Prognostic and Pharmacotypic Heterogeneity of Hyperdiploidy in Childhood ALL

Abstract

PURPOSE High hyperdiploidy, the largest and favorable subtype of childhood ALL, exhibits significant biological and prognostic heterogeneity. However, factors contributing to the varied treatment response and the optimal definition of hyperdiploidy remain uncertain. METHODS We analyzed outcomes of patients treated on two consecutive frontline ALL protocols, using six different definitions of hyperdiploidy: chromosome number 51-67 (Chr51-67); DNA index (DI; DI1.16-1.6); United Kingdom ALL study group low-risk hyperdiploid, either trisomy of chromosomes 17 and 18 or +17 or +18 in the absence of +5 and +20; single trisomy of chromosome 18; double trisomy of chromosomes 4 and 10; and triple trisomy (TT) of chromosomes 4, 10, and 17. Additionally, we characterized ALL ex vivo pharmacotypes across eight main cytotoxic drugs. RESULTS Among 1,096 patients analyzed, 915 had B-ALL and 634 had pharmacotyping performed. In univariate analysis, TT emerged as the most favorable criterion for event-free survival (EFS; 10-year EFS, 97.3% v 86.8%; P = .0003) and cumulative incidence of relapse (CIR; 10-year CIR, 1.4% v 8.8%; P = .002) compared with the remaining B-ALL. In multivariable analysis, accounting for patient numbers using the akaike information criterion (AIC), DI1.16-1.6 was the most favorable criterion, exhibiting the best AIC for both EFS (hazard ratio [HR], 0.45; 95% CI, 0.23 to 0.88) and CIR (HR, 0.45; 95% CI, 0.21 to 0.99). Hyperdiploidy and subgroups with favorable prognoses exhibited notable sensitivities to asparaginase and mercaptopurine. Specifically, asparaginase sensitivity was associated with trisomy of chromosomes 16 and 17, whereas mercaptopurine sensitivity was linked to gains of chromosomes 14 and 17. CONCLUSION Among different definitions of hyperdiploid ALL, DI is optimal based on independent prognostic impact and also the large proportion of low-risk patients identified. Hyperdiploid ALL exhibited particular sensitivities to asparaginase and mercaptopurine, with chromosome-specific associations.

Chromosomal Gains as a Favorable Prognostic Factor in Pediatric ALL

“…In the companion to this article, Lee et al 26 compared different methods for distinguishing cases with a very favorable prognosis within the high hyperdiploid subtype of pediatric ALL. The classic method to identify high hyperdiploidy is by cytogenetics, that is, assessing the chromosomal content of the leukemic bone marrow or peripheral blood cells by G-banding.…”

“…The limit of 1.16-1.6 cannot be directly translated to the number of chromosomes since these differ in size but will generally exclude cases with lower (51 to approximately 54) chromosome numbers and include some (very rare) cases with chromosome numbers >67. 11,28,29 Lee et al 26 compared different ways of defining and analyzing the good-risk group of high hyperdiploid pediatric ALL, including the classic definition of 51-67 chromosomes, specific chromosomal gains, and a DNA index of 1.16-1.6. They conclude that DNA index is the best predictor of a favorable prognosis and that this method should preferably be used to stratify high hyperdiploid pediatric ALL for treatment.…”

“…High hyperdiploid pediatric ALL is generally very sensitive to chemotherapy, but the role of the chromosomal gains and particularly whether specific extra chromosomes are associated with this improved response have not been thoroughly investigated. 30,31 Lee et al 26 performed pharmacotypic profiling of primary ALL samples, that is, leukemic blast cells were exposed to cytotoxic drugs ex vivo to determine drug sensitivity. They found that a DNA index of 1.16-1.6, triple trisomies, and cases with chromosome numbers 56-67 showed high sensitivity to asparaginase and cytarabine, with the latter two groups also being particularly sensitive to mercaptopurine and thioguanine, providing a biological reason for their favorable prognosis.…”

“…The report by Lee et al 26 is a step toward improved risk stratification of pediatric ALL by using DNA index to delineate a good-prognosis group that could possibly benefit from treatment deintensification. To further explore their findings of different extra chromosomes being associated with certain drug sensitivities/resistance, G-banding could be useful, but other methods to determine the full chromosome complement are also available, such as single-nucleotide polymorphism array analysis and massively parallel sequencing (MPS).…”

“…12,[19][20][21][22][23] Notably, double (concurrent 14 and 110) and triple trisomies (concurrent 14, 110, and 117) denote groups with superior outcome, 20,21,23,24 and a recent analysis of UKALL data reported that cases with concurrent 117 and 118 or 117/118 individually, without 15 and 120, have fewer high-risk relapses. 25 In the companion to this article, Lee et al 26 compared different methods for distinguishing cases with a very favorable prognosis within the high hyperdiploid subtype of pediatric ALL. The classic method to identify high hyperdiploidy is by cytogenetics, that is, assessing the chromosomal content of the leukemic bone marrow or peripheral blood cells by G-banding.…”