Internal tandem duplications of FLT3 containing exogenous sequences are associated with poor clinical outcomes in acute myeloid leukemia.

Abstract

The heterogeneity in internal tandem duplications (ITDs) of FMS-like tyrosine kinase 3 (FLT3) results in diverse clinical outcomes for acute myeloid leukemia (AML) patients with FLT3-ITD mutations. This study retrospectively analyzed 124 FLT3-ITD-positive AML patients, aiming to evaluate How ITDs with exogenous sequences affect the response to induction therapy and long-term prognosis. Among them, 45.97% (57/124) had ITDs with exogenous sequences, classified as the insertion group. The remaining 54.03% (67/124) had only repetitions of the original FLT3 sequence, classified as the duplication group. Comparisons between these two groups revealed that the rates of composite complete remission (CRc) (59.09% vs. 81.03%, P = 0.017) and negative measurable residual disease (MRD) identified by multiparameter flow cytometry (MFC) (25.00% vs. 48.28%, P = 0.018) were significantly lower in the insertion group than those in the duplication group after the first cycle of induction therapy. Moreover, survival analysis conducted on 68 patients who received at least two cycles of consolidation therapy revealed that patients in the insertion group had significantly lower relapse-free survival (RFS) (2-year RFS: 50.70% ± 10.40% vs. 71.40% ± 8.90%, P = 0.033) and overall survival (OS) (2-year OS: 52.90% ± 10.20% vs. 79.00% ± 7.90%, P = 0.017) compared with those in the duplication group. Cox regression analysis identified ITD types, DNMT3A co-mutations, MFC-MRD after the second cycle (C2) of chemotherapy and allogeneic hematopoietic stem cell transplantation (allo-HSCT) in the first CR (CR1) as independent factors affecting RFS and OS. Furthermore, nomograms were employed to predict RFS and OS, and a new prognostic re-stratification model based on ITD types for FLT3-ITD-positive AML was proposed.