
    • Approximately one-half of CRLF2-rearranged cases have JAK2 variants, which are not seen in children with Down syndrome and ALL who do not have CRLF2 rearrangements.
    • IKZF1 alterations occur in approximately 30% of cases with CRLF2 rearrangements but in only approximately 10% of cases without CRLF2 rearrangements.
    • Twenty-five percent of CRLF2-rearranged cases in patients with Down syndrome are classified by gene expression as BCR::ABL1-like, compared with 54% of CRLF2-rearranged non-Down syndrome ALL cases.
    • Overall, patients with CRLF2-rearranged ALL and Down syndrome have an intermediate prognosis. However, patients with a BCR::ABL1-like gene expression signature have worse outcomes than those without a BCR::ABL1-like gene expression signature and CRLF2 rearrangements (EFS rates, 39.5% ± 8.1% vs. 82% ± 4.4%; OS rates, 70.3% ± 8.7% vs. 86.9% ± 4.8%).
  • The IGH::IGF2BP1 gene fusion occurs in approximately 3% of patients with Down syndrome. This gene fusion is rare in patients with ALL who do not have Down syndrome. In one retrospective analysis, this fusion was associated with a relatively favorable outcome (EFS rate, 87.5% ± 11.7%).
  • C/EBP altered (C/EBPalt) B-ALL, which is characterized by aberrant activation of C/EBP family genes, is also markedly enriched in children with Down syndrome (10.5% of Down syndrome ALL vs. 0.1% of non-Down syndrome B-ALL).
    • Rearrangements of CEBPD are the most common C/EBPalt lesion, occurring in 7.5% of Down syndrome ALL cases. The fusion partner for more than 80% of CEBPD rearrangements is IGH. Less common fusion partners include MME, TPM4, 9p13.2, and 6q25.3.
    • Another 4% to 5% of Down syndrome ALL is characterized by alterations in other C/EBP family members, such as CEBPA and CEBPE.
    • C/EBPalt cases commonly harbor concomitant variants of FLT3, KDM6A, and SETD2.
    • C/EBPalt was associated with high rates of MRD-negative remission at the end of induction therapy (87.1%) and an intermediate outcome (10-year EFS rate, 73.9% ± 9.9%; 10-year OS rate, 76.7% ± 12.8%).

T-ALL cytogenetics/genomics

T-ALL is characterized by genomic alterations leading to activation of transcriptional programs related to T-cell development and by a high frequency of cases (approximately 60%) with variants in NOTCH1 and/or FBXW7 that result in activation of the NOTCH1 pathway.[162] Cytogenetic abnormalities common in B-ALL (e.g., hyperdiploidy, 51–65 chromosomes) are rare in T-ALL.[163,164]

In Figure 5 below, pediatric T-ALL cases are divided into 10 molecular subtypes based on their RNA expression and gene variant status. These cases were derived from patients enrolled in SJCRH and COG clinical trials.[1] Each subtype is associated with dysregulation of specific genes involved in T-cell development. Within a subtype, multiple mechanisms may drive expression of the dysregulated gene. For example, for the largest subtype, TAL1, overexpression of TAL1 can result from the STIL::TAL1 fusion and a noncoding insertion variant upstream of the TAL1 locus that creates a MYB-binding site.[162,165] As another example, within the HOXA group, overexpression of HOXA9 can result from multiple gene fusions, including KMT2A rearrangements, MLLT10 rearrangements, and SET::NUP214 fusions.[1,162,166] In contrast to the molecular subtypes of B-ALL, the molecular subtypes of T-ALL are not used to define treatment interventions based on their prognostic significance or therapeutic implications.

EnlargeFigure showing genomic subtypes of T-ALL.
Figure 5. Genomic subtypes of T-ALL. The figure represents data from 466 children, adolescents, and young adults diagnosed with T-ALL and enrolled in St. Jude Children’s Research Hospital or Children’s Oncology Group clinical trials. Adapted from Brady SW, Roberts KG, Gu Z, et al.: The genomic landscape of pediatric acute lymphoblastic leukemia. Nature Genetics 54: 1376-1389, 2022.

  • Notch pathway signaling.

    Notch pathway signaling is commonly activated by NOTCH1 and FBXW7 gene variants in T-ALL, and these are the most commonly altered genes in pediatric T-ALL.[162,167] NOTCH1-activating gene variants occur in approximately 50% to 60% of T-ALL cases, and FBXW7-inactivating gene variants occur in approximately 15% of cases. Approximately 60% of T-ALL cases have Notch pathway activation by variants in at least one of these genes.[168,169]

    The prognostic significance of NOTCH1 and FBXW7 variants may be modulated by genomic alterations in RAS and PTEN. The French Acute Lymphoblastic Leukaemia Study Group (FRALLE) and the Group for Research on Adult Acute Lymphoblastic Leukemia reported that patients having altered NOTCH1 or FBXW7 and wild-type PTEN and RAS constituted a favorable-risk group (i.e., low-risk group), while patients with PTEN or RAS variants, regardless of NOTCH1 and FBXW7 status, have a significantly higher risk of treatment failure (i.e., high-risk group).[170,171] In the FRALLE study, the 5-year disease-free survival rate was 88% for the genetic low-risk group of patients and 60% for the genetic high-risk group of patients.[170] However, using the same criteria to define the genetic risk group, the Dana-Farber Cancer Institute consortium was unable to replicate these results. They reported a 5-year EFS rate of 86% for genetic low-risk patients and 79% for the genetic high-risk patients, a difference that was not statistically significant (P = .26).[169]

  • Chromosomal translocations.

    Multiple chromosomal translocations have been identified in T-ALL that lead to deregulated expression of the target genes. These chromosome rearrangements fuse genes encoding transcription factors (e.g., TAL1, TAL2, LMO1, LMO2, LYL1, TLX1, TLX3, NKX2-I, HOXA, and MYB) to one of the T-cell receptor loci (or to other genes) and result in deregulated expression of these transcription factors in leukemia cells.[162,163,172–176] These translocations are often not apparent by examining a standard karyotype, but can be identified using more sensitive screening techniques, including FISH or PCR.[163] Variants in a noncoding region near the TAL1 gene that produce a super-enhancer upstream of TAL1 represent nontranslocation genomic alterations that can also activate TAL1 transcription to induce T-ALL.[165]

    Translocations resulting in chimeric fusion proteins are also observed in T-ALL.[170]

    • A NUP214::ABL1 fusion has been noted in 4% to 6% of T-ALL cases and is observed in both adults and children, with a male predominance.[177–179] The fusion is cytogenetically cryptic and is seen in FISH on amplified episomes or, more rarely, as a small homogeneous staining region.[179] T-ALL may also uncommonly show ABL1 fusion proteins with other gene partners (e.g., ETV6, BCR, and EML1).[179] ABL tyrosine kinase inhibitors, such as imatinib or dasatinib, may demonstrate therapeutic benefits in this T-ALL subtype,[177,178,180] although clinical experience with this strategy is very limited.[181–183]
    • Gene fusions involving SPI1 (encoding the transcription factor PU.1) were reported in 4% of Japanese children with T-ALL.[184] Fusion partners included STMN1 and TCF7. T-ALL cases with SPI1 fusions had a particularly poor prognosis; six of seven affected individuals died within 3 years of diagnosis of early relapse.
    • BCL11B is a zinc finger transcription factor that plays a dual role as a transcription activator and repressor. It is known to play a critical role in T-cell differentiation. In T-ALL, the BCL11B gene is involved in a t(5;14)(q35;q32) translocation where a distal BCL11B enhancer drives aberrant expression of TLX3 (or NKX2-5).[185] In the process of donating its enhancer, one allele of BCL11B is inactivated. However, the resulting haploinsufficient state itself may also play a role in tumor pathogenesis. The role of BCL11B as a tumor suppressor gene is supported by the finding that about 16% of patients have T-ALL that harbors deletions or missense variants.[162,186] As described in the sections for early T-cell precursor (ETP) and T/myeloid mixed phenotype acute leukemia (T/M MPAL), BCL11B may also be leukemogenic through overexpression.
    • Other recurring gene fusions in T-ALL patients include those involving MLLT10, KMT2A, NUP214, and NUP98.[162,166]
  • Ploidy.
    • Recurrent abnormalities in chromosome number are much less common in T-ALL than in B-ALL. One study included 2,250 pediatric patients with T-ALL who were treated in Associazione Italiana di Ematologia e Oncologia Pediatrica/Berlin-Frankfurt-Münster protocols. The study found that near tetraploidy (DNA index, 1.79–2.28 or 81–103 chromosomes), observed in 1.4% of patients, was associated with favorable disease features and outcomes.[187]

Early T-cell precursor (ETP) ALL cytogenetics/genomics

Detailed molecular characterization of ETP ALL showed this entity to be highly heterogeneous at the molecular level, with no single gene affected by variant or copy number alteration in more than one-third of cases.[188] Compared with other T-ALL cases, the ETP group had a lower rate of NOTCH1 variants and significantly higher frequencies of alterations in genes regulating cytokine receptors and RAS signaling, hematopoietic development, and histone modification. The transcriptional profile of ETP ALL shows similarities to that of normal hematopoietic stem cells and myeloid leukemia stem cells.[188]

Studies have found that the absence of biallelic deletion of the TCR-gamma locus (ABD), as detected by comparative genomic hybridization and/or quantitative DNA-PCR, was associated with early treatment failure in patients with T-ALL.[189,190] ABD is characteristic of early thymic precursor cells, and many of the T-ALL patients with ABD have an immunophenotype consistent with the diagnosis of ETP phenotype.

Allele-specific, generally high expression of BCL11B plays an oncogenic role in a subset of cases identified as ETP ALL (7 of 58 in one study) as well as in up to 30% to 40% of lineage ambiguous leukemia T/M mixed phenotype acute leukemia (T/M MPAL).[191,192] The dysregulated expression of BCL11B can occur by multiple mechanisms.

  • One such alteration is t(2;14)(q22;q32), which produces an in-frame ZEB2::BCL11B fusion gene.
  • Other structural variants leading to allele-specific deregulated BCL11B expression include structural variants that juxtapose regulatory sequences of active genes (e.g., ARID1B [chromosome 6], BENC [chromosome 7], and CDK6 [chromosome 7]) upstream or downstream of the BCL11B locus leading to aberrant expression in a process called enhancer hijacking.
  • Finally, in about 20% of cases with deregulated BCL11B expression, a translocation cannot be identified. In many such cases, amplification of a downstream enhancer, BCL11B enhancer tandem amplification (BETA), leads to BCL11B promoter driven transcription.
  • There is a high prevalence of FLT3 alterations and JAK/STAT activation in acute leukemias driven by genomic alterations leading to BCL11B expression.[191]

Mixed phenotype acute leukemia (MPAL) cytogenetics/genomics

For acute leukemias of ambiguous lineage, the WHO classification system is summarized in Table 3.[193,194] The criteria for lineage assignment for a diagnosis of MPAL are provided in Table 4.[106]

Table 3. Acute Leukemias of Ambiguous Lineage According to the World Health Organization Classification of Tumors of Hematopoietic and Lymphoid Tissuesa
Condition Definition
MPAL = mixed phenotype acute leukemia; NOS = not otherwise specified.
aAdapted from Béné MC: Biphenotypic, bilineal, ambiguous or mixed lineage: strange leukemias! Haematologica 94 (7): 891-3, 2009.[193] Obtained from Haematologica/the Hematology Journal website http://www.haematologica.org.
Acute undifferentiated leukemia Acute leukemia that does not express any marker considered specific for either lymphoid or myeloid lineage
MPAL with BCR::ABL1 (t(9;22)(q34;q11.2)) Acute leukemia meeting the diagnostic criteria for MPAL in which the blasts also have the (9;22) translocation or the BCR::ABL1 rearrangement
MPAL with KMT2A (t(v;11q23)) Acute leukemia meeting the diagnostic criteria for MPAL in which the blasts also have a translocation involving the KMT2A gene
MPAL, B/myeloid, NOS (B/M MPAL) Acute leukemia meeting the diagnostic criteria for assignment to both B and myeloid lineage, in which the blasts lack genetic abnormalities involving BCR::ABL1 or KMT2A
MPAL, T/myeloid, NOS (T/M MPAL) Acute leukemia meeting the diagnostic criteria for assignment to both T and myeloid lineage, in which the blasts lack genetic abnormalities involving BCR::ABL1 or KMT2A
MPAL, B/myeloid, NOS—rare types Acute leukemia meeting the diagnostic criteria for assignment to both B and T lineage
Other ambiguous lineage leukemias Natural killer–cell lymphoblastic leukemia/lymphoma
Table 4. Lineage Assignment Criteria for Mixed Phenotype Acute Leukemia According to the 2016 Revision to the World Health Organization Classification of Myeloid Neoplasms and Acute Leukemiaa
Lineage Criteria
aAdapted from Arber et al.[106]
bStrong defined as equal to or brighter than the normal B or T cells in the sample.
Myeloid lineage Myeloperoxidase (flow cytometry, immunohistochemistry, or cytochemistry); or monocytic differentiation (at least two of the following: nonspecific esterase cytochemistry, CD11c, CD14, CD64, lysozyme)
T lineage Strongb cytoplasmic CD3 (with antibodies to CD3 epsilon chain); or surface CD3
B lineage Strongb CD19 with at least one of the following strongly expressed: CD79a, cytoplasmic CD22, or CD10; or weak CD19 with at least two of the following strongly expressed: CD79a, cytoplasmic CD22, or CD10

The classification system for MPAL includes two entities that are defined by their primary molecular alteration: MPAL with BCR::ABL1 translocation and MPAL with KMT2A rearrangement. The genomic alterations associated with the MPAL, B/myeloid, NOS (B/M MPAL) and MPAL, T/myeloid, NOS (T/M MPAL) entities are distinctive, as described below:

  • B/M MPAL.
    • Among 115 MPAL cases for which genomic characterization was performed, 35 (30%) were B/M MPAL. There were an additional 16 MPAL cases (14%) with KMT2A rearrangements, 15 of whom showed a B/myeloid immunophenotype.
    • Approximately one-half of B/M MPAL cases had rearrangements of ZNF384 with recurrent fusion partners, including TCF3 and EP300. These cases had gene expression profiles indistinguishable from B-ALL cases with ZNF384 rearrangements.[102]
    • Approximately two-thirds of B/M MPAL cases had RAS pathway alterations, with NRAS and PTPN11 being the most commonly altered genes.[102]
    • Genes encoding epigenetic regulators (e.g., MLLT3, KDM6A, EP300, and CREBBP) are altered in approximately two-thirds of B/M MPAL cases.[102]
  • T/M MPAL.
    • Among 115 MPAL cases for which genomic characterization was performed, 49 (43%) were T/M MPAL.[102] The genomic features of the T/M MPAL cases shared commonalities with those of ETP ALL, suggesting that T/M MPAL and ETP ALL are similar entities along the spectrum of immature leukemias.
    • Compared with T-ALL, T/M MPAL showed a lower rate of alterations in the core T-ALL transcription factors (TAL1, TAL2, TLX1, TLX3, LMO1, LMO2, NKX2-1, HOXA10, and LYL1) (63% vs. 16%, respectively).[102] A similar lower rate was also observed for ETP ALL.
    • CDKN2A, CDKN2B, and NOTCH1 variants, which are present in approximately two-thirds of T-ALL cases, were much less common in T/M MPAL cases. By contrast, WT1 variants occurred in approximately 40% of T/M MPAL, but in less than 10% of T-ALL cases.[102]
    • One-third of T/M MPAL cases have genomic alterations associated with BCL11B that lead to allele-specific, generally high expression of BCL11B.[191,192]
      • One such alteration is t(2;14)(q22;q32), which produces an in-frame ZEB2::BCL11B fusion gene that leads to deregulated expression of BCL11B.
      • Other alterations leading to allele-specific deregulated BCL11B expression include structural variants that juxtapose regulatory sequences of active genes (e.g., ARID1B [chromosome 6], BENC [chromosome 7], and CDK6 [chromosome 7]) upstream or downstream of the BCL11B locus in a process called enhancer hijacking.
      • Finally, a translocation cannot be identified in about 20% of cases with deregulated BCL11B overexpression. In such cases, amplification of a downstream enhancer, BCL11B enhancer tandem amplification (BETA), leads to BCL11B promoter driven transcription.
      • There is a high prevalence of FLT3 alterations and JAK/STAT activation in acute leukemias driven by genomic alterations leading to BCL11B overexpression.
    • RAS and JAK-STAT pathway variants were common in the T/M MPAL and ETP ALL cases, while the PI3K signaling pathway is more commonly altered in T-ALL.[102] For T/M MPAL, the most commonly altered signaling pathway gene was FLT3 (43% of cases). FLT3 variants tended to be mutually exclusive with RAS pathway variants.
    • Genes encoding epigenetic regulators (e.g., EZH2 and PHF6) were altered in approximately two-thirds of T/M MPAL cases.[102]

Gene polymorphisms in drug metabolic pathways

Several polymorphisms of genes involved in the metabolism of chemotherapeutic agents have been reported to have prognostic significance in childhood ALL.[195–197]

  • TPMT.

