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H. Inaba and C.G. Mullighan
Table 1B. Major findings in the study reports.
Study
AIEOP/BFM ALL 2000
COG AALL0232
COG AALL0331
COG AALL0434
DFCI ALL Consortium Protocol 05-001
DCOG ALL10
MRC UK ALL 2003
NOPHO ALL2008
SJCRH Total XVI
Years of study
2000-2006
2004-2011
2005-2010
2007-2014 2005-2010
2004-2012
2003-2011
2008-2014
2007-2017
Dexamethasone in induction resulted in less relapse but more treatment-related mortality than did prednisone. There was no survival benefit with dexamethasone except for T-ALL patients with good prednisone response.
5-y EFS and OS were better with HD-MTX than with C-MTX. Patients aged 1-9 y who received dexamethasone and
HD-MTX had better outcomes than those in other groups.
SR patients had excellent outcomes. Adding intensified consolidation did not improve outcomes in patients with SR-average disease.
5-y DFS and OS were better with C-MTX than with HD-MTX.
IV PEG-asparaginase had similar toxicity and efficacy and resulted in less anxiety when compared with IM native
E. coli asparaginase.
MRD-based therapy reduction and intensification were successful.
MRD-based therapy reduction and intensification were successful.
Pediatric-based protocol is tolerable and effective for young adults.
Additional intrathecal therapy during early induction improved CNS control (any CNS relapse at 5-y: 1.5%).
AIEOP/BFM: Associazione Italiana di Ematologia e Oncologia Pediatrica/Berlin-Frankfurt-Münster; ALL: acute lymphoblastic leukemia; B: B-lineage; CI: confidence interval; CNS: central nervous sys- tem; C-MTX: Capizzi methotrexate; COG: Children’s Oncology Group; DCOG: Dutch Childhood Oncology Group; Dex: dexamethasone; DFCI: Dana-Farber Cancer Institute; DFS: disease-free-survival; EFS:event-freesurvival;HD-MTX:high-dosemethotrexate;HCT:hematopoieticcelltransplantation;HR:high-risk;IM:intramuscular;IR:intermediate-risk;IV:intravenous; k.×103/μL;LR:low-risk;MRC UK: Medical Research Council United Kingdom; MRD: minimal residual disease; MTX: methotrexate; n: number; NA: not available; NOPHO: Nordic Society of Pediatric Hematology and Oncology; OS: overall survival; PEG: polyethylene glycol; Pred: prednisolone; pts: patients; R: randomization; SE: standard error; SER: slow early response; SJCRH: St. Jude Children’s Research Hospital; SR: stan- dard-risk; T: T-lineage; WBC: white blood cell; y: year.
mutations can lead to both T-ALL and AML, and ETV6 variants predispose carriers to B-ALL and myelodyspla- sia.21,22
Genome-wide association studies (GWAS) have identi- fied non-coding variants in at least 13 loci associated with ALL. The relative risk associated with each variant is typ- ically low (corresponding to an increase of up to 1.5- or 2- fold) but cumulatively, they may result in an increase of up to 10-fold in ALL risk. Risk variants are frequently at/near hematopoietic transcription factor or tumor suppressor genes, including ARID5B, BAK1, CDKN2A/CDKN2B, BMI1-PIP4K2A, CEBPE, ELK3, ERG, GATA3, IGF2BP1, IKZF1, IKZF3, USP7, and LHPP.23-25 Several variants dis- play ancestry and ALL subtype-specific associations, such as those of GATA3 with Hispanics and Ph-like B-ALL, ERG with African Americans and TCF3-PBX1 B-ALL, and USP7 with African Americans and T-ALL with TAL1 deregulation.26-28
Finally, germline genomic analysis has identified addi- tional susceptibility variants in sporadic hyperdiploid B- ALL (NBN, ETV6, FLT3, SH2B3, and CREBBP), Down syn- drome-associated B-ALL (IKZF1, NBN, RTEL1), and T-ALL (Fanconi-BRCA pathway mutations).29-31
Prenatal origin of leukemia
Several lines of investigation indicate that a subset of childhood leukemia cases arise before birth.32,33 Chromosomal translocations, particularly ETV6-RUNX1 (TEL-AML1) may be detected at birth in blood spots and cord blood years before the clinical onset of leukemia, pro- viding support for a multi-step process of leukemogenesis. This is supported by genomic analyses of monozygotic, monochorionic twins concordant for leukemia, showing genetic identity of initiating lesions and discordance for secondary genetic alterations indicating inter-twin, intrauterine transmission of leukemia.33,34 Evidence for in utero origin is strongest for KMT2A-rearranged and ETV6- RUNX1 ALL. Anecdotal evidence supports in utero origin for other subtypes of B-ALL, including hyperdiploid and ZNF384-rearranged leukemia.35
Genetics of B-cell acute lymphoblastic leukemia
B-cell acute lymphoblastic leukemia (B-ALL) is the most common form of ALL, comprising >20 subtypes of vari- able prevalence according to age that are associated with distinct gene expression profiles and are driven by three main types of initiating genetic alteration: chromosomal aneuploidy, rearrangements that deregulate oncogenes or encode chimeric transcription factors, and point muta- tions (Table 2 and Figure 2). Each subtype typically has co-occurring genetic alterations that perturb lymphoid development, cell-cycle regulation, and kinase signaling and chromatin regulation, and the genes involved and their frequency of involvement vary between subtypes.36
High hyperdiploidy (>50 chromosomes) is present in up to 30% of childhood ALL and is associated with muta- tions in the Ras pathway, chromatin modifiers such as CREBBP, and favorable outcomes.37 Low hypodiploidy (31-39 chromosomes) is present in approximately 1% of children with ALL but in >10% of adults. It is character- ized by the deletion of IKZF2 and by near-universal TP53 mutations, which are inherited in approximately half the cases.10 Near haploidy (24-30 chromosomes) is present in approximately 2% of pediatric ALL and is associated with Ras mutations (particularly NF1) and deletions of IKZF3. Both low-hypodiploid and near-haploid ALL are associated with unfavorable outcomes. The prevalence of hypodiploidy may be underestimated because of the phe- nomenon of “masked” hypodiploidy, in which the hypodiploid genome is duplicated, leading to a hyper- diploid modal chromosome number.10,38 Distinguishing masked-hypodiploid ALL from high-hyperdiploid ALL is important in view of the genetic (germline TP53 alter- ations) and prognostic implications. Masked hypodiploidy may be suspected by the patterns of chro- mosomal gain (commonly diploid and tetrasomic chro- mosomes, rather than trisomies in high-hyperdiploid ALL) and may be formally confirmed by flow cytometric analysis of the DNA index, which commonly shows peaks for both non-masked and masked clones, and by techniques that assess loss of heterozygosity, such as SNP
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haematologica | 2020; 105(11)