Nationwide survey of pediatric hypodiploid acute lymphoblastic leukemia in Japan

Abstract

Background Ploidy is a highly significant prognostic factor for pediatric acute lymphoblastic leukemia (ALL). Children with hypodiploid ALL have poor outcomes despite current intensive chemotherapy. Little has been investigated with regard to hypodiploid ALL in Japanese children. Methods We retrospectively collected clinical data on hypodiploid ALL cases from the registries of prospective multicenter trials conducted by the four independent clinical study groups in Japan between 1997 and 2012. Results A total of 117 ALL patients with hypodiploidy were analyzed in this study. There were 101, eight, and eight patients with 45, 44, and fewer than 44 chromosomes, respectively. The 5 year overall survival rates differed significantly: 86.0%, 87.5%, and 62.5% for patients with 45, 44, and fewer than 44 chromosomes, respectively (P = 0.037). Of the eight patients with 44 chromosomes, seven were alive, including five patients who maintained complete remission without undergoing hematopoietic stem cell transplantation (HSCT). Of the eight patients with fewer than 44 chromosomes, six were good responders to prednisolone and none had induction failure, but the relapse rate was high (5/8). No patients had central nervous system relapse. Four patients underwent HSCT after relapse, but only one survived. Conclusions Outcomes of Japanese ALL patients with fewer than 44 chromosomes were poor, as previously reported in other countries. Although the sample size was small, patients with 44 chromosomes had better prognoses than those previously reported. Further studies including international collaboration are needed to improve outcomes for pediatric ALL patients with fewer than 44 chromosomes.

Overview on Aneuploidy in Childhood B-Cell Acute Lymphoblastic Leukemia

“…In the pediatric population with hyperdiploid B-ALL, the median age at diagnosis is 4 years in both Asian and European populations [64,104,128]. Several studies in Asian countries have found higher proportions of women in groups with high hypodiploidy, in contrast to the European population, where there is a higher proportion of men [41,104,128]. Patients with chromosomes 40-44 seem to have more in common with the 45-chromosome group than those with less than 40 chromosomes [103,106].…”

“…National Cancer Institute (NCI) analysis indicates that only measurable residual disease (MRD) at the end of induction (EOI) is a significant predictor of EFS in near-haploid and low-hypodiploid B-ALL groups [113]. Several groups escalated treatment based on MRD-based stratification protocols are associated with a better outcome after adjusting for sex, age, and leukocyte count, with a 5-year EFS of 62% [39,128,129]. Hematopoietic stem cell transplantation (HSCT) is often performed in first complete remission (CR1) and is traditionally reserved for pediatric patients with a very poor prognosis (EFS 50%), including patients with hypodiploidy (<44 chromosomes) [123,130].…”

“…High hypodiploidy is a very rare anomaly occurring in approximately 4% of diagnosed cases of hypodiploidy in both children and adults, but with a predominance of the younger group [38,104]. In the pediatric population with hyperdiploid B-ALL, the median age at diagnosis is 4 years in both Asian and European populations [64,104,128]. Several studies in Asian countries have found higher proportions of women in groups with high hypodiploidy, in contrast to the European population, where there is a higher proportion of men [41,104,128].…”

Near-Haploidy and Low-Hypodiploidy in B-Cell Acute Lymphoblastic Leukemia: When Less Is Too Much

“…Hypodiploidy -the loss of one or more whole chromosomes- is a rare cytogenetic finding (≤7%) in children and adults with B-ALL and is generally an adverse prognostic marker [ 12 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 ]. Most cases (~80%) of hypodiploid B-ALL present with 45 chromosomes and are classified as near-diploid B-ALL, a clinically distinct entity characterized by rearrangements that form dicentric chromosomes but that does not have outcomes as poor as those associated with hypodiploid B-ALL [ 21 ].…”

“…The low EFS rates observed in near-haploid and low-hypodiploid groups are related to a high relapse rate mostly from isolated BM relapses, and succumbing to the disease after first remission [ 24 , 25 ] ( Table 5 ). According to the review by Groeneveld-Krentz et al on patients with relapsed BCP-ALL [ 68 ], those with pediatric B-ALL with hypodiploidy <40 chromosomes show specific characteristics compared with other B-ALL groups, including: (i) association with older age at initial diagnosis, (ii) shorter time to first relapse, (iii) more frequent allocation to the high-risk treatment arm of the relapse trial, and (iv) inferior second remission rates [ 68 ].…”