Allogeneic Stem Cell Transplantation for FLT3-Mutated Acute Myeloid Leukemia: In vivo T-Cell Depletion and Posttransplant Sorafenib Maintenance Improve Survival. A Retrospective Acute Leukemia Working Party-European Society for Blood and Marrow Transplant Study

Abstract

Acute myeloid leukemia (AML) with FLT3-mutation carries a poor prognosis, and allogeneic stem cell transplantation (allo-SCT) is recommended at first complete remission (CR1). We assessed 462 adults (median age 50 years) with FLT3-mutated AML allografted between 2010 and 2015 from a matched related (40%), unrelated (49%), or haploidentical donor (11%). The median follow-up of alive patients was 39 months. Day-100 acute graft versus host disease (GVHD) grades II-IV and III-IV were encountered in 26% and 9%, whereas the 2-year incidence of chronic and extensive chronic GVHD were 34% and 16%, respectively. The 2-year incidences of relapse and nonrelapse mortality were 34% and 15%, respectively. The 2-year leukemia-free survival, overall survival (OS), and GVHD relapse-free survival (GRFS) were 51%, 59%, and 38%, respectively. In multivariate analysis, NPM1-mutation, transplantation in CR1, in vivo T-cell depletion, and posttransplant sorafenib improved OS, whereas more than one induction (late CR1) negatively affected OS. Similarly, NPM1-mutation, a haploidentical donor, T-cell depletion, and sorafenib maintenance improved GRFS, whereas late CR1 or persistent disease negatively affected it. In conclusion, FLT3mutated AML remains a challenge even following allo-SCT. In vivo T-cell depletion and posttransplant sorafenib significantly improve OS and GRFS, and may be considered as standard of care.

Measurable residual disease (MRD) testing for acute leukemia in EBMT transplant centers: a survey on behalf of the ALWP of the EBMT

“…This will likely increase the predictive value of pretransplant MRD status on relapse risk and OS above what has been observed with MRD positivity as currently ascertained in the EBMT registry database. Further, having these data in the registry will also benefit to study assessing the impact of prophylactic intervention such as posttransplant immunosuppression discontinuation, donor lymphocyte infusion, or targeted low-intensity therapies on leukemia progression [34][35][36][37][38][39].…”

Pre-transplant FLT3/ITD status predicts outcome in FLT3-mutated acute myeloid leukemia following allogeneic stem cell transplantation

“…Interestingly, the outcome of haplo-SCT for MRD-FC-positive patients was comparable with that demonstrated for subjects with pre-transplant MRD-FC-negativity [17]. In the light of the recent findings and when confirmed in prospective studies, it seems reasonable to consider FLT3 inhibitor as a part of induction therapy and post-transplant maintenance [18,19]. A double-blind randomized study showed that the addition of midostaurin to standard chemotherapy significantly improved overall and event-free survival in FLT3positive AML patients; however, midostaurin was not beneficial as maintenance treatment after transplantation [18].…”

Pharmacologic Therapies to Prevent Relapse of Acute Myeloid Leukemia After Allogeneic Hematopoietic Stem Cell Transplantation

“…Sorafenib was the first TKI studied in the setting of posttransplant maintenance therapy in AML with FLT3-ITD mutation. It showed benefit in survival and improvement of outcomes in a phase I study, several retrospective studies and two randomized studies (80)(81)(82)(83)(84)(85)(86)104). Chen and colleagues (80) reported the results of the first phase I trial on sorafenib after transplant in 22 patients with FLT3 mutated AML.…”

“…A recent update of this study after a median follow-up of 40 months further demonstrated promising long-term outcomes with sorafenib maintenance with 2-year PFS and OS of 73% and 80%, respectively. Recently Bazarbachi and colleagues (85) reported the results of European Society for Blood and Marrow Transplantation (EBMT) registry-based study on 462 allo-grafted FLT3-mutated AML patients (FLT3-ITD-95%) over a median follow-up of 39 months for surviving patients. Among these patients, 28 received posttransplant sorafenib maintenance as prophylactic (n = 19) or preemptive therapy (n = 9), started at a median of 55 days posttransplant (range 1-173 days) and a median dose of 800 mg/day (range 200-800 mg/day).…”