Optimized cytogenetic risk-group stratification of KMT2A-rearranged pediatric acute myeloid leukemia

A comprehensive international consensus on the cytogenetic risk -group strati fication of KMT2A -rearranged ( KMT2A -r) pediatric acute myeloid leukemia (AML) is lacking. This retrospective (2005-2016) International Berlin-Frankfurt-M & uuml;nster Study Group study on 1256 children with KMT2A -r AML aims to validate the prognostic value of established recurring KMT2A fusions and additional cytogenetic aberrations (ACAs) and to de fine additional, recurring KMT2A fusions and ACAs, evaluating their prognostic relevance. Compared with our previous study, 3 additional, recurring KMT2A -r groups were de fined: Xq24/ KMT2A :: SEPT6 , 1p32/ KMT2A :: EPS15 , and 17q12/t(11;17)(q23;q12). Across 13 KMT2A -r groups, 5-year event-free survival probabilities varied signi ficantly (21.8%-76.2%; P < .01). ACAs occurred in 46.8% of 1200 patients with complete karyotypes, correlating with inferior overall survival (56.8% vs 67.9%; P < .01). Multivariable analyses con firmed independent associations of 4q21/ KMT2A :: AFF1 , 6q27/ KMT2A :: AFDN , 10p12/ KMT2A :: MLLT10 , 10p11.2/ KMT2A :: ABI1 , and 19p13.3/ KMT2A :: MLLT1 with adverse outcomes, but not those of 1q21/ KMT2A :: MLLT11 and trisomy 19 with favorable and adverse outcomes, respectively. Newly identi fied ACAs with independent adverse prognoses were monosomy 10, trisomies 1, 6, 16, and X, add(12p), and del(9q). Among patients with 9p22/ KMT2A :: MLLT3 , the independent association of French-American- British -type M5 with favorable outcomes was con firmed, and those of trisomy 6 and measurable residual disease at end of induction with adverse outcomes were identi fied. We provide evidence to incorporate 5 adverse -risk KMT2A fusions into the cytogenetic risk - group strati fication of KMT2A -r pediatric AML, to revise the favorable -risk classi fication of 1q21/ KMT2A :: MLLT11 to intermediate risk, and to re fine the risk -strati fication of 9p22/ KMT2A :: MLLT3 AML. Future studies should validate the associations between the newly identi fied ACAs and outcomes and unravel the underlying biological pathogenesis of KMT2A fusions and ACAs.