    Patients with variant phenotypes of TPMT (a gene involved in the metabolism of thiopurines such as mercaptopurine) appear to have more favorable outcomes,[198] although such patients may also be at higher risk of developing significant treatment-related toxicities, including myelosuppression, infection, and second malignancies.[199,200] Patients with homozygosity for TPMT variants associated with low enzymatic activity tolerate only very low doses of mercaptopurine (approximately 10% of the standard dose) and are treated with reduced doses of mercaptopurine to avoid excessive toxicity. Patients who are heterozygous for this variant enzyme gene generally tolerate mercaptopurine without serious toxicity, but they do require more frequent dose reductions for hematologic toxicity than do patients who are homozygous for the normal allele.[201,202]

  • NUDT15.

    Germline pathogenic variants in NUDT15 that reduce or abolish activity of this enzyme also lead to diminished tolerance to thiopurines.[201,203] The NUDT15 variants are most common in East Asian and Hispanic patients, and they are rare in European and African patients. Patients homozygous for the risk variants tolerate only very low doses of mercaptopurine, while patients heterozygous for the risk alleles tolerate lower doses than do patients homozygous for the wild-type allele (approximately 25% dose reduction on average), but there is broad overlap in tolerated doses between the two groups.[201,204]

  • CEP72.

    Gene polymorphisms may also affect the expression of proteins that play central roles in the cellular effects of anticancer drugs. As an example, patients who are homozygous for a polymorphism in the promoter region of CEP72 (a centrosomal protein involved in microtubule formation) are at increased risk of vincristine neurotoxicity.[205]

  • Single nucleotide polymorphisms.

    Genome-wide polymorphism analysis has identified specific single nucleotide polymorphisms associated with high end-induction MRD and risk of relapse. Polymorphisms of interleukin-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.[206] Polymorphic variants involving the reduced folate carrier and methotrexate metabolism have been linked to toxicity and outcome.[207,208] While these associations suggest that individual variations in drug metabolism can affect outcome, few studies have attempted to adjust for these variations. It is unknown whether individualized dose modification on the basis of these findings will improve outcomes.

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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 cure varies substantially among subsets of children with ALL. Risk-based treatment assignment is used 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, potentially more toxic therapeutic approach is reserved for patients with a lower probability of long-term survival.[1,2]

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 the following:

  • Immunophenotype.
  • The presence or absence of extramedullary disease.
  • Steroid pretreatment.
  • The presence or absence of Down syndrome.
  • The National Cancer Institute (NCI) risk group classification.

The NCI risk group classification for B-ALL stratifies risk according to age and white blood cell (WBC) count, as follows:[3]

  • 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 on the basis of a variety of prognostic factors, including NCI risk group, immunophenotype, early response determinations, and cytogenetics and genomic alterations.[4] Detection of the BCR::ABL1 fusion (i.e., BCR::ABL1-positive ALL) leads to immediate changes in induction therapy, including the addition of a tyrosine kinase inhibitor, such as imatinib or dasatinib.[5]

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.[6] Factors affecting prognosis 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. Because prognostic factors are treatment dependent, improvements in therapy may diminish or abrogate the significance of any of these 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. For brief descriptions of the prognostic groupings currently applied in ongoing clinical trials in the United States, see the Prognostic (risk) groups under clinical evaluation section.

For information about important prognostic factors at relapse, see the Prognostic Factors After First Relapse of Childhood ALL section.

Prognostic Factors Affecting Risk-Based Treatment

Patient and clinical disease characteristics

Patient and clinical disease 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 at diagnosis.
  5. Down syndrome (trisomy 21).
  6. Sex.
  7. Race and ethnicity.
  8. Weight at diagnosis and during treatment.
Age at diagnosis

Age at diagnosis has strong prognostic significance in patients with B-ALL, reflecting the different underlying biology of ALL in different age groups.[7] Age at diagnosis is not prognostically relevant in T-ALL.[8]

  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:

    • Infants younger than 6 months (with an even poorer prognosis for those aged ≤90 days).[9–13]
    • Infants with extremely high presenting leukocyte counts (>200,000–300,000 × 109/L).[10]
    • Infants with a poor response to a prednisone prophase.[10]
    • Infants with a KMT2A gene rearrangement.[9–12]

    Up to 80% of infants with ALL have a translocation of 11q23 with numerous chromosome partners generating a KMT2A gene rearrangement.[10,12,14,15] The most common rearrangement is KMT2A::AFF1 (t(4;11)(q21;q23)), but KMT2A rearrangements with many other translocation partners are observed. Infants with leukemia and KMT2A rearrangements typically have very high WBC counts and an increased incidence of CNS involvement. Event-free survival (EFS) and overall survival (OS) rates are poor. The 5-year EFS and OS rates are 35% to 40% for infants with KMT2A-rearranged ALL.[10–12]

    The frequency of KMT2A gene rearrangements is extremely high in infants younger than 6 months. From 6 months to 1 year, the incidence of KMT2A rearrangements decreases but remains significantly higher than that observed in older children.[10,16] Blasts from infants with KMT2A rearrangements are often CD10 negative and express high levels of FLT3.[10,11,15,17] Conversely, infants whose leukemic cells show a germline KMT2A gene configuration frequently present with CD10-positive precursor-B immunophenotype. These infants have a significantly better outcome than do infants with ALL characterized by KMT2A rearrangements.[10,11,15,18]

    Black infants with ALL are significantly less likely to have KMT2A rearrangements than White infants.[16]

    A comparison of the landscape of somatic variants in infants and older children with KMT2A-rearranged ALL revealed significant differences between the two groups. This result suggests distinctive age-related biological behaviors for KMT2A-rearranged ALL that may relate to the significantly poorer outcome for infants.[19,20]

    For more information about infants with ALL, see the Infants With ALL section.

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

    Young children (aged 1 to <10 years) with B-ALL have a better disease-free survival (DFS) rate than older children, adolescents, and infants.[3,7,21–23] 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 to 65 chromosomes and/or favorable chromosome trisomies, or the ETV6::RUNX1 fusion (t(12;21)(p13;q22), previously known as the TEL::AML1 translocation).[7,24,25]

  3. Adolescents and young adults (aged ≥10 years).

    In general, the outcome of patients with B-ALL aged 10 years and older is inferior to that of patients aged 1 to younger than 10 years.[26] Patients aged 10 to 15 years fare better than those who are aged 16 to 21 years at diagnosis who were treated with pediatric regimens.[8] However, the outcome for older adolescents has improved significantly over time.[27–29] Five-year survival rates for adolescents aged 15 to 19 years increased from 36% (1975–1984) to 78% (2011–2017).[30–33]

    Multiple retrospective studies have established that adolescents aged 16 to 21 years have a better outcome when treated on pediatric versus adult protocols.[34–36] For more information about adolescents with ALL, see the Postinduction Treatment for Specific ALL Subgroups section.

WBC count at diagnosis

A WBC count of 50,000/µL is generally used as an operational cut point between better and poorer prognosis,[3] although the relationship between WBC count and prognosis is a continuous function rather than a step function. Patients with B-ALL and high WBC counts at diagnosis have an increased risk of treatment failure compared with patients with low initial WBC counts.[37]

The median WBC count at diagnosis is much higher for T-ALL (>50,000/µL) than for B-ALL (<10,000/µL), and there is no consistent effect of WBC count at diagnosis on prognosis for T-ALL.[37–46]

CNS involvement at diagnosis

The presence or absence of CNS leukemia at diagnosis has prognostic significance in both patients with B-ALL and T-ALL. 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 or clinical signs of CNS leukemia (i.e., facial nerve palsy, brain/eye involvement, or hypothalamic syndrome).

Children with B-ALL or T-ALL who present with CNS3 disease 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.[47–49] The prognostic implication of CNS2 status at diagnosis may differ between patients with B-ALL and T-ALL. Some studies have reported increased risk of CNS relapse and/or inferior EFS in patients with B-ALL and CNS2 status at diagnosis, compared with patients with CNS1 status,[50,51] while other studies have not.[47,52–54] In an analysis of 2,164 patients with T-ALL treated in two consecutive COG trials, there was no difference in EFS, DFS, or cumulative incidence of relapse between patients with CNS1 and CNS2 status.[49]

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,[47,53,55] but not others.[51,52,56] Patients with CNS2, CNS3, or traumatic lumbar puncture have a higher frequency of unfavorable prognostic characteristics than those with CNS1, including significantly higher WBC counts at diagnosis, older age at diagnosis, an increased frequency of the T-ALL phenotype, and KMT2A gene rearrangements.[47,52,53]

Most clinical trial groups have approached the treatment of CNS2 and traumatic lumbar puncture patients by using more intensive therapy, primarily additional doses of intrathecal therapy during induction.[47,57,58]; [52][Level of evidence B4]; [59][Level of evidence A1]

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.[60]

Testicular involvement at diagnosis

Overt testicular involvement at the time of diagnosis occurs in approximately 2% of males,[61,62] with a higher frequency in patients with T-ALL than in patients with B-ALL.[62]

In early ALL trials, testicular involvement at diagnosis was an adverse prognostic factor. With more aggressive initial therapy, however, it does not appear to have prognostic significance.[61,62] For example, a European Organization for Research and Treatment of Cancer trial (EORTC-58881) reported no adverse prognostic significance for overt testicular involvement at diagnosis.[62]

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.[61] 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)

Outcomes in children with Down syndrome and ALL have often been somewhat inferior to outcomes in children without Down syndrome.[63–67] However, in some studies, patients with Down syndrome appeared to fare as well as those without Down syndrome.[68,69] The lower EFS and OS of children with Down syndrome appear to be related to increased frequency of treatment-related mortality, as well as higher rates of induction failure and relapse.[63–66,70,71] The inferior anti-leukemic outcome may be due, in part, to the decreased prevalence of favorable biological features such as ETV6::RUNX1 or hyperdiploidy (51–65 chromosomes) with trisomies of chromosomes 4 and 10 in Down syndrome ALL patients.[70–72]

  • In a large retrospective study that included 653 patients with Down syndrome and ALL, patients with Down syndrome had a lower complete remission (CR) rate (97% vs. 99%, P < .001), higher cumulative incidence of relapse (26% vs. 15%, P < .001) and higher treatment-related mortality (7% vs. < 1%, P < .001) compared with patients without Down syndrome.[71] Among the patients with Down syndrome, 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.
  • In a report from the COG, among patients with B-ALL who lacked KMT2A rearrangements, BCR::ABL1, ETV6::RUNX1, and hyperdiploidy with trisomies of chromosomes 4 and 10, the EFS and OS rates were similar in children with and without Down syndrome.[70]
  • Certain genomic abnormalities, such as IKZF1 deletions, CRLF2 aberrations, and JAK variants, are seen more frequently in ALL arising in children with Down syndrome than in those without Down syndrome.[73–77] Studies of children with Down syndrome and ALL suggest that the presence of IKZF1 deletions (but not CRLF2 aberrations or JAK variants) is associated with an inferior prognosis.[71,77,78]
  • A retrospective analysis included 130 patients with CRLF2-rearranged ALL and Down syndrome. Patients with the BCR::ABL1-like signature (25% of the CRLF2-rearranged cases) had an inferior outcome compared with those who lacked the BCR::ABL1-like signature (EFS rates, 39.5% ± 8.1% vs. 82.0% ± 4.4%; hazard ratio [HR], 5.27).[72]
  • The IGH::IGF2BP1 gene fusion occurs in approximately 3% of patients with Down syndrome. This fusion is rare in patients with ALL who do not have Down syndrome. In one retrospective analysis, the fusion was associated with a relatively favorable outcome (EFS rate, 87.5% ± 1.7%).[72]
Sex

In some studies, the prognosis for girls with ALL is slightly better than it is for boys with ALL.[79–81] One reason 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.[79–81] While some reports describe outcomes for boys as closely approaching those of girls,[23,57,82] larger clinical trial experiences and national data continue to show somewhat lower survival rates for boys.[22,33,83,84]

Race and ethnicity

Over the last several decades in the United States, survival rates in Black and Hispanic children with ALL have been somewhat lower than those in White children with ALL.[85–88] One study included more than 18,031 patients with B-ALL and 1,892 patients with T-ALL who were aged 0 to 30 years and treated between 2004 and 2019 in COG clinical trials. The race- and ethnicity-based outcome disparities noted in older studies persisted with more contemporary therapy. Race- and ethnicity-based outcome disparities were observed for patients with B-ALL but not for patients with T-ALL. The study also noted a wider disparity in OS versus EFS for patients with B-ALL, suggesting that disparities might be greater in the setting of relapsed disease versus newly diagnosed disease.[89] Multivariable analysis adjusting for disease prognosticators (e.g., age and WBC count, cytogenetic risk group, CNS status) and insurance status substantially attenuated the increased risk of inferior EFS for Hispanic patients. However, the same adjustments did not attenuate the inferior EFS for non-Hispanic Black children.[89]

The following factors associated with race and ethnicity influence survival:

  • ALL subtype. The reason for better outcomes in White and Asian children than in Black and Hispanic children is at least partially explained by the different spectrum of ALL subtypes. For example, Black children have a higher relative incidence of T-ALL, lower rates of favorable genetic subtypes of B-ALL, and higher rates of the TFC3::PBX1 (t(1;19)) translocation. Hispanic and Latino children have a lower prevalence of the favorable ETV6::RUNX1 fusion gene.[90]

    Hispanic and Latino children have a higher frequency of CRLF2 rearrangements and IKZF1 deletions.[90–92] They also have a higher frequency of the IKZF1PLUS profile (IKZF1 deletion plus deletion of CDKN2A, CDKN2B, PAX5, or PAR1 [in the absence of ERG deletion]).[90]

  • Treatment adherence. Differences in outcome may also be related to treatment adherence, as illustrated by a study of adherence to oral mercaptopurine (6-MP) in maintenance therapy. In the first report from the 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, even with adherence rates of 90% or more, Hispanic children continued to demonstrate increased rates of relapse.[93] In the second report from the study, adherence rates were shown to be significantly lower in Asian American and African American patients than in non-Hispanic White patients. A greater percentage of patients in these ethnic groups had adherence rates of less than 90%, which was associated with a 3.9-fold increased risk of relapse.[94]
  • Ancestry-related genomic variations. Ancestry-related genomic variations may also contribute to racial and ethnic disparities in both the incidence and outcome of ALL.[95] For example, the differential presence of specific host polymorphisms in different racial and ethnic groups may contribute to outcome disparities, as illustrated by the occurrence of single nucleotide polymorphisms in the ARID5B gene that occur more frequently among Hispanic patients and are linked to both ALL susceptibility and to relapse hazard.[96] In a genome-wide association study (GWAS), the GATA3 variant, rs3824662, was associated with an increased risk of developing BCR::ABL1-like (Ph-like) ALL. Patients with this variant were at increased risk of high minimal residual disease (MRD) at end-induction and at greater risk of relapse. The rs3824662 risk allele is associated with Native American genetic ancestry. The risk allele frequency was 52% in Guatemalan patients, 40% in U.S. Hispanic patients, and 14% in patients of European descent.[97]
Weight at diagnosis and during treatment

