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FLT3-ITD allelic ratio and HLF expression predict FLT3 inhibitor efficacy in adult AML.

ABSTRACT: FLT3 internal tandem duplication (FLT3-ITD) is a frequent mutation in acute myeloid leukemia (AML) and remains a strong prognostic factor due to high rate of disease recurrence. Several FLT3-targeted agents have been developed, but determinants of variable responses to these agents remain understudied. Here, we investigated the role FLT3-ITD allelic ratio (ITD-AR), ITD length, and associated gene expression signatures on FLT3 inhibitor response in adult AML. We performed fragment analysis, ex vivo drug testing, and next generation sequencing (RNA, exome) to 119 samples from 87 AML patients and 13 healthy bone marrow controls. We found that ex vivo response to FLT3 inhibitors is significantly associated with ITD-AR, but not with ITD length. Interestingly, we found that the HLF gene is overexpressed in FLT3-ITD⁺ AML and associated with ITD-AR. The retrospective analysis of AML patients treated with FLT3 inhibitor sorafenib showed that patients with high HLF expression and ITD-AR had better clinical response to therapy compared to those with low ITD-AR and HLF expression. Thus, our findings suggest that FLT3 ITD-AR together with increased HLF expression play a role in variable FLT3 inhibitor responses observed in FLT3-ITD⁺ AML patients.

SUBMITTER: Kivioja J

PROVIDER: S-EPMC8651734 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:The adverse prognosis of internal tandem duplication in the FMS-like tyrosine kinase 3 gene(s) (FLT3-ITD) in patients with acute myelogenous leukemia (AML) may depend on allelic burden. We compared postremission treatment with chemotherapy and hematopoietic stem cell transplantation (HSCT) in 169 FLT3-ITDmut intermediate cytogenetic risk AML patients with allelic ratio evaluable at diagnosis who achieved first complete remission (CR1) with induction therapy. To minimize selection bias, the analysis was limited to patients who remained in CR1 for at least 4 months (median time to HSCT) after achieving CR1, and propensity score matching was implemented. Sensitivity analysis including patients who remained in CR1 for at least 3 months was applied as well. HSCT in CR1 was associated with longer relapse-free survival (RFS) and overall survival (OS), with 3-year estimated rates of 18% and 24%, respectively (P < .001), for patients receiving chemotherapy and 46% and 54%, respectively (P < .001), for those undergoing HSCT. Multivariate regression models showed that HSCT remained statistically significant with improved RFS and OS independent of FLT3-ITD allelic ratio and NPM1 status. Irrespective of postremission therapy, relapse remains the main reason for treatment failure, with a 3-year incidence of 68% in chemotherapy recipients versus 41% in HSCT recipients. Allogeneic HSCT improved disease outcomes compared with chemotherapy after propensity score matching was applied. The improvement observed for RFS (hazard ratio [HR], 0.55; P = .09) and OS (HR, 0.58; P = .10) with HSCT as postremission therapy in patients who remained in CR1 for at least 4 months did not reach statistical significance; however, the sensitivity analyses including patients who remained in CR1 for at least 3 months showed significant improvement in both RFS (HR, 0.31; P = .002) and OS (HR, 0.27; P = .02) after propensity score matching. Our results indicate that HSCT in CR1 for AML FLT3-ITDmut patients is associated with longer RFS and OS. Innovative transplantation strategies to improve relapse incidence are urgently needed.

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FLT3-ITD allelic ratio and HLF expression predict FLT3 inhibitor efficacy in adult AML.

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