Heterogeneous cytogenetic subgroups and outcomes in childhood acute megakaryoblastic leukemia: a retrospective international study

Abstract

Comprehensive clinical studies of patients with acute megakaryoblastic leukemia (AMKL) are lacking. We performed an international retrospective study on 490 patients (age £18 years) with non-Down syndrome de novo AMKL diagnosed from 1989 to 2009. Patients with AMKL (median age 1.53 years) comprised 7.8% of pediatric AML. Five-year event-free (EFS) and overall survival (OS) were 43.7% 6 2.7% and 49.0% 6 2.7%, respectively. Patients diagnosed in 2000 to 2009 were treated with higher cytarabine doses and had better EFS (P 5 .037) and OS (P 5 .003) than those diagnosed in 1989 to 1999. Transplantation in first remission did not improve survival. Cytogenetic data were available for 372 (75.9%) patients: hypodiploid (n 5 18, 4.8%), normal karyotype (n 5 49, 13.2%), pseudodiploid (n 5 119, 32.0%), 47 to 50 chromosomes (n 5 142, 38.2%), and >50 chromosomes (n 5 44, 11.8%). Chromosome gain occurred in 195 of 372 (52.4%) patients: 121 (n 5 106, 28.5%), 119 (n 5 93, 25.0%), 18 (n 5 77, 20.7%). Losses occurred in 65 patients (17.5%): -7 (n 5 13, 3.5%). Common structural chromosomal aberrations were t(1;22)(p13;q13) (n 5 51, 13.7%) and 11q23 rearrangements (n 5 38, 10.2%); t(9;11)(p22; q23) occurred in 21 patients. On the basis of frequency and prognosis, AMKL can be classified to 3 risk groups: good risk-7p abnormalities; poor risk-normal karyotypes, -7, 9p abnormalities including t(9;11)(p22;q23)/MLL-MLLT3, -13/13q-, and -15; and intermediate risk-others including t(1;22)(p13;q13)/OTT-MAL (RBM15-MKL1) and 11q23/MLL except t(9;11). Risk-based innovative therapy is needed to improve patient outcomes. (Blood. 2015;126(13):1575-1584

Recurrent abnormalities can be used for risk group stratification in pediatric AMKL: a retrospective intergroup study

“…A Cox regression analysis was performed for EFS, OS, and for the probability of relapse-free survival (RFS) considering the following covariables: cytogenetic subgroup, age, sex, white blood cell (WBC) count at diagnosis, and HSCT (as time-dependent variable), as well as the previously described poor prognostic factors for pediatric AMKL "normal karyotype" and monosomy 7. 11,24,25 Furthermore, we included a hyperdiploid karyotype and 7p-abnormalities in the Cox regression analysis, based on the association with pediatric AMKL. 11,26,27 Statistical analysis was restricted to groups with .5 cases.…”

“…11,24,25 Furthermore, we included a hyperdiploid karyotype and 7p-abnormalities in the Cox regression analysis, based on the association with pediatric AMKL. 11,26,27 Statistical analysis was restricted to groups with .5 cases. Statistical significance was considered if P values were ,.05.…”

“…4,[8][9][10] However, risk group stratification and treatment protocols are not yet optimized for this subtype of pediatric AML. 11 Translocation t(1;22)(p13;q13), resulting in a chimeric fusion of RBM15 and MKL1, formerly known as OTT/MAL, until recently was the only recurrent aberration described in pediatric AMKL, occurring in ;10% of the patients. [12][13][14] Conflicting results on the prognostic relevance of RBM15/MKL1 have been reported, as some series suggested the outcome to be poor and others favorable.…”

GATA factor mutations in hematologic disease

“…AMKL in children without DS is The outcomes for this class of AMKL vary among the different genetic subtypes, but on average, the 5-year event-free survival and overall survival were reported to be 43% and 49%, respectively. 67 In contrast, the genetic basis of adult AMKL is poorly defined and the outcome is dismal, with a median survival of 10.4 months. 68 Of note, children with DS-AMKL fare well, with 5-year event-free survival and overall survival approaching 80%.…”

One giant leap for pediatric AMKL

“…They also confirm, using sequencing methods, the poor prognosis imparted by monosomy 7 reported by Inaba and colleagues using traditional karyotyping in their landmark retrospective study of 490 pediatric AMKL patients in the International BFM (I-BFM) Study Group. 4 The molecular confirmation of poorprognosis lesions reported in this study will undoubtedly generate additional hypotheses about the role of associated fusions in the unique pathogenesis of myelomegakaryocytic differentiation and fuel the search for druggable targets. For example, several groups, including the authors of this study, have already reported a role for NUP98 fusion oncoproteins in dysregulated HOX gene expression as a proleukemogenic event in AML.…”