Influence of FLT3-ITD Mutation and Length on the Treatment Response and Prognosis in Cytogenetically Normal AML Patients

Abstract

BACKGROUND : Mutations of internal tandem duplication in FMS-like tyrosine kinase 3 (FLT3-ITD) contributed to poor prognosis in cytogenetically normal acute myeloid leukemia (CN-AML). FLT3 tyrosine kinase inhibitor sorafenib in combination with chemotherapy was applied to treat FLT3-ITD AML patients with limited efficacy. Allogeneic hematopoietic stem cell transplantation (allo-HSCT) was considered as a potent therapeutic regimen in FLT3-ITD patients, but additional sorafenib maintenance was indispensable to support their long-term survival after allo-HSCT. Studies showed that increasing ITD size may be accompanied with decreasing OS and RFS in AML patients, but it remained controversial about the prognostic implication of ITD mutant lengths, the prognostic influence was important to evaluate in determining the therapeutic strategy for AML patients with different ITD lengths. METHODS: Total 185 CN-AML patients with and without FLT3-ITD mutations were enrolled in this study. We retrospectively studied the clinical characteristic, treatment response, survival and relapse risk after chemotherapy or allo-HSCT plus sorafenib in these patients. Distribution of ITD lengths detected in AML patients suggested two groups including long (≥70bp) and short ITD length (<70bp). Influence of FLT3-ITD mutation and its length were investigated after chemotherapy or allo-HSCT plus sorafenib. RESULT: FLT3-ITD mutations were detected in 15 percentage of AML patients, and associated with leukocytosis, high blast percentage in bone morrow (BM) and increased risk of treatment failure. FLT3-ITD mutations indicated decreased complete remission (CR) rate, overall survival (OS) and relapse-free survival (RFS), and increased relapse risk (RR) in AML patients after chemotherapy plus sorafenib. Patients with long ITD length (≥70bp) had worse OS and RFS, and more relapse probability than these with short ITD length (< 0bp) or FLT3-WT, but patients with short ITD length and FLT3-WT had the similar RFS and RR after chemotherapy. Allo-HSCT plus sorafenib maintenance significantly prolonged OS and RFS, decreased RR in FLT3-ITD patients, especially in these with long ITD length instead of those with short ITD length. CONCLUSION: Our findings indicated that FLT3-ITD mutation and long ITD length had negative effect on treatment response and prognosis in CN-AML patients. Allo-HSCT plus sorafenib maintenance was an effective strategy to improve survival and decrease relapse probability, abrogated disadvantage from long ITD length in FLT3-ITD patients. Disclosures No relevant conflicts of interest to declare.

Prognostic significance of FLT3-ITD length in AML patients treated with intensive regimens

“…As in previous works, we analyzed the clinical significance of FLT3-ITD length among fit patients treated with intensive regimens 15,16 . Our median ITD length was 48 bp (range = 3 bp to 231 bp), similar to previous studies 12,14,17 . To test the prognostic significance of the ITD length and its clinical applicability, we used recurrent previously published cutoffs, which were analyzed in series ranging from 28 to 100 intensively treated patients.…”

“…To test the prognostic significance of the ITD length and its clinical applicability, we used recurrent previously published cutoffs, which were analyzed in series ranging from 28 to 100 intensively treated patients. Patients with an ITD fragment ≥ 39 bp or ≥ 70 bp had a significant reduction in OS and RFS in some of these studies, but we were unable to validate these findings 11,[15][16][17] . We obtained a P value of 0.055 in the analysis of RFS applying the 70 bp cutoff.…”

“…None of the studies has carried out an internal ITD length cutoff validation by dividing the patients into a training cohort and a validation cohort, which, given the arbitrary selection of the cutoffs used, would be necessary. Nevertheless, some thresholds have been applied in more than one study [i.e., 39 bp and 70 bp] 11, [15][16][17] . We aimed to shed light on the prognostic importance of the FLT3-ITD length and site of insertion by validating previously suggested sites of insertion and thresholds of ITD length.…”