Gilteritinib as Post-Transplant Maintenance for AML With Internal Tandem Duplication Mutation of FLT3

Abstract

Purpose: Allogeneic hematopoietic cell transplantation (HCT) improves outcomes for patients with AML harboring an internal tandem duplication mutation of FLT3 (FLT3-ITD) AML. These patients are routinely treated with a FLT3 inhibitor after HCT, but there is limited evidence to support this. Accordingly, we conducted a randomized trial of post-HCT maintenance with the FLT3 inhibitor gilteritinib (ClinicalTrials.gov identifier: NCT02997202) to determine if all such patients benefit or if detection of measurable residual disease (MRD) could identify those who might benefit.

Methods: Adults with FLT3-ITD AML in first remission underwent HCT and were randomly assigned to placebo or 120 mg once daily gilteritinib for 24 months after HCT. The primary end point was relapse-free survival (RFS). Secondary end points included overall survival (OS) and the effect of MRD pre- and post-HCT on RFS and OS.

Results: Three hundred fifty-six participants were randomly assigned post-HCT to receive gilteritinib or placebo. Although RFS was higher in the gilteritinib arm, the difference was not statistically significant (hazard ratio [HR], 0.679 [95% CI, 0.459 to 1.005]; two-sided P = .0518). However, 50.5% of participants had MRD detectable pre- or post-HCT, and, in a prespecified subgroup analysis, gilteritinib was beneficial in this population (HR, 0.515 [95% CI, 0.316 to 0.838]; P = .0065). Those without detectable MRD showed no benefit (HR, 1.213 [95% CI, 0.616 to 2.387]; P = .575).

Conclusion: 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. To our knowledge, these data are among the first to support the effectiveness of MRD-based post-HCT therapy.

FIG 1.

Screening, registration, random assignment, and reasons for discontinuing study treatment. GVHD, graft-versus-host disease; HCT, hematopoietic cell transplantation.

FIG 2.

Survival, relapse, and nonrelapse mortality (ITT population). (A) Relapse-free survival, (B) overall survival for the gilteritinib and placebo groups, (C) cumulative incidence of relapse for the gilteritinib group versus placebo group, and (D) cumulative incidence of nonrelapse mortality (defined as death without documentation of morphological relapse). HR, hazard ratio; ITT, intention-to-treat; OS, overall survival; RFS, relapse-free survival.

FIG 3.

The impact of measurable residual disease on relapse-free survival (ITT population). (A) Relapse-free survival, (B) overall survival for all participants irrespective of the treatment arm according to whether any (eg, FLT3-ITD variant allele frequency of 1 × 10⁻⁶ or above) MRD was detectable peri-HCT, (C) relapse-free survival in participants with any (eg, FLT3-ITD variant allele frequency of 1 × 10⁻⁶ or above) detectable peri-HCT MRD according to the treatment arm, and (D) relapse-free survival in participants with no detectable peri-HCT MRD, according to the treatment arm. FLT3-ITD, internal tandem duplication mutation of FLT3; HCT, hematopoietic cell transplantation; HR, hazard ratio; ITT, intention-to-treat; MRD, measurable residual disease; OS, overall survival; RFS, relapse-free survival.

FIG 4.

Relapse-free survival by treatment arm according to the geographic region: (A) North America (United States and Canada), (B) Europe (Greece, Belgium, France, Spain, Italy, United Kingdom, Denmark, Poland, Germany), (C) Asia Pacific and ROW (Japan, Korea, Taiwan, Australia, New Zealand), and (D) Relapse-free survival of placebo arms only from the three regions (NA, EU, and ROW). EU, Europe; HR, hazard ratio; NA, North America; ROW, rest of world.