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

  • Three studies did not demonstrate an independent effect of obesity on EFS.[98][Level of evidence B4]; [99,100][Level of evidence C2]
  • Two studies showed obesity to be an independent prognostic factor only in patients older than 10 years or in patients with intermediate-risk or high-risk disease.[101,102][Level of evidence C2]
  • The COG reported on the impact of obesity on outcome in 2,008 children, 14% of whom were obese, who were enrolled on a high-risk ALL trial (CCG-1961 [NCT00002812]).[103][Level of evidence B4] Obesity was found to be an independent variable for inferior outcome compared with nonobese patients (5-year EFS rates, 64% vs. 74%; P = .002). However, obese patients at diagnosis who then lost weight during the premaintenance period of treatment had outcomes similar to patients with normal weight at diagnosis.
  • In a retrospective study of patients treated at a single institution, obesity at diagnosis was linked to an increased risk of having MRD at the end of induction and an inferior EFS.[104][Level of evidence C2]
  • In a different retrospective study of 373 patients treated at a single institution, body mass index (BMI) at diagnosis was not associated with MRD at days 19 and 46, cumulative incidence of relapse, or EFS. OS was lower in patients with a high BMI, primarily resulting from treatment-related mortality and inferior salvage after relapse.[105][Level of evidence C1]
  • In one study, obesity at diagnosis was associated with increased toxicity and truncated administration of asparaginase, especially in older children and adolescents.[106]
  • In a study of 388 patients aged 15 to 50 years who were treated with Dana-Farber Cancer Institute (DFCI) ALL consortium regimens, greater BMI was associated with higher rates of relapse and nonrelapse mortality, as well as inferior OS. Higher BMI was associated with increased rates of hepatotoxicity and hyperglycemia. The deleterious effect of elevated BMI was more pronounced in older patients. Among patients aged 15 to 29 years at diagnosis (n = 254), the 4-year OS rate was 73% for those with high BMI, compared with 83% for those with BMI in the reference range (P = .09).[107]

In a study of 762 pediatric patients with ALL (aged 2–17 years), the Dutch Childhood Oncology Group found that those who were underweight at diagnosis (defined as BMI standard deviation score < -1.8; 8% of the population) had an almost twofold higher risk of relapse compared with patients who were not underweight (after adjusting for risk group and age), although this did not result in a difference in EFS or OS. Patients with a decrease in BMI during the first 32 weeks of treatment had similar rates of relapse as other patients, but had significantly worse OS, primarily because of poorer salvage rates after relapse.[108]

Leukemic characteristics

Leukemic cell characteristics affecting prognosis include the following:

  1. Immunophenotype.
  2. Cytogenetics/genomic alterations.
Immunophenotype

The 2016 revision to the World Health Organization (WHO) classification of myeloid neoplasms and acute leukemia classifies ALL as either B-lymphoblastic leukemia or T-lymphoblastic leukemia, with further subdivisions based on molecular characteristics.[109,110] For more information, see the Diagnosis section.

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

  1. B-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 B-ALL (precursor B-cell ALL).

    B-ALL, defined by the expression of CD19, HLA-DR, cytoplasmic CD79a, and other B-cell–associated antigens, accounts for 80% to 85% of childhood ALL. Approximately 90% of B-ALL cases express the CD10 surface antigen (formerly known as common ALL antigen). Absence of CD10 is often associated with KMT2A rearrangements, particularly t(4;11)(q21;q23), and a poor outcome.[10,111] It is not clear whether CD10 negativity has any independent prognostic significance in the absence of a KMT2A gene rearrangement.[112]

    The major immunophenotypic subtypes of B-ALL are as follows:

    • Common B-ALL (CD10 positive and no surface or cytoplasmic immunoglobulin [Ig]).

      Approximately three-quarters of patients with B-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 KMT2A 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)(q21;p13) translocation with the TCF3::PBX1 fusion.[113,114]

      Approximately 3% of patients have transitional pre-B ALL with expression of surface Ig heavy chain in the absence of Ig light chain expression, MYC gene involvement, and L3 morphology. Patients with this phenotype respond well to therapy used for B-ALL.[115]

    • Mature B-ALL (Burkitt lymphoma/leukemia).

      Approximately 2% of patients present with mature B-cell leukemia (surface Ig expression, generally with French-American-British criteria L3 morphology and an 8q24 translocation involving MYC), also called Burkitt leukemia. The treatment for mature B-cell ALL is based on therapy for non-Hodgkin lymphoma and is completely different from the treatment for B-ALL. Rare cases of mature B-cell leukemia that lack surface Ig but have L3 morphology with MYC gene translocations should also be treated as mature B-cell leukemia.[115] For more information about the treatment of children with mature B-cell lymphoma/leukemia and Burkitt lymphoma/leukemia, see Childhood Non-Hodgkin Lymphoma Treatment.

      A small number of cases of IG::MYC-translocated leukemias with precursor B-cell immunophenotype (e.g., absence of CD20 expression and surface Ig expression) have been reported.[116] These cases presented in both children and adults. Like Burkitt lymphoma/leukemia, they had a male predominance and most patients showed L3 morphology. The cases lacked variants in genes recurrently altered in Burkitt lymphoma (e.g., ID3, CCND3, or MYC), whereas variants in RAS genes (frequently altered in B-ALL) were common. The clinical significance and optimal therapy of IG::MYC–translocated leukemias with precursor B-cell phenotype and molecular characteristics requires further study.

  2. T-ALL.

    T-ALL is defined by expression of the T-cell–associated antigens (cytoplasmic CD3, with CD7 plus CD2 or CD5) on leukemic blasts. T-ALL is frequently associated with a constellation of clinical features, including the following:[21,39,82]

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

    While not true historically, with appropriately intensive therapy, children with T-ALL now have an outcome approaching that of children with B-ALL.[21,39,42,43,82,117]

    There are few commonly accepted prognostic factors for patients with T-ALL. Conflicting data exist regarding the prognostic significance of presenting leukocyte counts in T-ALL.[38–45,118] 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.[119]

    Early T-cell precursor (ETP) ALL.

    ETP ALL, a distinct subset of childhood T-ALL, was initially defined by identifying T-ALL cases with gene expression profiles highly related to expression profiles for normal early T-cell precursors.[120] The subset of T-ALL cases identified by these analyses represented 13% of all cases, and are characterized by a distinctive immunophenotype (CD1a and CD8 negativity, with weak expression of CD5 and coexpression of stem cell or myeloid markers). Another subgroup of T-ALL, called near-ETP ALL, has a similar immunophenotype as ETP ALL, except with strong CD5 expression. This subtype represents approximately 15% of cases.[46]

    Initial reports describing ETP ALL suggested that this subset of patients has a poorer prognosis than other patients with T-ALL.[120–122] In addition, studies have reported that patients with ETP and near-ETP ALL have a slower early response and higher frequency of induction failure.[45,46] However, despite higher rates of end-induction MRD and induction failure in these patients, the ETP and near-ETP subtypes do not appear to be independent predictors of inferior EFS or OS.[46,123] For instance, in a study from the U.K. Medical Research Council, the ETP ALL subgroup of patients had nonsignificantly inferior 5-year EFS rates compared with non-ETP patients (76% vs. 84%).[123] Similarly, in the COG AALL0434 [NCT00408005] trial, neither ETP nor near-ETP status had a statistically significant impact on EFS on multivariable analysis.[46] Based on these results, most ALL treatment groups do not change patient treatment based on ETP status.

  3. Myeloid antigen expression.

    Up to one-third of childhood ALL patients have leukemia cells that express myeloid-associated surface antigens. Myeloid-associated antigen expression appears to be associated with specific ALL subgroups, notably those with KMT2A rearrangements, ETV6::RUNX1, and BCR::ABL1.[124–126] Patients with B-ALL who have gene rearrangements involving ZNF384 also commonly show myeloid antigen expression.[127,128] No independent adverse prognostic significance exists for myeloid-surface antigen expression.[124,125]

    For information about leukemia of ambiguous lineage, see the 2016 WHO Classification of Acute Leukemias of Ambiguous Lineage section.

Cytogenetics/genomic alterations

For information about B-ALL and T-ALL cytogenetics/genomics and gene polymorphisms in drug metabolic pathways, see the Cytogenetics/Genomics of Childhood ALL section.

Response to initial treatment

The rapidity with which leukemia cells are eliminated after initiation of treatment and the level of residual disease at the end of induction are associated with long-term outcome. Because treatment response is influenced by the drug sensitivity of leukemic cells and host pharmacodynamics and pharmacogenomics,[129] early response has strong prognostic significance. Various ways of evaluating the leukemia cell response to treatment have been used, including the following:

  1. MRD determination in bone marrow at the end of induction (EOI) and end of consolidation (EOC).
  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. Peripheral blood MRD before end of induction (day 8, day 15).
  6. Persistent leukemia at the end of induction (induction failure).
MRD determination in bone marrow at the end of induction (EOI) and end of consolidation (EOC)

Morphological 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. To detect lower levels of leukemic cells in either blood or marrow, specialized techniques are required. Such techniques include polymerase chain reaction (PCR) assays, which determine unique Ig/T-cell receptor gene rearrangements and fusion transcripts produced by chromosome translocations, or flow cytometric assays, which detect leukemia-specific immunophenotypes. 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 (1 × 10-4 or 0.01%) can be detected routinely.[130] Newer techniques involving high-throughput sequencing (HTS) of Ig/T-cell receptor gene rearrangements can increase sensitivity of MRD detection to 1 in 1 million cells (1 × 10-6 or 0.0001%).[131]

Multiple studies have demonstrated that EOI MRD is an important, independent predictor of outcome in children and adolescents with B-lineage ALL.[132–134] MRD response discriminates outcome in subsets of patients defined by age, leukocyte count, and cytogenetic abnormalities.[135] In general, patients with higher levels of EOI MRD have a poorer prognosis than do those with lower or undetectable levels.[130,132–134] However, the absolute risk of relapse associated with specific MRD levels varies by genetic subtype. For example, at any given level of detectable EOI MRD, patients with favorable cytogenetics, such as ETV6::RUNX1 or high hyperdiploidy, have a lower absolute risk of subsequent relapse than do other patients, while patients with high-risk cytogenetics have a higher absolute risk of subsequent relapse than do other patients.[136] This observation may have important implications when MRD is used to develop risk classification plans.

EOI MRD is used by almost all groups as a factor in determining the intensity of postinduction treatment. Patients found to have higher EOI MRD levels (typically >0.1% to 0.01%) are allocated to more intensive therapies.[130,133,137]; [138][Level of evidence B4]

A study of 619 children with ALL compared the prognostic utility of MRD by flow cytometry with the more sensitive HTS assay. Using an EOI MRD cut point level of 0.01%, HTS identified approximately 30% more cases as positive (i.e., >0.01%). Patients identified as positive by HTS but negative by flow cytometry had an intermediate prognosis, compared with patients categorized as either positive or negative by both methods. Patients meeting the criteria for standard-risk ALL with undetectable MRD by HTS had an especially good prognosis (5-year EFS rate, 98.1%).[131]

MRD levels obtained 10 to 12 weeks after the start of treatment (EOC) have also been shown to be prognostically important. Patients with high levels of EOC MRD have a significantly inferior EFS compared with other patients.[134,135,139] In one study by the Dutch Children’s Oncology Group, patients with low but detectable EOC MRD (<0.05%, assessed by Ig/TR PCR assay) fared as well as those with nondetectable MRD at this time point, if their subsequent MRD assessments were negative. However, these patients did poorly if their subsequent MRD assessments remained detectable by the PCR assay.[140]

  • B-ALL. For patients with B-ALL, evaluating MRD at two time points (EOI and EOC) can identify the following three prognostically distinct patient subsets:[135]
    1. Low or undetectable EOI MRD: Best prognosis.
    2. High EOI MRD but low or negative EOC MRD: Intermediate prognosis.
    3. High EOC MRD (week 10–12 of therapy): Worst prognosis. The prognostic impact of EOC MRD is modulated by NCI risk criteria. NCI high-risk patients with high EOC MRD have DFS rates lower than NCI standard-risk patients who have similar MRD levels at this time point.[139]
  • T-ALL. There are fewer studies documenting the prognostic significance of MRD in patients with T-ALL. The United Kingdom Acute Lymphoblastic Leukaemia (UKALL) group reported that T-ALL patients with nondetectable EOI MRD had excellent outcomes, while those with very high MRD levels (>5%) at EOI had a poor prognosis. However, for all other T-ALL patients, an association between EOI MRD level and relapse risk was not found.[136] The DFCI ALL consortium also reported that T-ALL patients with very low EOI MRD (<10-4) had a very favorable outcome.[45] In the COG AALL0434 trial, high EOI MRD (>0.1%) was an independent predictor of inferior EFS and OS for patients with T-ALL on multivariable analysis.[46] In this trial, high EOI MRD was associated with inferior EFS in patients with non-ETP and near-ETP T-ALL, but not in those meeting the immunophenotypic definition of ETP.[46]

    Another study also indicated that MRD at a later time point may be more prognostically significant in T-ALL.[141] In the Associazione Italiana di Ematologia e Oncologia Pediatrica (AIEOP) ALL-BFM-2000 (NCT00430118) trial, MRD status at day 78 (week 12) was the most important predictor for relapse in patients with T-ALL.[141] Patients with detectable MRD at EOI who had negative MRD by day 78 generally had a favorable prognosis, similar to that of patients who achieved MRD-negativity at the earlier EOI time point.[141] In the COG AALL0434 trial, EOC MRD was evaluated in patients with T-ALL who had very high EOI MRD (>1%). High EOC MRD was associated with a markedly inferior outcome.[46] The COG AALL1231 study confirmed the prognostic significance of EOC marrow MRD for patients with T-ALL.[142]

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 rate, 97% ± 1%) for patients with precursor B-cell phenotype, NCI standard risk age/leukocyte count, CNS1 status, and favorable cytogenetic abnormalities (either high hyperdiploidy with favorable trisomies or the ETV6::RUNX1 fusion) who had less than 0.01% MRD levels at both day 8 (from peripheral blood) and EOI (from bone marrow).[133] The excellent outcomes in patients with low MRD at the EOI were sustained for more than 10 years from diagnosis.[143]

Modifying therapy on the basis of MRD determination has been shown to improve outcome.

  • 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 EOI MRD.[22][Level of evidence B1] In a randomized controlled trial, the UKALL2003 study also demonstrated improved EFS for standard-risk and intermediate-risk patients who received augmented therapy if EOI MRD was greater than 0.01% (5-year EFS rates, 89.6% for augmented therapy vs. 82.8% for standard therapy).[144]
  • The Dutch ALL10 trial stratified patients into the following three risk groups on the basis of MRD after the first month of treatment and after the second cycle of chemotherapy:[145][Level of evidence B4]
    • Standard risk (low MRD after the first month of treatment).
    • Moderate risk (high MRD after the first month of treatment, low MRD after the second cycle of chemotherapy).
    • High risk (high MRD after the second cycle of chemotherapy).

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

  • In the DFCI ALL Consortium 05-001 trial, B-ALL patients with high EOI MRD (defined as ≥1 × 10-3) were classified as very high risk regardless of other presenting characteristics. These patients received an intensified cytotoxic chemotherapy backbone. The 5-year DFS rate for these patients was 77%, significantly better than outcome for such patients on previous trials, when EOI MRD was not used to stratify therapy.[8]
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 patients who have slower clearance of leukemia cells from the bone marrow.[146] MRD assessments at the EOI 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.[133,147]

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 patients whose peripheral blast counts remain above 1,000/µL (a poor prednisone response).[21] Poor prednisone response is observed in fewer than 10% of patients.[21,148] Treatment stratification for protocols of the Berlin-Frankfurt-Münster (BFM) clinical trials group historically were partially based on early response to the 7-day prednisone prophase (administered immediately before the initiation of multiagent remission induction). The current trial being conducted by that group still uses prednisone response to risk-stratify patients with T-ALL but not B-ALL.

