Distinct clinico-biological features in AML patients with low allelic ratio FLT3-ITD: role of allogeneic stem cell transplantation in first remission

Abstract

The mutant burden of FLT3-ITD modulates its prognostic impact on patients with acute myeloid leukemia (AML). However, for patients with low allelic ratio (AR) FLT3-ITD (FLT3-ITD^low, AR < 0.5), clinical features, as well as genomic and transcriptomic profiles remain unclear, and evidence supporting allogeneic hematopoietic stem cell transplantation (allo-HSCT) in first complete remission (CR1) remains controversial. This study aimed to elucidate the genomic features, prognosis, and transplantation outcome of FLT3-ITD^Iow in AML patients with intermediate-risk cytogenetics. FLT3-ITD^low was associated with a negative enrichment of the leukemic stem cell signature, a marked enrichment of the RAS pathway, and with higher frequencies of RAS pathway mutations, different from those with FLT3-ITD^high. Concurrent CEBPA double mutations were favorable prognostic factors, whereas MLL-PTD, and mutations in splicing factors were unfavorable prognostic factors in FLT3-ITD^low patients. Patients with FLT3-ITD^low had a shorter overall survival (OS) and event-free survival (EFS) than those with FLT3^wt. Allo-HSCT in CR1 was associated with a significantly longer OS and EFS compared with postremission chemotherapy in patients with FLT3-ITD^low. In conclusion, FLT3-ITD^low is associated with different mutational and transcriptomic profiles compared with FLT3-ITD^high. The presence of concomitant poor-risk mutations exert negative prognostic impacts in patients with FLT3-ITD^low, who markedly benefit from allo-HSCT in CR1.