Objectives

To determine if participants with internal tandem duplication mutation of FLT3 (FLT3-ITD) acute myeloid leukemia undergoing allogeneic hematopoietic stem-cell transplantation (HCT) benefit from post-HCT maintenance with the FLT3 inhibitor gilteritinib or if benefit is restricted to those patients who have FLT3-ITD measurable residual disease at the time of HCT.

Background

Acute myeloid leukemia (AML) is stratified into different molecular subtypes to guide therapy. Internal tandem duplication mutations of FLT3 (FLT3-ITD) are common in AML and confer an increased relapse risk. Allogeneic hematopoietic stem cell transplantation (HCT) in first remission is considered the standard of care for these patients when feasible. At the time of this study, guidelines recommended post-HCT maintenance with FLT3 inhibitors to reduce the risk of relapse. However, treatment with FLT3 inhibitors can be toxic and not all patients undergo relapse. The presence of measurable residual disease (MRD) pre- or post-HCT has been shown to be highly predictive of outcomes. The presence of FLT3-ITD MRD in patients in remission correlates with relapse.

Gilteritinib is a potent, well-tolerated FLT3 inhibitor that has been approved as monotherapy for relapsed or refractory FLT3-mutated AML. The BMT CTN 1506 study was initiated to determine if post-HCT maintenance with gilteritinib provided benefit for participants with FLT3-ITD AML in first remission undergoing HCT and if FLT3-ITD MRD detection could be used to identify the patients who benefit.

Participants

Participants were adults with a diagnosis of AML harboring a FLT3-ITD mutation who were in continuous first remission (CR1), as defined by < 5% blasts in the bone marrow (BM) with no morphologic characteristics of acute leukemia in the BM with no evidence of extra-medullary leukemia, and who intended to undergo allogeneic HCT after induction and any consolidation within 1 year of achieving remission.

A total of 356 participants were randomly assigned, 178 in each arm (gilteritinib and placebo).

Design

BMT CTN 1506 was a double-blind, placebo-controlled, randomized, multi-center Phase III trial. Participants began preparative chemotherapy for allogeneic transplant as consolidation therapy within 30 days after the confirmatory registration BM aspirate. In order to receive the study drug, participants had to achieve engraftment, defined as absolute neutrophil count (ANC) ≥ 500 cells/µL and non-transfused platelet count ≥ 20000/µL. Participants were allowed to receive any conditioning regimen, any graft-versus-host disease (GVHD) prophylaxis regimen, and HCT from any graft- or donor-source. Participants were randomized to receive gilteritinib (120 mg per day) or placebo beginning after engraftment for a two-year period. Randomization was stratified by conditioning regimen intensity (myeloablative v reduced intensity/nonmyeloablative), time from transplantation to random assignment (30-60 v 61-90 days), and the presence of FLT3-ITD MRD at a level of 1 × 10^-4 or greater (present v absent/indeterminate) on the basis of the pre-HCT BM aspirate.

The primary objective was to compare relapse-free survival (RFS) between participants with FLT3-ITD AML in CR1 who underwent HCT and were randomized to receive gilteritinib or placebo beginning after the time of engraftment for a two-year period. Key secondary objectives were the safety and tolerability of gilteritinib after HCT as well as comparing the following measures between treatment arms: overall survival (OS), non-relapse mortality (NRM), event-free survival (EFS) (where events include relapse, death, stopping therapy and administration of donor lymphocyte infusion (DLI) or new therapy for suspicion of disease), 6-month cumulative incidence of grades II-IV and III-IV acute GVHD, 12-month and 24-month cumulative incidence of mild, moderate, and severe chronic GVHD, and incidence and severity of infection. Additionally, another secondary objective was to examine the effect of pre- and post-transplant MRD on RFS and OS.

Conclusions

Although the overall improvement in RFS was not statistically significant, RFS was higher for participants with detectable FLT3-ITD MRD pre- or post-HCT who received gilteritinib treatment. These data are among the first to support the effectiveness of MRD-based post-HCT therapy.

Levis MJ, Hamadani M, Logan B, et al. Gilteritinib as Post-Transplant Maintenance for AML With Internal Tandem Duplication Mutation of FLT3. J Clin Oncol. 2024;42(15):1766-1775. doi:10.1200/JCO.23.02474

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