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.[149] Rate of clearance of peripheral blasts has been found to be of prognostic significance in both T-cell and B-lineage ALL.[149]

Peripheral blood MRD before EOI (day 8, day 15)

MRD measured in 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. Increasing MRD levels were associated with a progressively poorer outcome.[133]
  • In multivariate analysis, EOI 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.[150] 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.

Persistent leukemia at the EOI (induction failure)

Nearly all children with ALL achieve complete morphological remission by the end of the first month of treatment. The presence of greater than 5% lymphoblasts by morphological assessment at the EOI phase is observed in 1% to 2% of children with ALL.[22,23,151–153]

Features associated with a higher risk of induction failure include the following:[153–155]

  • T-cell phenotype, especially the ETP phenotype.[46]
  • Higher WBC at diagnosis for patients with B-ALL.
  • Older age.
  • Unfavorable biology.
    • KMT2A rearrangement.
    • BCR::ABL1 rearrangement (before the use of tyrosine kinase inhibitors).
    • Rearrangement of PDGFRB (most commonly EBF1::PDGFRB), commonly associated with the BCR::ABL1-like subtype.[153,156] These patients represent less than 1% of B-ALL cases in children but account for as much as 10% of induction failure cases.[153] In one retrospective study, 43 of 49 patients (88%) with PDGFRB fusions had EOI MRD levels greater than 1%.[157]

In a large retrospective study, the OS rate of patients with induction failure was only 32%.[151] However, there was significant clinical and biological heterogeneity. A relatively favorable outcome was observed in patients with B-ALL between the ages of 1 and 5 years without adverse cytogenetics (KMT2A rearrangement or BCR::ABL1). This group had a 10-year survival rate exceeding 50%, and hematopoietic stem cell transplant (HSCT) in first remission was not associated with a survival advantage compared with chemotherapy alone for this subset. Patients with the poorest outcomes (10-year survival rate, <20%) included those who were aged 14 to 18 years, or who had the BCR::ABL1 fusion or KMT2A rearrangement. B-ALL patients younger than 6 years and T-ALL patients (regardless of age) appeared to have better outcomes if treated with allogeneic HSCT after achieving CR than those who received further treatment with chemotherapy alone.[151] However, in the COG AALL0434 (NCT00408005) study, an advantage for HSCT in first CR for T-ALL patients with induction failure (defined as M3 marrow at EOI) was not observed. In this study, T-ALL patients were assigned to receive nelarabine during several postinduction treatment phases and high-dose methotrexate during the first interim maintenance phase. The 5-year EFS rate of these patients was 53.1%, with no significant difference between those who proceeded to HSCT in first CR (n = 20) and those who did not (n = 23) (P = .42).[158]

Flow cytometry versus morphology

MRD is now being integrated with morphological assessment into the response to induction therapy, on the basis of studies that showed that patients with MRD levels above 5%, despite morphological CR, had outcomes similar to patients with morphological induction failure.

  1. In the UKALL2003 (NCT00222612) study, 59 of 3,113 patients (1.9%) had morphological induction failure.[153]
    • The 5-year EFS rate was 51%, and the OS rate was 58%.
    • 2.3% of patients had a morphological remission but had MRD of ≥5% measured by real-time quantitative IgH–T-cell receptor PCR. This group had a 5-year EFS rate of 47%, similar to those with morphological induction failure.
    • The authors suggested that using both morphological and MRD criteria to define induction failure would more precisely identify patients with poor outcomes.
  2. A study of 9,350 patients enrolled on COG clinical trials between 2004 and 2014 compared characteristics of patients and their outcomes categorized by morphology (M1 vs. M2/M3) and MRD status assessed by flow cytometry (<5% vs. ≥5%). Morphological remission (M1 status) was achieved for 98.6% of B-ALL patients and 93.8% of T-ALL patients at the EOI.[159]
    • Morphology and MRD were concordant in 97.4% of children. However, only 87.3% of T-ALL patients were M1 with MRD of <5%, while 97.8% of B-ALL patients were in concordant remission.
    • Approximately 20% of patients (40 of 202) with M2/M3 morphology had MRD of <5%. B-ALL patients with M2/M3 morphology but MRD of <5% had a 5-year OS rate of 72.7%, which was inferior to that of patients concordantly in remission (5-year OS rate, 93.8%) but superior to that of patients with M3 marrow (5-year OS rate, 43.4%).
    • Among B-ALL and T-ALL patients with M1 marrow, 0.9% of B-ALL patients and 6.9% of T-ALL patients had MRD of ≥5%. Their outcome was compared with that of patients with M1 marrow and MRD of <5% and are shown in Table 5 below.
    • Table 5 shows that for children with B-ALL with M1 marrow and MRD of ≥5%, the 5-year EFS rate was significantly inferior to that of children concordantly in remission (59.1% vs. 87.1%) but was superior to that of children concordantly not in remission (M2 with MRD ≥5%: 5-year EFS rate, 39.1%).
    • The impact on EFS for MRD of ≥5% for children with B-ALL in morphological remission was driven by NCI high-risk patients, as there was no significant difference in EFS between NCI standard-risk patients in morphological remission with or without MRD of ≥5%.
    • Inferior EFS rates were also observed for patients with T-ALL with M1 marrow and MRD of ≥5% compared with those in concordant remission (87.6% vs. 80.3%). However, outcome for T-ALL patients not in remission (whether by morphology or MRD or both) was superior to that of comparable patients with B-ALL.
    • Factors predictive of discordant MRD (≥5%) for patients in morphological remission at EOI included age 10 years and older, WBC count at presentation of 50,000/µL or higher, neutral or unfavorable cytogenetics, and ETP ALL (for patients with T-ALL).
Table 5. 5-Year Survival Outcomes Among Patients With Concordant in Remission, Discordant, and Concordant Not in Remission End-of-Induction Bone Marrow MRD Levelsa
Outcome M1/MRD <5% P valueb M1/MRD ≥5% P valuec M2/MRD ≥5%
HR = high risk; MRD = minimal residual disease; SR = standard risk.
aAdapted from Gupta et al.[159]
bP value is comparing M1/MRD <5% with M1/MRD ≥5%.
cP value is comparing M1/MRD ≥5% with M2/MRD ≥5%.
Event-free survival rates:
B-ALL, overall 87.1% ± 0.4% (n = 7,682) <.0001 59.1% ± 6.5% (n = 66) .009 39.1% ± 7.9% (n = 40)
  B-ALL, SR 90.8% ± 0.4% (n = 5,000) .25 85.9% ± 7.6% (n = 22) .45 76.2% ± 15.2% (n = 9)
  B-ALL, HR 80% ± 0.9% (n = 2,682) <.0001 44.9% ± 8.3% (n = 44) .05 29% ± 8.2% (n = 31)
T-ALL 87.6% ± 1.5% (n = 1,303) .01 80.3% ± 7.3% (n = 97) .13 62.7% ± 13.5% (n = 40)
Overall survival rates:
B-ALL, overall 93.8% ± 0.3% (n = 7,682) <.0001 77.2% ± 5.6% (n = 66) .01 59% ± 8.9% (n = 40)
  B-ALL, SR 96.6% ± 0.3% (n = 5,000) .24 95.5% ± 4.6% (n = 22 ) .75 88.9% ± 12.1% (n = 9)
  B-ALL, HR 88.4% ± 0.7% (n = 2,682) <.0001 66.9% ± 8.3% (n = 44) .06 51.4% ± 10.4% (n = 31)
T-ALL 91.9% ± 1.3% (n = 1,303) .005 83.4% ± 6.8% (n = 97) .34 76.7% ± 12.3% (n = 40)

Prognostic (Risk) Groups

For decades, clinical trial groups studying childhood ALL have used risk classification schemes to assign patients to therapeutic regimens on the basis of their estimated risk of treatment failure. Initial risk classification systems used clinical factors such as age and presenting WBC count. Response-to-therapy measures were subsequently added, with some groups using early morphological bone marrow response (e.g., at day 8 or day 15) and with other groups using response of circulating leukemia cells to single-agent prednisone. Contemporary risk classification systems continue to use clinical factors such as age and presenting WBC count and incorporate cytogenetics and genomic lesions of leukemia cells at diagnosis (e.g., favorable and unfavorable translocations) and response to therapy based on detection of MRD at EOI (and in some cases at later time points).[141] 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) on the basis of 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%.[4,57,148,160,161] Additional factors, including cytogenetic abnormalities and measures of early response to therapy (e.g., MRD levels in peripheral blood on day 8 and in bone marrow samples at the EOI), 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%.[4,133]

Patients who are at very high risk of treatment failure include the following:[162–165]

  • Infants with KMT2A rearrangements.
  • Patients with hypodiploidy (<44 chromosomes).
  • Patients with initial induction failure.

Berlin-Frankfurt-Münster (BFM) risk groups

Since 2000, risk stratification on BFM protocols has been based on treatment response criteria, as well as biology. Treatment response is assessed primarily via MRD measurements at two time points, EOI (time point 1, week 5) and end of the IB phase (similar to COG consolidation phase) at week 12 (time point 2). High MRD at both time points is defined as higher than 5 × 10-4.

The BFM defines 3 risk groups based on early response:[135]

  • Standard risk: Patients who have negative MRD at both time points.
  • Intermediate risk: Patients who have high MRD at time point 1 and negative MRD at time point 2.
  • High risk: Patients with high MRD at time point 2. Patients with T-ALL with a poor response to the prednisone prophase are also considered high risk, regardless of subsequent MRD.

Biological factors used to stratify patients as high risk (regardless of MRD at either time point) include KMT2A::AFF1, TCF3::HLF, and hypodiploidy (<45 chromosomes). Patients with IKZF1-plus status (IKZF1 deletions that co-occurred with deletions in CDKN2A, CDKN2B, PAX5, or PAR1 in the absence of ERG deletion) [166] are considered high risk if they have high MRD at EOI, regardless of EOC MRD. Age, presenting leukocyte count, and CNS status at diagnosis do not factor into the current risk classification schema.

Prognostic (risk) groups under clinical evaluation

  1. COG AALL1731 (NCT03914625) standard-risk and AALL1732 (NCT03959085) high-risk clinical trials: The COG classifies patients into six risk groups for patients with B-ALL (standard-risk favorable, standard-risk average, standard-risk high, high-risk favorable, high risk, and very high risk) on the basis of the following:
    • Age and presenting leukocyte count (using NCI risk-group criteria).[3]
      • NCI standard (low) risk: Includes children aged 1 year to <10 years with WBC <50,000/µL at the time of diagnosis.
      • NCI high risk: Includes children aged ≥10 years and/or children who have WBC ≥50,000/µL at the time of diagnosis.
    • Extramedullary disease (presence or absence of CNS and/or testicular leukemia).
      • CNS1: Absence of blasts on CSF cytospin preparation, regardless of the number of WBCs.
      • CNS2: Presence of <5 WBC/μL in CSF and cytospin positive for blasts; or traumatic LP, ≥5 WBC/μL, cytospin positive for blasts but negative by Steinherz/Bleyer algorithm.
      • CNS3 is divided and defined as follows:
        • CNS3a: <10 RBC/μL; ≥5 WBC/μL and cytospin positive for blasts.
        • CNS3b: ≥10 RBC/μL; ≥5 WBC/μL and positive by Steinherz/Bleyer algorithm.
        • CNS3c: Clinical signs of CNS leukemia (such as facial nerve palsy, brain/eye involvement or hypothalamic syndrome).
    • Genomic alterations in leukemia cells.
    • Day 8 peripheral blood MRD.
    • Day 29 bone marrow morphological response and MRD.
    • EOC MRD.
    • Steroid pretreatment.

    Morphological 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 separate trials and are not risk classified in this way.

    For patients with B-ALL, the definitions of favorable, unfavorable, and neutral cytogenetics are as follows:

    • Favorable cytogenetic features include the following:
      • Hyperdiploidy with double trisomies of chromosomes 4 and 10 (double trisomy); or
      • ETV6::RUNX1 fusion.
    • Unfavorable cytogenetic features include the following:
      • Hypodiploidy (<44 chromosomes or DNA index <0.81).
      • KMT2A rearrangements.
      • t(17;19)(q21-q22;p13.3) or resultant TCF3::HLF fusion transcript.
      • Intrachromosomal amplification of chromosome 21 (iAMP21); and
      • BCR::ABL1 (Ph+ or t(9;22)(q34;q11)). Patients with BCR::ABL1 ALL are treated on a separate clinical trial.
    • Neutral cytogenetics: Lacking favorable and unfavorable cytogenetic features.

    NCI standard-risk patients are divided into a highly favorable group (standard-risk favorable; 5-year DFS rate, >95%), a group with favorable outcome (standard-risk average; 5-year DFS rate, 90%–95%), and a group with a 5-year DFS rate below 90% (standard-risk high). Patients classified as standard-risk high receive postinduction backbone chemotherapy as per high-risk B-ALL regimens with intensified consolidation, interim maintenance, and reinduction therapy. Criteria for these three groups are provided in Table 6, Table 7, and Table 8 below.

    Table 6. Standard-Risk Favorable B-ALL (Non-Down Syndrome and Down Syndrome)
    NCI Risk Group CNS Stage Steroid Pretreatmenta Favorable Genetics (ETV6::RUNX1 or DT) PB MRD Day 8 BM MRD Day 29
    BM = bone marrow; CNS = central nervous system; DT = double trisomy; MRD = minimal residual disease; NCI = National Cancer Institute; PB = peripheral blood; SR = standard risk.
    aWithin one month prior to diagnosis.
    SR 1, 2 None Yes <1% <0.01%
    Table 7. Standard-Risk Average B-ALL (Non-Down Syndrome and Down Syndrome)
    NCI Risk Group CNS Stage ETV6::RUNX1 DT Neutral Cytogenetics PB MRD Day 8 BM MRD Day 29
    BM = bone marrow; CNS = central nervous system; DT = double trisomy; MRD = minimal residual disease; NCI = National Cancer Institute; PB = peripheral blood; SR = standard risk.
    SR 1, 2 Yes to either No ≥1% <0.01%
    SR 1, 2 No Yes No Any ≥0.01 to <0.1%
    SR 1 No No Yes Any <0.01%
    Table 8. Standard-Risk High B-ALL
    NCI Risk Group CNS Stage ETV6::RUNX1 DT Neutral Cytogenetics Unfavorable Cytogenetics PB MRD Day 8 BM MRD Day 29
    BM = bone marrow; CNS = central nervous system; DT = double trisomy; MRD = minimal residual disease; NCI = National Cancer Institute; PB = peripheral blood; SR = standard risk.
    SR 1, 2 Yes No No No Any ≥0.01%
    SR 1, 2 No Yes No No Any ≥0.1%
    SR 1 No No Yes No Any ≥0.01%
    SR 2 No No Yes No Any Any
    SR 1, 2 No No No Yes Any Any

    High-risk favorable B-ALL is defined by the characteristics in Table 9. These patients have an EFS rate higher than 90% on past COG clinical trials for high-risk patients.

    Table 9. Characteristics of High-Risk Favorable B-ALL Patients
    NCI Risk Group Age (y) CNS Status Testicular Leukemia Steroid Pretreatment Favorable Genetics (ETV6::RUNX1 or DT) Bone marrow MRD EOI
    HR <10 1 None ≤24 hoursa Yes <0.01%
    CNS = central nervous system; DT = double trisomy; EOI = end of induction; HR = high risk; MRD = minimal residual disease; NCI = National Cancer Institute.
    aWithin two weeks of diagnosis.

    High-risk B-ALL is defined by the characteristics in Table 10. NCI standard-risk patients are elevated to high-risk status based on steroid pretreatment and CNS and/or testicular involvement.

