KEY TAKEAWAYS
- The phase 3 MORPHO study determined the efficacy of gilteritinib, a FLT3 inhibitor, as a post-HCT maintenance therapy.
- The study’s primary aim was to determine if gilteritinib could enhance relapse-free survival (RFS) over placebo for pts who experienced their initial remission following an FLT3-ITD AML transplant. The secondary objective was OS.
- Gilteritinib benefited half of the patients with detectable MRD pre or post-HCT. Its main side effects were myelosuppression and increased chronic GVHD.
Individuals diagnosed with acute myeloid leukemia containing the FLT3-ITD mutation (FLT3-ITD AML) are at a heightened risk of the disease returning. These patients (pts) typically receive allogeneic hematopoietic cell transplantation (HCT). Although FLT3 inhibitors are often given after HCT to reduce the risk of relapse, this method primarily relies on trials of sorafenib, which included patients treated with FLT3 inhibitors before transplantation.
The phase 3 BMT-CTN1506 (“MORPHO”) trial investigated the efficacy of the FLT3 inhibitor, gilteritinib, as a maintenance therapy following HCT. Its main aim was to evaluate if gilteritinib could enhance relapse-free survival (RFS) compared to a placebo for patients who had their first remission after an FLT3-ITD AML transplant. The secondary endpoint was overall survival (OS). Additional secondary objectives included studying the impact of measurable residual disease (MRD) on RFS and OS before and after transplantation. This also included assessing non-relapse mortality rates, event-free survival, and the occurrence of both acute and chronic graft-versus-host disease (GVHD) in participants receiving gilteritinib compared to those on placebo.
Eligible pts were adults diagnosed with FLT3-ITD AML who had received up to two induction therapy cycles and planned on HCT within a year of remission. Following induction and any consolidation treatment, patients were enrolled and proceeded with HCT. Once they achieved engraftment, which occurred between 30-90 days post-HCT, they were divided into groups receiving either a placebo or 120 mg/day of gilteritinib for a period of 24 months. Marrow aspirates for MRD were taken before the transplant, before the division into groups, and then at intervals of 3, 6, 12, 18, and 24 months after randomization. The PCR-NGS assay used for MRD analysis was sensitive enough to identify a FLT3-ITD mutation at a ratio of 1 x 10-6. The division of patients into groups was influenced by factors like the MRD level of 10-4 or higher before HCT, the intensity of the conditioning regimen, and whether the period from HCT to the division into groups was -/+ 60 days.
Out of 620 individuals screened, 356 were chosen for the study. In the intention-to-treat analysis, the RFS was higher for patients assigned to gilteritinib. However, this difference wasn’t statistically significant with an HR of 0.679 and a 95% CI ranging from 0.459 to 1.005. The 2-sided p-value was 0.0518. The OS was comparable between the two groups, with an HR of 0.846 and a 95% CI between 0.554 and 1.293. The p-value for this was 0.4394. After two years, the RFS was 77.2% (with a 95% CI of 70.1% to 82.8%) for those on gilteritinib and 69.9% (with a 95% CI of 62.4% to 76.2%) for those on the placebo. Over half (50.6%) of the pts had MRD of 10-6 or more before HCT or being randomized.
A predefined subgroup analysis revealed a more marked effect of gilteritinib on pts with detectable MRD. In this group, the HR was 0.515 with a 95% CI from 0.316 to 0.838 and a p-value of 0.0065. This effect was in contrast to those without detectable MRD, where the HR was 1.213 with a 95% CI from 0.616 to 2.387 and a p-value of 0.575. In the gilteritinib group, 143 patients (or 80.3%) experienced interruptions in their dose, compared to 129 patients (or 72.9%) in the placebo group. Furthermore, 97 patients (or 54.5%) in the gilteritinib group required dose reductions, in contrast to 45 patients (or 25.4%) in the placebo group. Treatment-related adverse events (TEAEs) were more prevalent in the gilteritinib group. This includes a decrease in neutrophils (42.1% for gilteritinib vs. 15.8% for placebo) and chronic GVHD (52.2% for gilteritinib vs. 42.1% for placebo). There was also a higher occurrence of TEAEs that led to treatment withdrawal in the gilteritinib group.
Gilteritinib was beneficial for 50% of patients with detectable MRD before or after HCT, compared to those without. TEAEs linked with gilteritinib were primarily myelosuppression and a heightened rate of chronic GVHD. These findings provide initial evidence advocating for MRD-focused maintenance therapy post-HCT.
Clinical Trial: https://classic.clinicaltrials.gov/ct2/show/NCT02997202
BMT-CTN 1506 (MORPHO): A RANDOMIZED TRIAL OF THE FLT3 INHIBITOR GILTERITINIB AS POST-TRANSPLANT MAINTENANCE FOR FLT3-ITD AML. EHA Library. Faculty / Presenters. 06/01/2023; 391322; LB2711
