Gilteritinib as Maintenance Shows Benefit in MRD+ FLT3-Mutant AML Post HCT

Mark J. Levis, MD, PhD

While the phase 3 BMT-CTN 1506/MORPHO trial (NCT02997202) of gilteritinib (Xospata) did not demonstrate statistically significant improvement of relapse-free survival (RFS), there was clinical improvement of RFS among patients with FLT3-ITD–mutant acute myeloid leukemia (AML) and detectable minimal residual disease (MRD) after hematopoietic stem cell transplant (HCT).¹

The findings, which were presented during the 2023 EHA Congress, showed a hazard ratio (HR) of 0.515 favoring gilteritinib (95% CI, 0.316-0.838; P = .0065) in those with detectable MRD. The 2-year RFS rates with gilteritinib and placebo were 72.4% and 57.4%, respectively.⁴

However, when RFS was evaluated in the overall study population, gilteritinib resulted in an estimated 32% reduction in the risk of relapse vs placebo (HR, 0.679; 95% CI, 0.459-1.005; P = .0518), which was not found to be statistically significant and missed the study’s primary end point.1 The 2-year RFS rates were 77.2% with gilteritinib vs 69.9% with placebo.²

The data showed that the RFS benefit with gilteritinib was lower in patients with MRD-negative disease (P = .5750).¹

“The study did not meet its primary end point, but I think this was a successful study. We learned how to use these drugs and in whom,” lead study author Mark J. Levis, MD, PhD, program leader, Hematologic Malignancies and Bone Marrow Transplant Program, Sidney Kimmel Comprehensive Cancer Center, and professor of oncology, Johns Hopkins Medicine, said in a presentation of the results. “These data prospectively demonstrate a correlation between MRD and survival in posttransplant therapy in FLT3-ITD AML. Gilteritinib should be a standard of care for those who are MRD-positive.”

Patients with AML who harbor a FLT3-ITD mutation often have a high risk of relapse as well as undergo allogeneic hematopoietic cell transplantation.2 Furthermore, detectable MRD before transplant is highly predictive for posttransplant outcomes. Although sorafenib (Nexavar) is often administered as posttransplant maintenance therapy, it is an off-label option and often poorly tolerated.

The FDA approved gilteritinib, a potent and oral FLT3 inhibitor, in November 2018, for the treatment of adult patients with relapsed/refractory AML with a FLT3 mutation as detected by an FDA-approved test.³ The regulatory agency simultaneously approved an expanded indication for a companion diagnostic, the LeukoStrat CDx FLT3 Mutation Assay, to include for use with gilteritinib and detect FLT3 mutation in this patient population.

In the international, double-blind, placebo-controlled, phase 3 MORPHO trial, investigators sought to determine whether posttransplant therapy with gilteritinib has clinical benefit in patients with FLT3-ITD–mutant AML, and whether MRD should be used to guide gilteritinib treatment in this setting.¹ The study was part of an international consortium through the Blood and Marrow Transplant Clinical Trials Network.

Patients with FLT3-ITD–mutant AML, who were enrolled across 16 countries and 110 centers, must have had a morphologic first remission with only 1 or 2 induction treatments, and signed consent to be eligible for enrollment. Following registration, patients had their marrow aspirate samples taken for MRD analysis, which was evaluated through a two-step PCR-next-generation sequencing assay. Allogeneic transplant was conducted within 1 year of first response and any conditioning, donor, or graft-vs-host disease (GVHD) prophylaxis treatment was permitted. On days +30 and +90 posttransplant, patients underwent engraftment (absolute neutrophil count ≥500, platelets ≥20K, transfusion independent), needed to be able to take oral medication, and could not have active grade 2 to 4 acute GVHD that required more than 0.5 mg/kg of prednisone daily.

Next, 356 patients were randomized to receive maintenance gilteritinib at 120 mg orally daily or placebo for 24 months. Stratification factors included conditioning regimen intensity (myeloablative vs reduced intensity), time from transplant to randomization (30 to 60 days vs 61 to 90 days), and MRD of at least 10^-4 (presence vs absence from registration sample).

The primary end point was RFS, and secondary end points were overall survival (OS), effect of pre- and post-HCT MRD on RFS/OS, graft vs host-free RFS (GRFS), event-free survival (EFS), non-relapse mortality, acute GVHD, chronic GVHD, and incidence of infections.

In the pretransplant setting, investigators identified 46% of patients as having detectable MRD (MRD4, 21.1%; MRD5, 15.4%; and MRD6, 9.6%). Fifty-two percent of patients’ MRD was not detected and MRD analysis was not performed in 2% of patients. In the posttransplant setting and pre-randomization, 19.9% of patients had detectable MRD6 or higher, which included 4.5% of patients with MRD levels that were undetectable prior to transplant.

A total 52.8% of patients on the gilteritinib arm vs 53.9% on the placebo arm completed 2 years of treatment; 17.4% discontinued due to adverse effects (AEs), relapse (8.4%), patient withdrawal (7.3%), death (4.5%), GVHD (2.8%), and other (6.7%). These rates were 5.6%, 23.0%, 9.6%, 1.1%, 3.9%, and 2.8%, respectively.

Regarding baseline characteristics, the median age was 53 years (range, 18-78), and 48.5% of patients were female. Forty-three percent of patients were from North America, 26% were from Europe, and 31% were from the Asia/Pacific region. Sixty percent of patients received myeloablative conditioning therapy and 60% also received a FLT3 inhibitor before transplant. Moreover, 34.5% of patients had NPM1-mutated disease. Pre-transplant MRD of at least 10^-4 was seen in 21.5% of patients, MRD at least 10^-6 was observed in 47% of patients, and pre- or posttransplant MRD at 10^-6 or higher was seen in 51.5% of patients.