    Table 10. Characteristics of High-Risk B-ALL Patients
    NCI Risk Group Age (y) CNS and/or Testicular Leukemia Steroid Pretreatment Cytogenetics Bone marrow MRD EOI Bone marrow MRD EOC
    CNS = central nervous system; EOC = end of consolidation; EOI = end of induction; HR = high risk; MRD = minimal residual disease; N/A = not applicable; NCI = National Cancer Institute; SR = standard risk.
    aCNS3.
    bPhiladelphia chromosome–positive (Ph+) ALL is excluded.
    cOnly subjects with EOI bone marrow MRD ≥0.01% will have a bone marrow MRD assessment at EOC.
    dWithin 2 weeks of diagnosis.
    eCNS2 or CNS3.
    SR <10 Yesa Any Anyb Any <1%c
    SR <10 No >24 hoursd Anyb Any <1%c
    HR ≥10 Any Any Anyb <0.01% N/A
    HR <10 Yese Any Anyb <0.01% N/A
    HR <10 No >24 hoursd Anyb <0.01% N/A
    HR <10 No ≤24 hoursd Neutral/unfavorableb <0.01% N/A
    HR Any Any Any Anyb ≥0.01% <0.01%

    NCI high-risk patients with EOC marrow MRD ≥0.01% are classified as very high risk and are eligible for a chimeric antigen receptor (CAR) T-cell clinical trial in first remission (NCT03792633).

    Patients with B-ALL and Down syndrome are classified into risk groups similar to other children, but Down syndrome patients classified as high risk receive a treatment regimen that is modified to reduce toxicity.

Current Clinical Trials

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

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  128. Qian M, Zhang H, Kham SK, et al.: Whole-transcriptome sequencing identifies a distinct subtype of acute lymphoblastic leukemia with predominant genomic abnormalities of EP300 and CREBBP. Genome Res 27 (2): 185-195, 2017. [PUBMED Abstract]
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  131. Wood B, Wu D, Crossley B, et al.: Measurable residual disease detection by high-throughput sequencing improves risk stratification for pediatric B-ALL. Blood 131 (12): 1350-1359, 2018. [PUBMED Abstract]
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  133. Borowitz MJ, Devidas M, Hunger SP, et al.: Clinical significance of minimal residual disease in childhood acute lymphoblastic leukemia and its relationship to other prognostic factors: a Children’s Oncology Group study. Blood 111 (12): 5477-85, 2008. [PUBMED Abstract]
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  135. Conter V, Bartram CR, Valsecchi MG, et al.: Molecular response to treatment redefines all prognostic factors in children and adolescents with B-cell precursor acute lymphoblastic leukemia: results in 3184 patients of the AIEOP-BFM ALL 2000 study. Blood 115 (16): 3206-14, 2010. [PUBMED Abstract]
  136. O’Connor D, Enshaei A, Bartram J, et al.: Genotype-Specific Minimal Residual Disease Interpretation Improves Stratification in Pediatric Acute Lymphoblastic Leukemia. J Clin Oncol 36 (1): 34-43, 2018. [PUBMED Abstract]
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  139. Rau RE, Dai Y, Devidas M, et al.: Prognostic impact of minimal residual disease at the end of consolidation in NCI standard-risk B-lymphoblastic leukemia: A report from the Children’s Oncology Group. Pediatr Blood Cancer 68 (4): e28929, 2021. [PUBMED Abstract]
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Treatment Option Overview for Childhood ALL

Phases of Therapy

Treatment for children with acute lymphoblastic leukemia (ALL) is typically divided into the following phases:

  1. Remission induction chemotherapy (at the time of diagnosis).
  2. Postinduction therapy (after achieving complete remission).

Sanctuary Sites

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

Central nervous system (CNS)

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

Testes

Overt testicular involvement at the time of diagnosis occurs in approximately 2% of males. In early ALL trials, testicular involvement at diagnosis was an adverse prognostic factor. With more aggressive initial therapy, however, the prognostic significance of initial testicular involvement is unclear.[1,2] The role of radiation therapy for testicular involvement is also unclear. A study from St. Jude Children’s Research Hospital suggests that a good outcome can be achieved with aggressive conventional chemotherapy without radiation.[1] The Children’s Oncology Group has also adopted this strategy for boys with testicular involvement that resolves completely during induction chemotherapy.

References
  1. Hijiya N, Liu W, Sandlund JT, et al.: Overt testicular disease at diagnosis of childhood acute lymphoblastic leukemia: lack of therapeutic role of local irradiation. Leukemia 19 (8): 1399-403, 2005. [PUBMED Abstract]
  2. Sirvent N, Suciu S, Bertrand Y, et al.: Overt testicular disease (OTD) at diagnosis is not associated with a poor prognosis in childhood acute lymphoblastic leukemia: results of the EORTC CLG Study 58881. Pediatr Blood Cancer 49 (3): 344-8, 2007. [PUBMED Abstract]

Special Considerations for the Treatment of Children With ALL

The treatment of children and adolescents with acute lymphoblastic leukemia (ALL) entails complicated risk assignment, extensive therapies, and intensive supportive care (e.g., transfusions; management of infectious complications; and emotional, financial, and developmental support). Because of these factors, the evaluation and treatment of these patients are best coordinated by a multidisciplinary team in cancer centers or hospitals with all of the necessary pediatric supportive care facilities.[1] This multidisciplinary team approach incorporates the skills of the following pediatric specialists and others to ensure that children receive treatment, supportive care, and rehabilitation to achieve optimal survival and quality of life:

  • Primary care physicians.
  • Pediatric medical oncologists and hematologists.
  • Pediatric surgeons.
  • Pathologists.
  • Pediatric radiation oncologists.
  • Pediatric intensivists.
  • Rehabilitation specialists.
  • Pediatric oncology nurses.
  • Social workers.
  • Child-life professionals.
  • Psychologists.
  • Nutritionists.

For specific information about supportive care for children and adolescents with cancer, see the summaries on Supportive and Palliative Care.

The American Academy of Pediatrics has outlined guidelines for pediatric cancer centers and their role in the treatment of children and adolescents with cancer.[1] Treatment of childhood ALL typically involves chemotherapy given for 2 to 3 years. Because myelosuppression and generalized immunosuppression are anticipated consequences of leukemia and chemotherapy treatment, adequate facilities must be immediately available for both hematological support and treatment of infections and other complications throughout all phases of therapy. Approximately 1% to 3% of patients die during the remission induction phase, and another 1% to 3% die after having achieved complete remission from treatment-related complications.[2–6] It is important that the clinical centers and the specialists directing the patient’s care maintain contact with the referring physician in the community. Strong lines of communication optimize any urgent or interim care required when the child is at home.

Clinical trials are generally available for children with ALL, with specific protocols designed for children at standard (low) risk of treatment failure and for children at higher risk of treatment failure. Clinical trials for children with ALL are generally designed to compare standard therapy for a particular risk group with a potentially better treatment approach that may improve survival and/or diminish toxicities associated with the standard treatment regimen. Other types of clinical trials test novel therapies when there is no standard therapy for a cancer diagnosis. Many of the therapeutic innovations that produced increased survival rates in children with ALL were achieved through clinical trials, and it is appropriate for children and adolescents with ALL to be offered participation in a clinical trial. Information about ongoing clinical trials is available from the NCI website.

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

References
  1. American Academy of Pediatrics: Standards for pediatric cancer centers. Pediatrics 134 (2): 410-4, 2014. Also available online. Last accessed February 25, 2025.
  2. Rubnitz JE, Lensing S, Zhou Y, et al.: Death during induction therapy and first remission of acute leukemia in childhood: the St. Jude experience. Cancer 101 (7): 1677-84, 2004. [PUBMED Abstract]
  3. Christensen MS, Heyman M, Möttönen M, et al.: Treatment-related death in childhood acute lymphoblastic leukaemia in the Nordic countries: 1992-2001. Br J Haematol 131 (1): 50-8, 2005. [PUBMED Abstract]
  4. Vrooman LM, Stevenson KE, Supko JG, et al.: Postinduction dexamethasone and individualized dosing of Escherichia Coli L-asparaginase each improve outcome of children and adolescents with newly diagnosed acute lymphoblastic leukemia: results from a randomized study–Dana-Farber Cancer Institute ALL Consortium Protocol 00-01. J Clin Oncol 31 (9): 1202-10, 2013. [PUBMED Abstract]
  5. Lund B, Åsberg A, Heyman M, et al.: Risk factors for treatment related mortality in childhood acute lymphoblastic leukaemia. Pediatr Blood Cancer 56 (4): 551-9, 2011. [PUBMED Abstract]
  6. Alvarez EM, Malogolowkin M, Li Q, et al.: Decreased Early Mortality in Young Adult Patients With Acute Lymphoblastic Leukemia Treated at Specialized Cancer Centers in California. J Oncol Pract 15 (4): e316-e327, 2019. [PUBMED Abstract]

Treatment of Newly Diagnosed Childhood ALL

Standard Induction Treatment Options for Newly Diagnosed ALL

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

  1. Chemotherapy.

Remission induction chemotherapy

The goal of the first phase of therapy (remission induction) is to induce a complete remission (CR). This induction phase typically lasts 4 weeks. Overall, approximately 98% of patients with newly diagnosed B-ALL achieve CR by the end of this phase, with somewhat lower rates in infants and in noninfant patients with T-ALL or high presenting leukocyte counts.[1–5]

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

  • Vincristine.
  • Corticosteroid (either prednisone or dexamethasone).
  • Asparaginase.
  • Intrathecal chemotherapy.

The Children’s Oncology Group (COG) protocols administer a three-drug induction (vincristine, corticosteroid, and pegaspargase) to National Cancer Institute (NCI) standard-risk B-ALL patients and a four-drug induction (vincristine, corticosteroid, and pegaspargase plus anthracycline) to NCI high-risk B-ALL and all T-ALL patients. Other groups use a four-drug induction for all patients.[1–3]

Corticosteroid therapy

Many current regimens use dexamethasone instead of prednisone during remission induction and later phases of therapy, although controversy exists as to whether dexamethasone benefits all subsets of patients. Some trials also suggest that dexamethasone during induction may be associated with more toxicity than prednisone, including higher rates of infection, myopathy, and behavioral changes.[1,6–8] The COG reported that dexamethasone during induction was associated with a higher risk of osteonecrosis in older children (aged >10 years),[8] although this finding has not been confirmed in other randomized studies.[1,7]

Evidence (dexamethasone vs. prednisone during induction):

  1. The Children’s Cancer Group conducted a randomized trial that compared dexamethasone and prednisone in standard-risk B-ALL patients receiving a three-drug induction without an anthracycline.[6]
    • Dexamethasone was associated with a superior event-free survival (EFS).
    • Dexamethasone was associated with a higher frequency of reversible steroid myopathy and hyperglycemia. No significant differences in rates of infection during induction were observed between the two randomized arms.
  2. Another randomized trial that included both standard-risk and high-risk patients was conducted by the United Kingdom Medical Research Council (MRC).[7]
    • The trial demonstrated that dexamethasone was associated with a more favorable outcome than prednisolone in all patient subgroups.
    • Patients who received dexamethasone had a significantly lower incidence of both central nervous system (CNS) and non-CNS relapses than did patients who received prednisolone.
    • Dexamethasone was associated with a higher incidence of steroid-associated behavioral problems and myopathy, but an excess risk of osteonecrosis was not observed. There was no difference in induction death rates between the randomized groups.
  3. The Associazione Italiana di Ematologia e Oncologia Pediatrica (AIEOP) ALL-BFM-2000 (NCT00430118) trial randomly assigned 3,720 patients to receive either dexamethasone (10 mg/m2/d) or prednisone (60 mg/m2/d) during multiagent remission induction (including an anthracycline for all patients) after a 7-day prednisone prophase.[9]
    • Dexamethasone was associated with higher incidence of life-threatening events (primarily infections), resulting in a significantly higher induction death rate (2.5% for dexamethasone vs. 0.9% for prednisone; P = .00013).
    • There was no difference in rates of osteonecrosis between the randomized groups.
    • The 5-year cumulative incidence of relapse was significantly lower with dexamethasone (11% vs. 16%; P < .0001), resulting in superior 5-year EFS rates (84% for dexamethasone vs. 81% for prednisone, P = .024) despite the increased induction death rate.
    • No difference in overall survival (OS) was observed based on steroid randomization, although the study was not sufficiently powered to detect small differences in OS.
    • In a predefined subgroup analysis, a survival benefit was observed with dexamethasone treatment in patients with T-ALL and a good response to the prednisone prophase (5-year OS rates, 91% with dexamethasone vs. 83% with prednisone, P = .036).
  4. The COG conducted a randomized trial of dexamethasone and prednisone in NCI high-risk B-ALL patients.[8] Patients were randomly assigned to receive 14 days of dexamethasone or 28 days of prednisone during a four-drug induction (with an anthracycline). This trial also included a randomized comparison of high-dose and escalating-dose methotrexate during the interim maintenance phase.
    • Dexamethasone was associated with a higher rate of infection, but there was no difference in the induction death rate when comparing dexamethasone and prednisone.
    • For patients who were younger than 10 years at diagnosis, there was a significant interaction between the corticosteroid and methotrexate randomizations. However, the best outcome for this group of patients was observed in those who received both dexamethasone during induction and high-dose methotrexate during interim maintenance.
    • The corticosteroid randomization was closed early for patients aged 10 years or older at diagnosis because of excessive rates of osteonecrosis in patients randomly assigned to dexamethasone. However, there was no EFS benefit associated with dexamethasone in these older patients (5-year EFS rates of 73.1% with dexamethasone and 73.9% with prednisone; P = .78)

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

Asparaginase

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

Pegaspargase (PEG-asparaginase)

Pegaspargase is a form of L-asparaginase in which the E. coli–derived enzyme is modified by the covalent attachment of polyethylene glycol. It is commonly used during both induction and postinduction phases of treatment in newly diagnosed patients treated in Western Europe. Pegaspargase is not available in the United States, but it is still available in other countries.

Pegaspargase may be given either intramuscularly (IM) or intravenously (IV).[11] Pharmacokinetics and toxicity profiles are similar for IM and IV pegaspargase administration.[11] There is no evidence that IV administration of pegaspargase is more toxic than IM administration.[11–13]

Pegaspargase has a much longer serum half-life than native E. coli L-asparaginase, producing prolonged asparagine depletion after a single injection.[14]

Serum asparaginase enzyme activity levels of more than 0.1 IU/mL have been associated with serum asparagine depletion. Studies have shown that a single dose of pegaspargase given either IM or IV as part of multiagent induction results in serum enzyme activity of more than 0.1 IU/mL in nearly all patients for at least 2 to 3 weeks.[11,12,15,16] In one study of 54 NCI high-risk patients conducted by the COG, plasma asparaginase activity as low as 0.02 IU/mL was associated with serum asparagine depletion. Using that cutoff value, it was estimated that 96% of patients maintained the therapeutic effect (plasma asparagine depletion) for 22 to 29 days after a single pegaspargase dose of 2,500 IU/m2.[17] In one randomized study, higher doses of pegaspargase (3,500 IU/m2) did not improve outcome when compared with standard doses (2,500 IU/m2).[18][Level of evidence A1]

In another study, doses of pegaspargase were reduced in an attempt to decrease toxicity.[19] While lower doses were successful in maintaining appropriate asparaginase levels of more than 0.1 IU/mL, the frequency of asparaginase-related toxicities was similar to the frequency of toxicities reported in previous studies that used higher doses of pegaspargase. This study did not report on the impact of lower doses of pegaspargase on EFS.

Evidence (use of pegaspargase versus native E. coli L-asparaginase):

  1. A randomized comparison of IV pegaspargase versus IM native E. coli asparaginase was conducted. Each agent was administered for a 30-week period after the achievement of CR.[13][Level of evidence A3]
    • Serum asparaginase activity (SAA) levels were significantly higher with IV pegaspargase and exceeded goal therapeutic levels (>0.1 IU/mL) in nearly all patients throughout the 30-week period.
    • There was no significant difference in EFS and OS between the randomized arms.
    • There was no difference in rates of asparaginase-related toxicities, including hypersensitivity, pancreatitis, and thromboembolic complications.
    • Similar outcome and similar rates of asparaginase-related toxicities were observed for both groups of patients.
    • IV pegaspargase was associated with less treatment-related anxiety, as assessed by patient and parent surveys.
  2. Another randomized trial of patients with standard-risk ALL assigned patients to receive either pegaspargase or native E. coli asparaginase during induction and in each of two delayed intensification courses.[15]
    • A single dose of pegaspargase given in conjunction with vincristine and prednisone during induction therapy appeared to have similar activity and toxicity as nine doses of IM E. coli L-asparaginase (3 times a week for 3 weeks).[15]
    • The use of pegaspargase was associated with more rapid blast clearance and a lower incidence of neutralizing antibodies.

