Should We Utilize Maintenance Therapy Post-Hematopoietic Cell Transplantation in Patients With FLT3/ITD-positive AML?

A Multicenter, Randomized, Double-blind, Placebo-controlled Phase III Trial of the FLT3 Inhibitor Gilteritinib Administered as Maintenance Therapy Following Allogeneic Transplant for Patients With FLT3/ITD AML, Blood and Marrow Transplant Clinical Trials Network (BMT CTN) 1506

NCT02997202

National Heart Lung and Blood institute; National Cancer Institute; Astellas Pharma Global Development, Inc.

This clinical trial plans to randomly assign 173 participants per treatment arm (346 total participants).

The study is open at 139 locations including academic centers as well as some larger community oncology practices in the Unites States, Europe, and Asia.

This trial is enrolling adult patients with FMS-like tyrosine kinase 3 (FLT3)/internal tandem duplication (ITD; FLT3/ITD) acute myeloid leukemia (AML) in first morphologic complete remission (CR1, as defined by < 5% blasts in the bone marrow [BM] with no morphologic characteristics of acute leukemia, in marrow with no evidence of extramedullary disease) who undergo allogeneic hematopoietic cell transplantation (HCT). This is a double-blind, placebo-controlled, randomized, multi-center phase III trial in which participants are randomized to receive gilteritinib or placebo beginning after the time of engraftment, for a two-year period. Participants are stratified according to three factors: 1) conditioning regimen intensity (myeloablative vs. reduced intensity/nonmyeloablative), 2) time from first day of hematopoietic cell infusion to randomization (30-60 days vs. 61-90 days) and 3) presence versus absence of or unknown minimal residual disease (MRD) from a preregistration BM aspirate. The primary objective is to compare relapse-free survival (RFS) between the arms at two years.

FLT3 is a common mutation seen in approximately 30 percent of AML cases. It usually presents with proliferative white blood cell counts, often in younger patients. These patients are at high risk of relapse even if they achieve a remission.¹  There is an increased chance to achieve CR1 with administrations of FLT3 tyrosine kinase inhibitors (TKIs) in induction or at relapse^2,3  as well as to pursue a potential cure with HCT.⁴  The current BMTCTN 1506 trial is well-positioned to evaluate the impact of maintenance therapy with gilteritinib on the RFS of participants with FLT3/ITD AML who have successfully undergone allogeneic transplantation. A dose of 120 mg has been chosen on the basis of a monotherapy trial, which demonstrated complete FLT3 inhibition in patients with FLT3/ITD AML.⁵  A maintenance period of two years has been chosen based on Center for International Blood and Marrow Transplant Research (CIBMTR) data that indicate the vast majority of relapses occur by this time after allogeneic HCT. Because it is placebo-controlled and double-blinded, the results that emerge from this study will establish whether FLT3 inhibition in this setting can prevent relapse, and whether it has an effect on graft-versus-host disease in these participants. Additionally, the trial may establish the utility of monitoring MRD using a next-generation sequencing (NGS) platform.⁶ 

This is a vital study in the AML field given the high prevalence of FLT3 mutations in AML. The investigators are observing the potential benefits of post-transplantation TKI maintenance therapy in FLT3-ITD AML. The downsides of maintenance could be the drug toxicity of the TKIs or the long-term potentially detrimental health effects of FLT3 inhibition in addition to drug and health care costs. Smaller studies addressing maintenance TKIs post HCT were presented at the 2018 ASH Annual Meeting but have yet to definitively answer the question. The randomized, phase II SORMAIN study in Austria and Germany assigned engrafted patients post-HCT to receive sorafenib for up to 24 months versus placebo. During the five years of accrual to this study, only 83 patients were randomized, and the study terminated due to low accrual. At 30 months, overall survival favored the sorafenib arm, with a hazard ratio of 0.447 (p=0.03).⁷  The RADIUS study in the United States accrued 60 patients who were randomly assigned to receive midastaurin for 12 four-week cycles. The study was (by design) not powered to detect a statistical difference between the two arms, and median RFS was not reached for either cohort.⁸  The BMTCTN1502 study chairs recently addressed the question of equipoise in the setting of these results and provided a compelling rationale for randomization on their trial.⁹  This study represents the largest international effort to date in FLT3 AML for maintenance therapy and will generate helpful data for physicians and patients. It is accruing well and on target to complete enrollment within 24 months.