Tailoring Transplant Conditioning and Maintenance Therapy in FLT3-ITD AML: Insights on NPM1 Mutations and Measurable Residual Disease

Introduction

Acute myeloid leukemia (AML) harboring FLT3 internal tandem duplication (FLT3-ITD) mutations remains a challenging clinical entity despite intensive therapeutic approaches. Allogeneic hematopoietic cell transplantation (HCT) in first remission is widely employed to improve outcomes for these patients. However, predictive markers such as measurable residual disease (MRD) and concomitant molecular mutations like NPM1 have garnered increasing attention as critical determinants in tailoring transplant strategies. Specifically, the choice between myeloablative conditioning (MAC) and reduced-intensity conditioning (RIC), as well as the role of posttransplant FLT3 inhibitor maintenance therapy, remain topics of significant clinical investigation.

The Blood and Marrow Transplant Clinical Trials Network (BMT CTN) 1506 (MORPHO) trial provided a unique dataset to explore these factors. This randomized, global, double-blind study evaluated gilteritinib versus placebo as post-HCT maintenance in FLT3-ITD AML. A comprehensive post hoc analysis of this trial elucidated interactions between conditioning intensity, MRD status, and NPM1 mutation comutations, offering new paradigms for personalized transplant approaches in this subset of AML.

Study Design and Methods

BMT CTN 1506 enrolled 356 adult patients with FLT3-ITD mutated AML achieving complete remission (CR) after up to two courses of intensive chemotherapy, proceeding to allogeneic HCT within one year of remission. Key inclusions allowed for all conditioning regimens, graft sources, and graft-versus-host disease prophylaxis. Participants were randomized postengraftment, between 30 and 90 days after HCT, to either gilteritinib 120 mg daily or placebo. Bone marrow samples for MRD were collected pre-HCT (within 30 days before conditioning) and post-HCT (before randomization).

Conditioning regimens were rigorously classified by adjudication, with MAC defined by specific thresholds of irradiation or chemotherapeutic doses, while regimens below these thresholds were considered RIC. FLT3-ITD and NPM1 mutation statuses were locally determined at diagnosis.

FLT3-ITD MRD was quantified using a sensitive, next-generation sequencing–based amplicon assay analyzing marrow DNA, focusing on variant allele frequency (VAF). MRD positivity was defined at VAF ≥ 1 × 10⁻⁴. Statistical analyses included Kaplan-Meier survival estimates, Cox proportional hazards for relapse-free survival (RFS), and Fine-Gray models for cumulative incidence functions of relapse, stratified by conditioning intensity, MRD status, and NPM1 comutation.