Patients with an allergic reaction to pegaspargase are typically switched to Erwinia L-asparaginase. A COG analysis investigated the deleterious effect on disease-free survival (DFS) of early discontinuation of treatment with pegaspargase in patients with high-risk B-ALL. The study found that the adverse effect on outcome could be reversed with the use of Erwinia L-asparaginase to complete the planned course of asparaginase therapy.[20][Level of evidence C2] Measurement of SAA levels after a mild or questionable reaction to pegaspargase may help to differentiate patients for whom the switch to Erwinia is indicated (because of inadequate SAA) versus those for whom a change in preparation may not be necessary.[21,22]

Evidence (adverse prognostic impact of early discontinuation of pegaspargase or silent inactivation of asparaginase):

  1. Several studies have identified a subset of patients who experience silent inactivation of asparaginase, which is defined as the absence of therapeutic SAA levels without overt allergy.[23,24]
    • In a trial conducted by the Dana-Farber Cancer Institute (DFCI) Consortium, 12% of patients who were initially treated with native E.coli L-asparaginase demonstrated silent inactivation. These patients had a superior EFS if their asparaginase preparation was changed.[24]
    • Patients who were treated with pegaspargase appear to have lower levels of silent inactivation (<10%).[13,23,25]

    Determination of the optimal frequency of pharmacokinetic monitoring for pegaspargase-treated patients, and whether such screening impacts outcome, awaits further investigation.

  2. A report from the COG included 8,196 patients with newly diagnosed B-ALL who were enrolled between 2004 to 2011.[20][Level of evidence C2]
    • The cumulative incidence of pegaspargase discontinuation (because of toxicity) was 12.2% in NCI standard-risk patients and 25.4% in NCI high-risk patients.
    • In multivariable analysis, NCI high-risk patients who discontinued pegaspargase early had inferior DFS (hazard ratio [HR], 1.5; P = .002) than did those who received all prescribed doses. For NCI standard-risk patients, there was no impact of pegaspargase discontinuation on DFS, except in patients with slow-early response who received intensified postinduction therapy (HR, 1.7; P = .03).
    • NCI high-risk patients who discontinued pegaspargase but then switched to Erwinia asparaginase and received all subsequent intended doses, did not have an increased risk of relapse (HR, 1.1; P = .69).
  3. An analysis of 1,115 non–high-risk ALL patients from the Nordic Society of Pediatric Hematology and Oncology (NOPHO) ALL2008 protocol reported the following:[25]
    • 255 patients received a truncated asparaginase course because of toxicity, and 46 patients had evidence of silent inactivation on therapeutic drug monitoring.
    • The 7-year cumulative incidence of relapse was 11.1% in the 301 patients who received a truncated asparaginase course, compared with 6.7% in the remaining 814 patients who received the planned courses (HR, 1.73; P = .03).
    • In a Cox model, suboptimal asparaginase treatment (because of either truncated pegaspargase or silent inactivation) was significantly associated with a higher relapse risk (HR, 1.69; P = 0.03).

In an attempt to decrease hypersensitivity reactions to pegaspargase, the Dutch Childhood Oncology Group-ALL11 protocol randomly assigned patients to receive either continuous or noncontinuous dosing after induction therapy. The occurrence of inactivating hypersensitivity reactions was seven times lower and antibody levels were significantly lower in the continuous-dosing arm. There was no difference in total number of asparaginase toxicities or the 5-year incidences of relapse, death, or disease-free survival between the treatment arms.[26]

Calaspargase pegol

Calaspargase pegol is another formulation of pegylated asparaginase that is also available for the treatment of children and adolescents with ALL.[27] This formulation is similar in structure to pegaspargase, except with a different linker between the L-asparaginase enzyme and the PEG moiety, resulting in a longer half-life.[28,29]

Evidence (calaspargase pegol vs. pegaspargase):

  1. In a COG study, 165 patients with high-risk B-ALL were randomly assigned to receive either calaspargase pegol or pegaspargase during the induction phase of ALL therapy.[28]
    • The mean half-life of calaspargase pegol was approximately 2.5 times longer than pegaspargase.
    • The total systemic exposure to calaspargase pegol was greater than for pegaspargase.
    • Twenty-five days after a dose of calaspargase pegol, 95% of patients maintained an asparaginase level higher than 0.1 IU/mL, compared with 28% of patients who received pegaspargase.
    • Evidence of end-induction minimal residual disease (MRD) negativity was similar between the two drugs (74% and 72%).
    • The toxicity profile of the two drugs was similar.
  2. In a DFCI trial of calaspargase pegol in patients with newly diagnosed ALL, all patients received one dose of either calaspargase pegol or pegaspargase as part of induction therapy. After induction, 230 patients were randomly assigned to receive either calaspargase pegol every 3 weeks (10 doses) or pegaspargase every 2 weeks (15 doses).[29]
    • At day 25 after the induction dose, 88% of patients who received calaspargase pegol had an asparaginase level higher than 0.1 IU/mL, compared with 17% of patients who received pegaspargase.
    • There was no difference in end-of-induction MRD.
    • There was no difference in the frequency of toxicities (37%).
    • The 5-year EFS rates were similar for calaspargase pegol and pegaspargase (88.1% vs. 84.9%).

Calaspargase pegol has only been approved for use in the United States for patients younger than 22 years.

Asparaginase Erwinia chrysanthemi (Erwinia L-asparaginase)

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

The half-life of Erwinia L-asparaginase (0.65 days) is much shorter than that of native E. coli (1.2 days) or pegaspargase (5.7 days).[14] If Erwinia L-asparaginase is used, the shorter half-life of the Erwinia preparation requires more frequent administration to achieve adequate asparagine depletion.

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

  1. A COG trial demonstrated that IM Erwinia L-asparaginase given three times a week to patients with an allergy to pegaspargase leads to therapeutic serum asparaginase enzyme activity levels (defined as a level ≥0.1 IU/mL).[30]
    • On this trial, 96% of children achieved a level of 0.1 IU/mL or more at 2 days after a dose of Erwinia L-asparaginase and 85% did so at 3 days after a dose.
  2. A trial of IV Erwinia L-asparaginase given on a Monday-Wednesday-Friday schedule to patients with an allergy to pegaspargase demonstrated therapeutic serum asparaginase enzyme activity (defined as ≥0.1 IU/mL) in 83% of patients 48 hours after a dose but in only 43% of patients 72 hours after a dose.[31]
    • If IV Erwinia is given on a Monday-Wednesday-Friday schedule, the authors suggest that 72-hour nadir enzyme activity levels be monitored to ensure therapeutic levels.

A recombinant form of Erwinia L-asparaginase, asparaginase erwinia chrysanthemi (recombinant)-rywn, was studied in a phase II/III COG trial. When it was given on a Monday (25 mg/m2), Wednesday (25 mg/m2), and Friday (50 mg/m2) schedule for six doses, the proportion of patients who achieved asparaginase levels of 0.1 IU/mL or greater was 90% at 72 hours (44 of 49 patients) and 96% at 48 hours (47 of 49 patients). The safety profile was comparable with other forms of asparaginase.[32] In 2022, the U.S. Food and Drug Administration approved asparaginase erwinia chrysanthemi (recombinant)-rywn for IM use in children and adults with ALL on the Monday, Wednesday, and Friday schedule used in the COG trial.

Anthracycline use during induction

The COG protocols administer a three-drug induction (vincristine, corticosteroid, and pegaspargase) to NCI standard-risk B-ALL patients and a four-drug induction (vincristine, corticosteroid, and pegaspargase plus an anthracycline) to NCI high-risk B-ALL and all T-ALL patients. Other groups use a four-drug induction for all patients.[1–3]

In induction regimens that include an anthracycline, either daunorubicin or doxorubicin are typically used. In a randomized trial comparing the two agents during induction, there were no differences in early response measures, including reduction in peripheral blood blast counts during the first week of therapy, day 15 marrow morphology, and end-induction MRD levels.[33][Level of evidence B3]

Response to remission induction chemotherapy

More than 95% of children with newly diagnosed ALL will achieve a CR within the first 4 weeks of treatment. Of those who fail to achieve CR within the first 4 weeks, approximately one-half will experience a toxic death during the induction phase (usually caused by infection) and the other half will have resistant disease (persistent morphological leukemia).[34–36]; [37][Level of evidence C1]

Remission is classically defined as an end-induction bone marrow examination by routine microscopic cytomorphology with fewer than 5% lymphoblasts at the end of induction (M1). The Ponte de Legno consortium includes approximately 15 large national and international cooperative groups devoted to the study and treatment of childhood ALL. This group published a consensus definition of complete remission, as follows:[38]

  • Achievement of MRD levels of less than 1% and/or M1 cytomorphology.
    • MRD is the gold standard and takes precedence over cytomorphology.
    • MRD is determined by either flow cytometry or polymerase chain reaction techniques.
  • Resolution of extramedullary disease, assessed no earlier than the end of induction.

Most patients with persistence of morphologically detectable leukemia at the end of the 4-week induction phase have a poor prognosis and may benefit from an allogeneic hematopoietic stem cell transplant (HSCT) once CR is achieved.[4,39,40] In a retrospective study of 1,041 patients with persistent disease after induction therapy (induction failure) who were treated between 1985 and 2000, the 10-year OS rate was 32%.[41] A trend for superior outcome with allogeneic HSCT compared with chemotherapy alone was observed in patients with T-cell phenotype (any age) and B-ALL patients older than 6 years. B-ALL patients who were aged 1 to 5 years at diagnosis and did not have any adverse cytogenetic abnormalities (KMT2A rearrangement, BCR::ABL1) had a relatively favorable prognosis, without any advantage in outcome with the utilization of HSCT compared with chemotherapy alone.[41]

A follow-up retrospective study reported the outcomes of 325 children and adolescents with T-ALL and initial induction failure who were treated between 2000 and 2018.[42] The 10-year OS rate was 54.7%, which was significantly better than the rates of patients in historical cohorts who were treated between 1985 and 2000 (10-year OS rate, 27.6%). Complete remission was eventually achieved in 93% of patients with T-ALL and initial induction failure. Of the patients who achieved complete remission, 72% underwent HSCT. Adjusting for time to transplant, the 10-year OS rate was 66.2% for these patients, compared with 50.8% for those who did not undergo transplants.

The incorporation of nelarabine may be of value for patients with T-ALL and have induction failure. The COG AALL0434 (NCT00408005) study included 43 patients with more than 25% blasts in an end-induction bone marrow aspirate. Of these patients, 23 patients were nonrandomly assigned to therapy that included high-dose methotrexate and nelarabine as part of a multidrug regimen, and 20 patients underwent allogeneic transplant. The 5-year EFS rate was 53.1% (± 9.4%) for the patients who received high-dose methotrexate and nelarabine. There was no difference in outcome for these two groups (HR, 0.66; 95% CI, 0.24–1.83; P = .423).[43]

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

  • The percentage of morphologically detectable marrow blasts at 7 and 14 days after starting multiagent remission induction therapy has been correlated with relapse risk,[44] and has been used in the past by the COG to risk-stratify patients. However, in multivariate analyses, when end-induction MRD is included, these early marrow findings lose their prognostic significance.[45,46]
  • End-induction levels of submicroscopic MRD, assessed by multiparameter flow cytometry, polymerase chain reaction, or next-generation sequencing assays strongly correlates with long-term outcome.[45,47–50] Intensification of postinduction therapy for patients with high levels of end-induction MRD is a common component of most ALL treatment regimens. In a randomized trial conducted by the United Kingdom Acute Lymphoblastic Leukaemia (UKALL) group, augmented postinduction therapy was shown to improve outcome for standard-risk and intermediate-risk patients with high end-induction MRD.[51]
  • MRD levels earlier in induction (e.g., days 8 and 15) and at later postinduction time points (e.g., week 12 after starting therapy) have also been shown to have prognostic significance in both B-ALL and T-ALL.[45,46,49,52–55]
  • Nearly all patients with a positive end-of-induction MRD will become MRD negative at the end of 4 to 8 weeks of consolidation therapy. In a COG study, patients with high-risk B-ALL who had a positive end-of-induction MRD but a negative end-of-consolidation MRD had a significantly improved DFS compared with patients who were MRD positive at end of consolidation (5-year DFS rate, 79.5% vs. 39.5%).[46]

For more information, see the Response to initial treatment section.

For specific information about CNS therapy to prevent CNS relapse in children with newly diagnosed ALL, see the CNS-Directed Therapy for Childhood ALL section.

Standard Postinduction Treatment Options for Childhood ALL

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

  1. Chemotherapy.

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

Consolidation/intensification therapy

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

The most commonly used intensification schema is the BFM backbone. This therapeutic backbone, first introduced by the BFM clinical trials group, includes the following:[1]

  1. An initial consolidation (referred to as induction IB) immediately after the initial induction phase. This phase includes intrathecal therapy, cyclophosphamide, low-dose cytarabine, and mercaptopurine.

    An interim maintenance phase, which includes intrathecal therapy and four doses of high-dose methotrexate (typically 5 g/m2) with leucovorin rescue.

  2. Reinduction (or delayed intensification), which typically includes agents and schedules similar to those used during the induction and initial consolidation phases.
  3. Maintenance, typically consisting of daily mercaptopurine (6-MP), weekly low-dose methotrexate, and sometimes, intermittent administration of vincristine and a corticosteroid, as well as continued intrathecal therapy.

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

  • Intensification for higher-risk patients by including additional doses of vincristine and pegaspargase, as well as repeated interim maintenance and delayed intensification phases.[56,57]
  • The use of escalating doses of methotrexate (starting at a dose of 100 mg/m2) without leucovorin rescue instead of or in addition to high-dose methotrexate during interim maintenance phases.
  • Elimination or truncation of some of the phases for lower-risk patients to minimize acute and long-term toxicity.

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

  • DFCI: The DFCI ALL Consortium protocols include 30 weeks of pegaspargase therapy beginning at week 7 of therapy, given in conjunction with maintenance regimen (vincristine/dexamethasone pulses, weekly low-dose methotrexate, daily mercaptopurine).[3] These protocols also do not include a delayed intensification phase, but high-risk patients receive additional doses of doxorubicin (instead of low-dose methotrexate) during the first six months of postinduction therapy.
  • NOPHO: The NOPHO also emphasizes the use of pegaspargase during consolidation and intensification. In the ALL2008 trial, all patients received five doses of pegaspargase given every other week after induction. Patients then received an additional ten doses at 2-week intervals or three doses at 6-week intervals. Both regimens produced equally excellent survival rates, with reduced toxicity in the three-dose regimen.[58]
  • SJCRH: SJCRH follows a BFM backbone but augments the reinduction and maintenance phases for some patients by including intensified dosing of pegaspargase, frequent vincristine/corticosteroid pulses, and rotating drug pairs during maintenance (mercaptopurine/methotrexate, cyclophosphamide/cytarabine, dexamethasone/vincristine).[59]
Standard-risk ALL

In children with low- and standard-risk B-ALL, there has been an attempt to limit exposure to drugs such as anthracyclines and alkylating agents that may be associated with an increased risk of late toxic effects.[60–62] The COG regimen for standard-risk B-ALL postinduction therapy can be delivered in the outpatient setting and has multiple favorable characteristics, including low-intensity 4-week consolidation, limited anthracycline (75 mg/m2) and alkylator exposure (1 gm/m2), only two doses of pegaspargase, and interim maintenance phases consisting of escalating doses of methotrexate (without leucovorin rescue) rather than high-dose IV methotrexate.[63][Level of evidence B4]

Favorable outcomes for standard-risk patients with B-ALL were also reported in trials that used a limited number of courses of intermediate-dose or high-dose methotrexate as consolidation followed by maintenance therapy (without a reinduction phase).[61,64,65] More specifically, a subset of patients with standard-risk B-ALL with favorable cytogenetics, no evidence of CNS or testicular disease at diagnosis, and rapid achievement of low levels of MRD, have been treated with exposure to no or low doses of anthracyclines and alkylating agents. The 5-year DFS rate was almost 99%, and the OS rate was 100%.[66] The DFCI ALL Consortium study used multiple doses of pegaspargase (30 weeks) as consolidation, without postinduction exposure to alkylating agents or anthracyclines.[67,68]

However, the prognostic impact of end-induction and/or consolidation MRD has influenced the treatment of patients originally diagnosed as NCI standard risk. Multiple studies have demonstrated that higher levels of end-induction MRD are associated with poorer prognosis.[45,47,48,69,70] Augmenting therapy has been shown to improve the outcome in standard-risk patients with elevated MRD levels at the end of induction.[51] Patients with NCI standard-risk B-ALL with high-risk features (including increased end-of-induction MRD levels as well as CNS2 status at diagnosis, and/or unfavorable genetics) are treated with more intensified therapy. For more information, see the Prognostic (risk) groups under clinical evaluation section.

