Haploidentical Stem Cell Transplantation Attenuates the Prognostic Impact of FLT3-ITD in Acute Myeloid Leukemia

Background

Acute myeloid leukemia (AML) patients harboring the fms-like tyrosine kinase 3 internal tandem duplication (FLT3-ITD) mutation are considered a particularly high risk patient subset preferentially allocated for allogeneic stem cell transplantation in first remission. Whether FLT3-ITD retains a prognostic role in haploidentical stem cell transplantation (haplo-SCT) is currently unknown.

Patients and methods

To determine whether FLT3-ITD is prognostically significant in T-cell replete haplo-SCT transplanted AML patients, we performed a comparative analysis between FLT3^wt and FLT3-ITD using the multicenter registry of the acute leukemia working party of the European society for blood and marrow transplantation. Patients included in this analysis were AML patients over the age of 18 who underwent a first T-cell replete haplo-SCT in first remission.

Results

We evaluated 293 de-novo AML patients (202 FLT3^wt and 91 FLT3-ITD) transplanted in first remission with T-cell replete haplo-SCT between 2005-2016. Both groups did not differ to a significant degree in terms of patient age, donor age, performance status, cytomegalovirus donor-recipient matching, and conditioning intensity. FLT3-ITD patients were more likely to be nucleophosmin1 (NPM1) mutated as well as be in the Medical Research Council (MRC) intermediate risk cytogenetic risk category. In multivariate analysis, patients with FLT3-ITD had comparable rates of relapse incidence [Hazard ratio (HR)=1.34, confidence interval (CI) 95%, 0.67-2.7; P=0.9] and leukemia-free survival (HR=0.99, CI 95%, 0.62-1.57; P=0.9) to those of FLT3^wt patients. Survival was not significantly impacted by FLT3-ITD status (HR=0.96, CI 95%, 0.58-1.59; P=0.8), nor were the incidence of non-relapse mortality (HR=0.78, CI 95%, 0.41-1.46; P=0.44), and graft versus host disease-free/relapse-free survival (HR=0.84, CI 95%, 0.54-1.28; P=0.42). A separate analysis for patients treated either on anti-thymocyte globulin (ATG) protocols or post-transplant cyclophosphamide (PTCy) did not significantly associate FLT3-ITD status with clinical outcome in either of these groups. Finally, a focused subset analysis of patients with MRC intermediate risk cytogenetics confirmed the absence of a prognostic impact of FLT3-ITD also for this group of patients.

Conclusions

In AML patients undergoing T-cell replete haplo-SCT, the FLT3-ITD mutation probably does not retain its prognostic significance, potentially indicative of haplo-SCT's capacity to overcome the negative prognostic consequences of FLT3-ITD in AML.