A new therapeutic option is under study for use in a difficult-to-treat subset of patients with acute myeloid leukemia (AML), according to a presentation during the European Hematology Association (EHA) 2023 Hybrid Congress.¹

Exploratory results of the phase III MORPHO trial showed a benefit to the FLT3 inhibitor gilteritinib vs placebo as maintenance therapy after transplantation for patients with FLT3-ITD–mutated AML, especially those with detectable measurable residual disease (MRD). According to the study authors, these findings highlight the value of incorporating MRD testing into clinical decision-making and support the need for further research to optimize the use of targeted therapies for AML.

“These data prospectively demonstrate the correlation between MRD and survival in posttransplant therapy for FLT3-ITD AML,...”

— Mark J. Levis, MD, PhD

Tweet this quote

“Although the MORPHO trial did not meet its primary endpoint, it successfully showed the potential of gilteritinib for patients with FLT3-ITD AML who have detectable MRD after transplantation,” said Mark J. Levis, MD, PhD, Program Leader of the Hematologic Malignancies and Bone Marrow Transplant Program at Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins Medicine. “We can use this assay to identify patients who may benefit the most from gilteritinib, improving MRD eradication for patients with detectable MRD.”

Gilteritinib is available in the United States, Japan, China, and selected European countries for the treatment of adults who have relapsed or refractory FLT3-positive AML.

Study Background and Methods

As Dr. Levis explained, patients who have FLT3-ITD AML have a high risk of relapse. As a FLT3 inhibitor, gilteritinib has demonstrated activity against FLT3-ITD, a common driver mutation that presents with a high disease burden and a poor prognosis, and FLT3 tyrosine kinase domain mutations.

The BMT-CTN 1506 MORPHO study is an international phase III randomized, placebo-controlled, double-blind study of maintenance therapy with gilteritinib after hematopoietic stem cell transplantation.

Researchers chose gilteritinib for its tolerability as monotherapy for relapsed or refractory FLT3-mutant AML. The study aimed to determine whether maintenance therapy with gilteritinib over a period of 2 years after allogeneic hematopoietic stem cell transplantation would benefit all patients with FLT3-ITD AML and whether MRD could be used to identify which patients may benefit the most.

The study’s primary endpoint was relapse-free survival. Secondary endpoints included overall survival and the effect of MRD on those endpoints. A total of 488 participants registered, and 356 were randomly assigned, with 178 in each treatment arm.

New Standard of Care for MRD-Positive Patients?

One of the critical aspects of the MORPHO trial was the use of MRD as a stratification tool to determine which patients would benefit the most from gilteritinib. Although findings from the study failed to demonstrate statistically significant improvement in relapse-free survival in the entire cohort (hazard ratio [HR] = 0.68; P = .0518), there was clinical improvement in relapse-free survival in a subgroup of patients with detectable MRD. At 2 years, patients without detectable MRD, on the other hand, had no improvement in relapse-free survival (HR = 1.213; P = .575).

“These data prospectively demonstrate the correlation between MRD and survival in posttransplant therapy for FLT3-ITD AML,” Dr. Levis reported. “Gilteritinib confers a clear benefit for the 50% of patients with detectable MRD and should be a standard of care for those who achieve MRD positivity.”

Safety and Regional Differences

With respect to safety, adverse events were more common in the gilteritinib arm, often leading to dose reduction, interruption, or withdrawal of treatment. The most frequent treatment-emergent adverse events were decrease in neutrophil count, diarrhea, and nausea, which were generally consistent with previous studies of gilteritinib.

In patients who have FLT3-ITD AML, treatment-emergent adverse events associated with gilteritinib compared with placebo were neutrophil decrease (42.1% vs 15.8%) and an increased incidence of chronic graft-vs-host disease (52.2% vs 42.1%). There was no significant increase in acute graft-vs-host disease with the use of the FLT3 inhibitor.

The study also highlighted regional differences in practice patterns and patient populations, with North American patients receiving a greater benefit from gilteritinib than their European and Asian counterparts. Although the reasons for these differences are not entirely clear, they may reflect variations in clinical practice patterns, patient populations, and prior treatments received. Additional research is required to better understand the impact of regional differences on treatment outcomes and to determine the most appropriate strategy for patients from various geographic locations, Dr. Levis concluded. 

DISCLOSURE: Dr. Levis has received honoraria from AbbVie, Amgen, Astellas Pharma, Bristol Myers Squibb, Daiichi Sankyo, Takeda, and Pfizer; and has received research funding from Agios, Astellas Pharma, and Daiichi Sankyo.

REFERENCE

1. Levis MJ, Hamadani M, Logan B, et al: BMT-CTN 1506 (MORPHO): A randomized trial of the FLT3 inhibitor gilteritinib as post-transplant maintenance for FLT3-ITD AML. EHA 2023 Hybrid Congress. Abstract LB2711. Presented June 11, 2023.