Hypodiploidy in Childhood Acute Myeloid Leukemia: A Retrospective Cohort Study within the International Berlin-Frankfurt-Münster Study Group

Background: Despite major improvements in survival, relapse is still a frequent and severe event in pediatric acute myeloid leukemia (AML). Cytogenetic abnormalities represent important predictors of outcome. Improved risk stratification encompassing the identification of novel cytogenetic subsets may allow refinements in treatment strategies and increase survival rates. Hypodiploidy, defined as a modal number (MN) below 46 chromosomes, is associated with an adverse outcome in pediatric acute lymphoblastic leukemia. In childhood AML, the predominant cause of hypodiploidy is loss of a sex chromosome accompanying t(8;21). The most commonly lost autosome is chromosome 7, associated with a poor prognosis. However, other chromosome losses in pediatric AML have not been independently explored. We aimed to investigate the occurrence, genetic characteristics, and prognostic impact of hypodiploidy in childhood AML. Methods: This study was conducted as a retrospective cohort study within the I-BFM-AML framework. Children 0-18 years of age diagnosed with de novo AML between January 2000 to December 2015 and a hypodiploid karyotype were eligible for inclusion. Patients with constitutional hypodiploidy, monosomy 7, composite karyotypes, and t(8;21) with loss of a sex chromosome were excluded. Cytogenetic review was performed according to International System for Human Cytogenetic Nomenclature. Hypodiploidy was considered clonal when occurring in at least three metaphases. The clone with the lowest MN defined the ploidy level. The log-rank test was applied for estimating difference in survival. Considering allografting in first complete remission (CR1) as a time-dependent event, the effect of stem cell transplantation (SCT) on overall survival (OS) was estimated by the Mantel-Byar method. Multivariate analyses included sex, complex karyotype (≥3 non-recurrent aberrations), FLT3-ITD mutation status, and white blood cell count as covariates. As all patients with FLT3-ITD mutations had same MN (MN=45) leading to a skewed imputation model, multiple imputation was not performed, and multivariate analyses included complete cases only (n=54). Results: Hypodiploidy was detected in 81/6,409 patients with full karyotyping from 14 collaborative study groups, yielding a frequency of 1.2% in childhood AML. The cohort displayed a balanced sex distribution (male/female: 42/39) and a median age of 6 (range: 0-17). MNs 45 (n=66), 44 (n=10) and 43 (n=5) were observed. No patient had MN b