Additional findings showed that the HR for OS was 0.846 (95% CI, 0.554-1.293; P = .4394).

Irrespective of study treatment arm, OS in patients with MRD6 at registration either before or after transplant was worse than those with MRD-negative disease (HR, 0.514; 95% CI, 0.331-0.798; P = .0025).

Moreover, MRD status was found to influence both RFS with myeloablative conditioning (HR, 0.378; 95% CI, 0.208-0.688; P <.001) and OS (HR, 0.426; 95% CI, 0.217-0.839; P = .0109). Myeloablative conditioning with gilteritinib showed an RFS benefit in patients who were MRD positive (HR, 0.418; 95% CI, 0.213-0.818; P = .0087) over those who were MRD negative (HR, 1.511; 95% CI, 0.538-4.247; P = .4282).

“So, conditioning doesn’t help you in the setting of MRD,” Levis said.

Furthermore, MRD evaluation with a sensitivity of 10-6 (MRD6) eradication from randomization on study was 68.8% with gilteritinib and 43.6% of placebo, which Levi said highlights the potential of using FLT3-ITD to guide management of these patients.

Patients in the North American subgroup also had a significantly higher RFS with gilteritinib than placebo (HR, 0.397; 95% CI, 0.215-0.733; P = .0022), but this was not observed in those from Europe (HR, 1.424; 95% CI, 0.672-3.016; P = .3537) or Asia Pacific/rest of world (HR, 0.807; 95% CI, 0.378-1.724; P = .5801).

Levis noted that patients in North America also went onto transplant a mean of 26 days sooner than those in Europe and Asia Pacific/rest of world, received fewer chemotherapy courses pre-transplant, and were more likely to be treated with a FLT3 inhibitor before transplant (93.5% vs 36.6%, respectively).

The RFS benefit with gilteritinib was seen across levels of detectable MRD present (10-4 at randomization from CRF, HR, 0.23; 10-6 from CRF, HR, 0.04) and prior use of FLT3 inhibitors (HR, 0.60). Myeloablative conditioning therapy was linked with improved OS vs reduced-intensity conditioning (HR, 0.529; 95% CI, 0.346-0.808; P = .0027) and also irrespective of MRD status (MRD positive: HR, 0.562; 95% CI, 0.331-0.955; P = .0307; MRD negative: HR, 0.423; 95% CI 0.205-0.873; P = .0164)

Regarding safety, grade 3 or higher treatment-related AEs were higher with gilteritinib compared with placebo at 61.2% vs 25.4%, respectively, as well as grade 3 or higher treatment-emergent infections (32.6% vs 21.5%, respectively). Grade 3 or higher myelosuppression was higher with gilteritinib (24.7%) than placebo (7.9%), as well as decreased platelet count (15.2% vs 5.6%, respectively), anemia (6.2% vs 1.7%), increased alanine aminotransferase (3.4% vs 2.2%), and increased creatine phosphokinase (6.7% vs 0%).

The gilteritinib arm also harbored more treatment-related dose interruptions (18.0%) and treatment-related withdrawals (15.2%) vs placebo (6.8% and 7.9%, respectively).

“While we are continuing to conduct a thorough assessment of the full data set from our phase 3 MORPHO trial, we are encouraged by these data which explore the potential of gilteritinib in a maintenance setting," Ahsan Arozullah, MD, MPH, senior vice president and head of oncology development, Astellas, the developer of gilteritinib, stated in a news release.4 “[Patients with] AML with a FLT3-ITD mutation often face worse outcomes than those with other mutations and have restricted post-HSCT treatment options with unmet need. With these findings, we remain focused on sharing updates with the scientific community to inform continued innovation for the AML community."

Editor’s Note: Levis cited advisory board or honoraria disclosures with Abbvie, Amgen, Astellas, Bristol-Myers-Squibb, Daiichi-Sankyo, GlaxoSmithKline, Jazz Pharmaceuticals, Menarini, Pfizer, Sumitomo-Dainippon, Syndax, and Takeda.

References

• Levis M, BMT-CTN 1506 (MORPHO): A randomized trial of the FLT3 inhibitor gilteritinib as post-transplant maintenance for FLT3-ITD AML. Presented at: 2023 European Hematology Association Congress; June 8-11, 2023; Frankfurt, Germany. Abstract LBA2711.

• Gilteritinib shows promise as posttransplant maintenance therapy for FLT3-ITD AML patients. News release. European Hematology Association. June 9, 2023. Accessed June 9, 2023.

• FDA approves gilteritinib for relapsed or refractory acute myeloid leukemia (AML) with a FLT3 mutation. FDA. November 18, 2018. Accessed June 9, 2023. https://www.fda.gov/drugs/fda-approves-gilteritinib-relapsed-or-refractory-acute-myeloid-leukemia-aml-flt3-mutatation

• Gilteritinib as maintenance therapy demonstrated benefit in subgroups of FLT3-ITD acute myeloid leukemia patients. News release. Astellas Pharma Inc. and the Blood and Marrow Transplant Clinical Trials Network. June 9, 2023. Accessed June 9, 2023. https://www.prnewswire.com/news-releases/gilteritinib-as-maintenance-therapy-demonstrated-benefit-in-subgroups-of-flt3-itd-acute-myeloid-leukemia-patients-301846826.html