Evidence (intensification for standard-risk B-ALL):

  1. Clinical trials conducted in the 1980s and early 1990s demonstrated that the use of a delayed intensification phase improved outcome for children with standard-risk ALL treated with regimens using a BFM backbone.[71–73] The delayed intensification phase on such regimens, including those of the COG, consists of an 8-week phase of reinduction (including dexamethasone and an anthracycline) and reconsolidation containing cyclophosphamide, cytarabine, and 6-thioguanine given approximately 4 to 6 months after remission is achieved.[35,71,74]
  2. The former Children’s Cancer Group (CCG) study (CCG-1991/COG-1991) for standard-risk ALL used dexamethasone in a three-drug induction phase and tested the utility of a second delayed intensification phase. This study also compared escalating IV methotrexate (without leucovorin rescue) in conjunction with vincristine versus a standard maintenance combination with oral methotrexate given during two interim maintenance phases.[75][Level of evidence B1]
    • A second delayed intensification phase provided no benefit in patients who were rapid early responders (M1 or M2 marrow by day 14 of induction).
    • Escalating IV methotrexate during the interim maintenance phases, compared with oral methotrexate during these phases, produced a significant improvement in EFS, which was because of a decreased incidence of isolated extramedullary relapses, particularly those involving the CNS.
    • Successful therapies for patients with standard-risk ALL that have decreased the use of drugs associated with long-term toxicities have focused on children with B-ALL, not T-ALL.[61,62,64,65,67,68] The COG, Dutch Children’s Oncology Group (DCOG), DFCI, NOPHO, and other large cooperative groups have excluded patients with T-cell ALL from low and standard-risk therapies. Patients with NCI standard-risk features but a T-cell immunophenotype had an inferior EFS and OS compared with patients with NCI standard-risk B-ALL treated on the same regimens on CCG1952 and CCG1991.[76]
  3. The COG AALL0331 (NCT00103285) study stratified intensity of therapy for NCI standard-risk patients on the basis of biology and early response. Rapid early response was defined as less than 5% bone marrow blasts by day 15 based on local morphological interpretation and an M1 bone marrow with MRD levels of less than 0.1% at day 29. Standard-risk low patients were those with favorable biology (ETV6::RUNX1 or high hyperdiploidy with triple trisomy), CNS1 status, and a rapid early response. Standard-risk average patients were those lacking favorable or unfavorable biology who also had a rapid early response. Standard-risk high patients were those with slow early response and/or CNS3 status, or KMT2A-rearranged patients with rapid early response. All patients received a three-drug prednisone-based induction (no anthracycline). Standard-risk average patients were randomly assigned to either intensified consolidation (augmented BFM) or standard consolidation. Standard-risk high patients were nonrandomly assigned to the full augmented BFM therapy used for NCI high-risk patients, including two delayed intensification phases.[77]
    • The 6-year EFS rate for all patients was 89%, and the OS rate was 96%.
    • For standard-risk low patients, this study evaluated the addition of four doses of pegaspargase (added in consolidation and interim maintenance phases) to standard therapy, which included two doses of pegaspargase (administered in induction and delayed intensification phases). Standard-risk low patients had highly favorable outcomes (6-year DFS and OS rates were 94.7% ± 0.6% and 98.7% ± 0.3%, respectively). The augmentation of standard-risk low therapy with additional pegaspargase did not improve outcomes.[63][Level of evidence B4]
    • For standard-risk average patients, the augmented consolidation regimen did not improve rates of continuous complete remission (CCR) or OS. The 6-year rates of CCR and OS for the standard-risk average cohort were 88% to 89% and 95% to 96%, respectively.
    • Standard-risk average patients with end-induction MRD levels of 0.01% to <0.1% had an inferior outcome compared with those with MRD levels of <0.01% (6-year CCR rates, 77% vs. 91%, respectively). Augmented consolidation was not associated with a better outcome in standard-risk average patients with higher levels of MRD.
    • The standard-risk high cohort achieved a relatively favorable 6-year CCR rate of 86% and an OS rate of 93%.
  4. In a randomized study conducted in the United Kingdom, children and young adults with ALL who lacked high-risk features (including adverse cytogenetics, and/or M3 marrow morphology at day 8 or day 15 of induction) were risk-stratified on the basis of MRD level at the end of induction (week 4) and at week 11 of therapy. Patients with undetectable MRD at week 4 (or with low MRD at week 4 and undetectable by week 11) were considered low risk, and were eligible to be randomly assigned to therapy with either one or two delayed intensification phases.[78][Level of evidence B1]
    • There was no significant difference in EFS between patients who received one and those who received two delayed intensification phases.
    • There was no significant difference in treatment-related deaths between the two arms; however, the second delayed intensification phase was associated with grade 3 or 4 toxic events in 17% of the 261 patients randomly assigned to that arm, and one patient experienced a treatment-related death during that phase.
  5. In the AIEOP ALL-BFM-2000 (NCT00430118) trial, standard-risk patients (defined as those with undetectable MRD at days 33 and 78 and absence of high-risk cytogenetics) were randomly assigned to receive treatment with a single delayed-intensification phase of either standard intensity or reduced intensity (shorter duration, with reduced total dosages of dexamethasone, vincristine, doxorubicin, and cyclophosphamide).[79]
    • Reduced-intensity delayed intensification was associated with an inferior 8-year DFS rate (89% vs. 92%, P = .04), resulting from an increased risk of relapse.
    • In a subset analysis, for patients with the ETV6::RUNX1 fusion, no difference in outcome between the two treatment arms was observed (8-year DFS rate, approximately 94% for both arms).
  6. The Malaysia-Singapore ALL MS2010 trial for patients with favorable-risk B-ALL evaluated a deintensified, modified BFM regimen. This regimen omitted anthracyclines, had fewer doses of high-dose methotrexate, and fewer doses of low-dose cytarabine.[80]
    • The long-term EFS in this trial (6-year EFS rate, 96.5%) was noninferior, compared with the predecessor trial conducted by the same group.
    • This regimen was also less toxic, with significantly decreased rates of bacteremia and septic shock/intensive care unit admissions.
  7. Patients who are standard or intermediate risk at diagnosis, but have high levels of end-induction MRD, have been shown to have a poorer prognosis and should be treated as high-risk patients. The UKALL2003 (NCT00222612) trial used augmented postinduction therapy (extra doses of pegaspargase and vincristine and an escalated-dose of IV methotrexate without leucovorin rescue) to treat standard- or intermediate-risk patients with high levels of end-induction MRD.[51][Level of evidence B1]
    • Augmented postinduction therapy resulted in an increased EFS that was comparable to that of patients with low levels of end-induction MRD.
High-risk ALL

In high-risk patients, a number of different approaches have been used with comparable efficacy.[67,81]; [74][Level of evidence B4] Treatment for high-risk patients is generally more intensive than that for standard-risk patients and typically includes higher cumulative doses of multiple agents, including anthracyclines and/or alkylating agents. Higher doses of these agents increase the risk of both short-term and long-term toxicities, and many clinical trials have focused on reducing the side effects of these intensified regimens.

Evidence (intensification for high-risk ALL):

  1. The former CCG developed an augmented BFM treatment regimen that included a second interim maintenance and delayed intensification phase. This regimen featured repeated courses of escalating-dose IV methotrexate (without leucovorin rescue) given with vincristine and pegaspargase during interim maintenance and additional vincristine and pegaspargase pulses during initial consolidation and delayed intensification. In the CCG-1882 trial, NCI high-risk patients with slow early response (M3 marrow on day 7 of induction) were randomly assigned to receive either standard- or augmented-BFM therapy.[56]
    • The augmented-therapy regimen in the CCG-1882 trial produced significantly better EFS and OS rates (75% and 78%) than did the standard CCG modified-BFM therapy (55% and 66.7%).
    • There was a significantly higher incidence of osteonecrosis in patients older than 10 years who received the augmented therapy (which included two 21-day postinduction dexamethasone courses), compared with those who were treated on the standard arm (one 21-day postinduction dexamethasone course).[82]
  2. In an Italian study, investigators showed that two applications of delayed intensification therapy (protocol II) significantly improved outcome for patients with a poor response to a prednisone prophase.[83]
  3. The CCG-1961 study used a 2 × 2 factorial design to compare both standard- versus augmented-intensity therapies and therapies of standard duration (one interim maintenance and delayed intensification phase) versus increased duration (two interim maintenance and delayed intensification phases) among NCI high-risk patients with a rapid early response. This trial also tested whether continuous versus alternate-week dexamethasone during delayed intensification phases affected rates of osteonecrosis.
    • Augmented therapy was associated with an improvement in EFS. There was no EFS benefit associated with the administration of the second interim maintenance and delayed intensification phases.[57,84][Level of evidence A1]
    • The cumulative incidence of osteonecrosis at 5 years was 9.9% for patients aged 10 to 15 years and 20.0% for patients aged 16 to 21 years, compared with 1.0% for patients aged 1 to 9 years (P = .0001). For patients aged 10 to 21 years, alternate-week dosing of dexamethasone during delayed intensification phases was associated with a significantly lower cumulative incidence of osteonecrosis, compared with continuous dosing (8.7% vs. 17.0%, P = .0005).[85][Level of evidence A3]
  4. In the UKALL2003 (NCT00222612) trial, patients with high end-induction MRD (>0.01%) and/or high-risk cytogenetics were randomly assigned to receive either a standard-intensity or an augmented BFM chemotherapy backbone.[86]
    • The 10-year EFS rate was 87.1% for patients assigned to the augmented chemotherapy backbone, compared with 82.1% for those assigned the standard-intensity chemotherapy backbone (P = .09).
    • Patients with high-risk cytogenetics had a significantly lower risk of relapse when treated with augmented therapy (10-year relapse rate, 22.1% vs. 52.4% with standard-intensity therapy; P = .016).
  5. In the COG AALL0232 (NCT00075725) study (2004–2011), patients with high-risk B-ALL received an augmented BFM backbone with one interim maintenance and delayed intensification phase. Only patients with end-induction MRD greater than 0.1% or M2/M3 marrow at day 15 received two interim maintenance/delayed intensification phases. Patients were randomly assigned to receive either high-dose methotrexate or escalating dose IV methotrexate (Capizzi methotrexate) plus pegaspargase during the interim maintenance phase (the first phase only for those receiving two of these phases).[8,46]
    • The methotrexate randomization was terminated early when planned interim monitoring indicated that high-dose methotrexate was associated with superior outcome. The 5-year EFS rate of patients randomly assigned to high-dose methotrexate was 79.6%, compared with 75% for those randomly assigned to the Capizzi methotrexate arm. High-dose methotrexate was also associated with a superior 5-year OS (P = .025).[8]
    • Patients with MRD less than 0.01% at end of induction had a 5-year EFS rate of 87%, compared with 74% for those with MRD 0.01% to 0.1%. Those with MRD levels greater than 0.1% fared worse.[46]
    • High-dose methotrexate was associated with a superior EFS rate in patients with end-induction MRD greater than 0.01% (high-dose methotrexate, 68%; Capizzi methotrexate, 58%; P = .008).[46]

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

Evidence (cardioprotective effect of dexrazoxane):

  1. In a DFCI ALL Consortium trial, children with high-risk ALL were randomly assigned to receive doxorubicin alone (30 mg/m2/dose to a cumulative dose of 300 mg/m2) or with dexrazoxane during the induction and intensification phases of multiagent chemotherapy.[87,88]
    • The use of the cardioprotectant dexrazoxane before doxorubicin resulted in better left ventricular fractional shortening and improved end-systolic dimension Z-scores without any adverse effect on EFS or increase in second malignancy risk, compared with the use of doxorubicin alone 5 years posttreatment.
    • A greater long-term protective effect was noted in girls than in boys.
  2. On the POG-9404 trial, patients with T-ALL were randomly assigned to receive dexrazoxane or not before each dose of doxorubicin (cumulative dose 360 mg/m2).[89]
    • There was no difference in EFS between patients with T-ALL who were treated with dexrazoxane and patients who were not treated with dexrazoxane (cumulative doxorubicin dose, 360 mg/m2).
    • Three years after initial diagnosis, left ventricular shortening fraction and left ventricular wall thickness were both significantly worse in patients who received doxorubicin alone than in patients who received dexrazoxane, indicating that dexrazoxane was cardioprotective. The frequency of grade 3 and 4 toxicities that occurred during therapy was similar between the randomized groups, and there was no difference in cumulative incidence of second malignant neoplasms.

Evidence (reducing risk of osteonecrosis):

  1. In the CCG-1961 study, alternate-week dosing of dexamethasone during delayed intensification was studied with the goal of reducing the frequency of osteonecrosis.[85] Patients with high-risk B-ALL and a rapid early morphological response to induction therapy were randomly assigned to receive either one or two delayed intensification phases. Patients randomly assigned to one delayed intensification phase received daily dosing of dexamethasone (21 consecutive days), while those randomly assigned to two delayed intensification phases received alternate-week dosing of dexamethasone (days 0–6 and 14–21) during each delayed intensification phase.
    • For patients aged 10 years or older at diagnosis, those who received two delayed intensification phases (alternate-week dosing of dexamethasone) had a significantly lower risk of symptomatic osteonecrosis (5-year cumulative incidence of 8.7%, compared with 17% for patients receiving one delayed intensification phase with continuous dexamethasone dosing; P = .001).
    • The greatest impact was seen in females aged 16 to 21 years, who showed the highest incidence of osteonecrosis with standard therapy containing continuous dexamethasone; the incidence of osteonecrosis with alternative-week dexamethasone was 5.6%, compared with 57.6% for those receiving continuous dosing.

For more information, see the Osteonecrosis section.

Very high-risk ALL

Approximately 10% to 20% of patients with ALL are classified as very high risk, including the following:[74,90]

  • Infants younger than 1 year, especially if there is a KMT2A gene rearrangement present. For more information about infants with ALL, see the Infants With ALL section.
  • Patients with adverse cytogenetic abnormalities, including BCR::ABL1, TCF3::HLF, KMT2A gene rearrangements, and low hypodiploidy (<44 chromosomes).
  • Patients who achieve CR but have a slow early response to initial therapy, including those with a high absolute blast count after a 7-day steroid prophase, and patients with high MRD levels at the end of induction (week 4) or later time points (e.g., week 12).
  • Patients who have morphologically persistent disease after the first 4 weeks of therapy (induction failure), even if they later achieve CR.

Patients with very high-risk features have been treated with multiple cycles of intensive chemotherapy during the consolidation phase (usually in addition to the typical BFM backbone intensification phases). These additional cycles often include agents not typically used in frontline ALL regimens for standard-risk and high-risk patients, such as high-dose cytarabine, ifosfamide, and etoposide.[74] However, even with this intensified approach, reported long-term EFS rates range from 30% to 50% for some of these very high-risk subsets.[39,74] The DCOG reported the outcomes of 107 patients with very high-risk features who were treated with three to six intensive chemotherapy blocks in two consecutive trials. Sixty of these patients received an allogeneic HSCT in first CR. The 5-year EFS rate was 73%, and the OS rate was 79% for all patients. With this intensified treatment approach, the cumulative incidence of treatment-related mortality was 12.3%, which was similar to the cumulative incidence of relapse, at 13%.[91]

On some clinical trials, very high-risk patients have also been considered candidates for allogeneic HSCT in first CR.[39,92–94] However, there are limited data regarding the outcome of very high-risk patients treated with allogeneic HSCT in first CR. Controversy exists regarding which subpopulations could potentially benefit from HSCT.

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

  1. In a European cooperative group study conducted between 1995 and 2000, very high-risk patients were defined as one of the following: morphologically persistent disease after a four-drug induction, BCR::ABL1 or KMT2A::AFF1 fusions, or poor response to prednisone prophase in patients with either T-cell phenotype or presenting white blood cells (WBC) >100,000/μL. These patients were assigned to receive either an allogeneic HSCT in first CR (based on the availability of a human lymphocyte antigen–matched related donor) or intensive chemotherapy.[39]
    • Using an intent-to-treat analysis, patients assigned to allogeneic HSCT (on the basis of donor availability) had a superior 5-year DFS rate compared with patients assigned to intensive chemotherapy (57% ± 7% for transplant vs. 41% ± 3% for chemotherapy, P = .02).
    • There was no significant difference in OS rates (56% ± 6% for transplant vs. 50% ± 3% for chemotherapy; P = .12).
    • For patients with T-ALL and a poor response to prednisone prophase, both DFS and OS rates were significantly better with allogeneic HSCT.[92]
  2. In a large retrospective series of patients with initial induction failure, the 10-year OS rate for patients with persistent leukemia was 32%.[41]
    • A trend for superior outcome with allogeneic HSCT, compared with chemotherapy alone, was observed in patients with T-cell phenotype (any age) and with B-ALL who were older than 6 years.
    • Patients with B-ALL who were aged 1 to 5 years at diagnosis and did not have any adverse cytogenetic abnormalities (KMT2A rearrangement, BCR::ABL1) had a relatively favorable prognosis, without any advantage in outcome with the utilization of HSCT compared with chemotherapy alone.
  3. The AIEOP ALL-BFM-2000 (NCT00430118) study (2000–2006) classified patients as high risk if they met any of the following criteria: poor response to prednisone prophase, failure to achieve CR at the end of the first month of treatment, high MRD levels after induction IB (day 78 of therapy), and KMT2A::AFF1 fusion. These patients were allocated to allogeneic HSCT in first CR per protocol on the basis of donor availability and investigator preference.[95][Level of evidence B4]
    • The overall 5-year EFS rate of patients meeting high-risk criteria was 58.9%.
    • The 5-year EFS rate was 74% for patients whose only high-risk feature was prednisone-poor response. There was no significant difference in DFS (P = .31) or OS (P = .91) when comparing HSCT and chemotherapy for patients with poor prednisone response in whom HSCT was allowed per protocol (those with T-ALL and/or WBC ≥100,000/mm3).
    • All other high-risk patients (i.e., those with initial induction failure, high day 78 MRD and/or KMT2A::AFF1 fusion) had EFS rates less than 50%. For these patients, there was no statistically significant difference in DFS between those who received HSCT (n = 66) and those who received chemotherapy only (n = 88), after adjusting for waiting time to HSCT (5.7 months).
  4. On the NOPHO ALL2008 (NCT00819351) protocol, patients were allocated to HSCT in first CR if they had MRD levels of 5% or greater at the end of induction or MRD levels of 0.1% or greater at end of consolidation. All patients allocated to HSCT received at least three blocks of intensive chemotherapy before HSCT to reduce levels of MRD.[96]
    • In the intent-to-treat analysis of 69 patients who met HSCT criteria (10 of whom did not undergo HSCT), the 5-year DFS rate was 78%.
    • Comparing the patients in this cohort who did and did not receive HSCT, receipt of HSCT was not significantly associated with survival (HR, 1.4; P = .69).
    • For patients who underwent HSCT, superior outcomes (better DFS and lower cumulative incidence of relapse) were observed in patients who had nondetectable MRD before HSCT.
  5. In the DCOG ALL-10 and ALL-11 trials, patients with very high-risk features received an intensified treatment regimen that included three high-dose chemotherapy blocks after consolidation. After the three blocks, 60 patients received an allogeneic HSCT, and 22 patients continued with a chemotherapy-only approach, which included three additional high-dose blocks. In these trials, very high-risk disease was defined by any of the following features: morphologically detectable disease at end of induction, high end-consolidation MRD (time point 2), t(4;11), or poor response to a prednisone prophase.[91]
    • The 5-year EFS rate was 72.8% for all patients.
    • In a landmark analysis of EFS from the end of the third high-dose chemotherapy block, no difference was observed in the outcomes of patients who received HSCT versus those who received chemotherapy only.
  6. Two retrospective analyses investigated the role of HSCT in first CR for patients with hypodiploid ALL. The studies showed no clear evidence that HSCT improved outcomes when 1) transplanting all patients with hypodiploid ALL, or 2) transplanting hypodiploid patients deemed at high risk on the basis of high MRD after induction. The studies did not examine the strategy of HSCT for persistent MRD after consolidation, nor did they analyze the status of MRD at the time of HSCT.
    1. In a study of 306 hypodiploid patients from 16 ALL cooperative groups treated between 1997 and 2013, a subgroup of 228 patients (42 who underwent HSCT) with 44 or fewer chromosomes who achieved remission were analyzed.[97][Level of evidence C2]
      • Favorable prognostic factors included a chromosome number of 44 (compared with 43 or fewer), MRD less than 0.01% after induction, and treatment on an MRD-stratified protocol that intensified therapy for patients with higher MRD after induction.
      • After correction for median time to transplant, patients with low MRD who underwent HSCT had a DFS rate of 73.6%, compared with a DFS rate of 70% for those treated with chemotherapy alone (P = .81). Patients with higher MRD after induction who underwent HSCT had a DFS rate of 55.9%, compared with a DFS rate of 40.3% for those treated with chemotherapy (P = .29).
    2. The COG published an analysis of 113 evaluable patients with hypodiploid ALL who were treated between 2003 and 2011; 61 of those patients underwent HSCT in first CR.[98][Level of evidence C1]
      • The 5-year EFS rate was 57.4% for patients who underwent HSCT and 47.8% for patients in the chemotherapy cohorts (P = .49). The OS rate was 66.2% for patients who underwent HSCT and 53.8% for patients in the chemotherapy cohorts (P = .34).
      • Patients with high MRD after induction (≥0.01%) had a very poor EFS rate of 26.7% at 5 years, with no difference between the patients who received HSCT and the patients who received chemotherapy.

Maintenance therapy

Backbone of maintenance therapy

The backbone of maintenance therapy in most protocols includes daily oral mercaptopurine and weekly oral or parenteral methotrexate. On many protocols, intrathecal chemotherapy for CNS sanctuary therapy is continued during maintenance therapy. Also, vincristine/steroid pulses during maintenance are used by some groups but not others (see below). It is imperative to carefully monitor children on maintenance therapy for both drug-related toxicity and for compliance with the oral chemotherapy agents used during maintenance therapy.[99] A protocol conducted by the COG suggested there are significant differences in compliance with oral mercaptopurine regimens among various racial and socioeconomic groups and that level of adherence impacts relapse risk.[99,100]

In the past, clinical practice generally called for the administration of oral mercaptopurine in the evening, on the basis of evidence from older studies that this practice may improve EFS.[101] However, in a study conducted by the NOPHO group, in which details of oral intake were prospectively captured, timing of mercaptopurine administration (nighttime vs. other times of day) was not of prognostic significance.[102] In a COG study, taking mercaptopurine at varying times of day rather than consistently at nighttime was associated with higher rates of nonadherence. However, among adherent patients (i.e., those who took >95% of prescribed doses), there was no association between timing of mercaptopurine ingestion and relapse risk.[103]

Some patients may develop severe hematologic toxicity when receiving conventional dosages of mercaptopurine because of an inherited deficiency (homozygous mutant) of thiopurine S-methyltransferase, an enzyme that inactivates mercaptopurine.[104,105] These patients are able to tolerate mercaptopurine only in much lower dosages than those conventionally used.[104,105] Patients who are heterozygous for the variant generally tolerate mercaptopurine without serious toxicity, but they do require more frequent dose reductions for hematologic toxicity than do patients who are homozygous for the normal allele.[104] Polymorphisms of the NUDT15 gene, observed most frequently in East Asian and Hispanic patients, have also been linked to extreme sensitivity to the myelosuppressive effects of mercaptopurine.[106–108]

Evidence (maintenance therapy):

  1. A meta-analysis of randomized trials compared thiopurines and found the following:
    • Thioguanine did not improve the overall EFS, although particular subgroups may benefit from its use.[109]
    • The use of continuous thioguanine instead of mercaptopurine during the maintenance phase is associated with an increased risk of hepatic complications, including veno-occlusive disease (sinusoidal obstruction syndrome) and portal hypertension.[110–114]
    • Because of the increased toxicity of thioguanine, mercaptopurine remains the standard drug of choice.
  2. In the COG AALL0932 (NCT01190930) trial, NCI standard-risk patients with average-risk features were randomly assigned to receive weekly oral methotrexate during maintenance at one of two starting doses: 20 mg/m2 (standard) or 40 mg/m2 (investigational).[115][Level of evidence A1]
    • There was no significant difference in 5-year DFS from the start of maintenance therapy between the two treatment arms (5-year DFS rate, 95.1% for patients who received the standard dose vs. 94.2% for patients who received the investigational dose; P = .92), indicating no advantage for the higher dose of oral methotrexate.
  3. An intensified maintenance regimen, consisting of rotating pairs of agents, including cyclophosphamide and epipodophyllotoxins along with more standard maintenance agents, has been evaluated in several clinical trials conducted by SJCRH and other groups.[2]
    • The intensified maintenance with rotating pairs of agents was associated with more episodes of febrile neutropenia [116] and a higher risk of secondary acute myelogenous leukemia,[117,118] especially when epipodophyllotoxins were included.[116]

      On the basis of these findings, SJCRH modified the agents used in the rotating pair schedule during the maintenance phase. On the Total XV study, standard-risk and high-risk patients received three rotating pairs (mercaptopurine plus methotrexate, cyclophosphamide plus cytarabine, and dexamethasone plus vincristine) throughout this treatment phase. Low-risk patients received more standard maintenance (without cyclophosphamide and cytarabine).[59]

    • A randomized study from Argentina demonstrated no benefit from this intensified approach compared with a more standard maintenance regimen for patients who receive induction and consolidation phases based on a BFM backbone.[116]
Vincristine/corticosteroid pulses

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

Evidence (vincristine/corticosteroid pulses):

  1. A CCG randomized trial conducted in the 1980s demonstrated improved outcome in patients who received monthly vincristine/prednisone pulses.[119]
  2. A meta-analysis combining data from six clinical trials from the same treatment era showed an EFS advantage for vincristine/prednisone pulses.[120,121] However, overall EFS from these trials was lower than is observed with more contemporary regimens.
  3. A systematic review of the impact of vincristine plus steroid pulses from more recent clinical trials raised the question of whether such pulses are of value in current ALL treatment, which includes more intensive early therapy and risk stratification incorporating early response (MRD) and biological factors.[121]
  4. In a multicenter randomized trial in children with intermediate-risk ALL being treated on a BFM regimen, there was no benefit associated with the addition of six pulses of vincristine/dexamethasone during the continuation phase, although the pulses were administered less frequently than in other trials in which a benefit had been demonstrated.[122]
  5. A small multicenter trial of average-risk patients demonstrated superior EFS in patients receiving vincristine plus corticosteroid pulses. In this study, there was no difference in outcome based on type of steroid (prednisone vs. dexamethasone).[123][Level of evidence A1]
  6. In the COG AALL0932 (NCT01190930) trial, standard-risk patients were randomly assigned during maintenance to receive vincristine/dexamethasone pulses every 4 weeks or every 12 weeks.[115][Level of evidence A1]
    • For the randomly assigned standard-risk patients, the 5-year DFS rate from the start of maintenance was 94.6%. There was no significant difference between the every-4-week group and the every-12-week group.
  7. The Chinese Children’s Cancer Group conducted a randomized noninferiority trial to determine whether vincristine/dexamethasone pulses could be omitted during the second year of maintenance therapy. One year after the initiation of therapy, 5,054 patients with non-BCR::ABL1 fusion–positive ALL (B-ALL and T-ALL, aged 0–18 years) were randomly assigned to receive either vincristine/dexamethasone pulses every 8 weeks (seven pulses total) or no pulses during the second year of maintenance chemotherapy. Noninferiority was defined by calculating the one-sided 95% upper confidence bound of the difference in EFS probability between arms to ensure that an EFS decrement of 5% or more was ruled out.[124]
    • For low-risk patients (NCI standard-risk B-ALL with high hyperdiploidy or ETV6::RUNX1 and low end-induction MRD), the EFS difference between arms met the protocol definition of noninferiority, indicating that omission of vincristine/dexamethasone pulses during the second year of maintenance did not result in a decrement of EFS that was greater than 5%.
    • For intermediate-risk and high-risk patients, the difference in 5-year EFS between arms did not meet the protocol definition of noninferiority (the 95% upper confidence bound for the difference was 0.055, which exceeded the preset noninferiority margin of 0.05); therefore, it could not be concluded that vincristine/dexamethasone pulses could be omitted in these patients without resulting in an EFS decrement exceeding 5%.
  8. The Japanese Childhood Cancer Group ALL-B12 trial included 1,107 patients with standard-risk B-ALL (i.e., NCI standard risk, good response to prednisone, day 15 marrow M1/2, end-of-induction marrow M1 without high-risk features [CNS3, KMT2A rearranged, TCF3::HLF fusion, TCF4::HLF fusion, hypodiploid]). Patients were randomly assigned to receive maintenance therapy, either with or without every 4-week vincristine/dexamethasone pulses.[125]
    • There was no difference in EFS or adverse events between the two treatment groups.
  9. A systematic review and meta-analysis evaluated the effect of reducing vincristine/steroid pulses on EFS, OS, and toxicity in patients with B-ALL. Twenty-five publications that included more than 12,000 patients were examined.[126]
    • This study demonstrated that the benefit of these pulses noted in historical trials was not seen in contemporary trials.
    • However, there was an increased risk of grade 3+ nonhepatic toxicity in the high-pulse frequency group.
    • The authors concluded that decreasing or removing pulses likely does not affect survival or risk of relapse, but it is associated with reduced toxicity.

For regimens that include vincristine/steroid pulses, a number of studies have addressed which steroid (dexamethasone or prednisone) should be used. From these studies, it appears that dexamethasone is associated with superior EFS, but also may lead to a greater frequency of steroid-associated complications, including bone toxicity and infections, especially in older children and adolescents.[6,7,24,71,127] Compared with prednisone, dexamethasone has also been associated with a higher frequency of behavioral problems.[7] In a randomized study of 50 patients aged 3 to 16 years who received maintenance chemotherapy, concurrent administration of hydrocortisone (at physiological dosing) during dexamethasone pulses reduced the frequency of behavioral difficulties, emotional lability, and sleep disturbances.[128]

Evidence (dexamethasone vs. prednisone):

  1. In a CCG study, dexamethasone was compared with prednisone during the induction and maintenance phases for children aged 1 to younger than 10 years with lower-risk ALL.[6,71]
    • Patients randomly assigned to receive dexamethasone had significantly fewer CNS relapses and a significantly better EFS rate.
  2. In a MRC United Kingdom Acute Lymphoblastic Leukaemia (UKALL) trial, dexamethasone was compared with prednisolone during the induction and maintenance phases in both standard-risk and high-risk patients.[7]
    • The EFS and incidence of both CNS and non-CNS relapses improved with the use of dexamethasone.
    • Dexamethasone was associated with an increased risk of steroid-associated toxicities, including behavioral problems, myopathy, and osteopenia.
  3. In a DFCI ALL Consortium trial, patients were randomly assigned to receive either dexamethasone or prednisone during all postinduction treatment phases.[24]
    • Dexamethasone was associated with a superior EFS, but also with a higher frequency of infections (primarily episodes of bacteremia) and, in patients aged 10 years or older, an increased incidence of osteonecrosis and fracture.

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