Gilteritinib maintenance therapy shows benefit in MRD+FLT 3-mutant AML after HCT

Although Gilteritinib Phase 3 BMT-CTN The 1506/MORPHO trial (NCT02997202) did not show a statistically significant improvement in relapse-free survival (RFS), but there was a clinical improvement in RFS in patients with FLT3-ITD mutant acute myeloid leukemia (AML) and detectable minimal residual disease (MRD) after hematopoietic stem cell transplantation (HCT). Published results showed that geritinib had a hazard ratio (HR) of 0.515 (95% CI, 0.316-0.838; P=.0065) in patients with detectable MRD. The 2-year RFS rates of the geritinib group and the placebo group were 72.4% and 57.4%, respectively.

However, when RFS was evaluated in the entire study population, giltinib resulted in an approximately 32% reduction in the risk of relapse compared with placebo (HR, 0.679; 95% CI, 0.459-1.005; P=0.0518), which was not found to be statistically significant and did not meet the study's primary endpoint. The 2-year RFS rate was 77.2% in the geritinib group and 69.9% in the placebo group. The data showed that in patients with MRD-negative disease, the RFS benefit of giritinib was lower (P=0.7550). These data prospectively demonstrate the association between MRD and survival in post-transplant treatment of FLT3-ITD AML. Giritinibshould become the standard of care for MRD-positive patients.

AML patients carryingFLT3-ITD mutations often have a higher risk of relapse and undergo allogeneic hematopoietic cell transplantation. Furthermore, detectable MRD before transplantation is highly predictive of post-transplantation prognosis. Although sorafenib is frequently used as post-transplant maintenance therapy, it is an off-label option and is poorly tolerated. The U.S. Food and Drug Administration (FDA) approved giritinib, a potent oral FLT3 inhibitor, in November 2018 for the treatment of adult patients with relapsed/refractory AML who have FLT3 mutations detected by an FDA-approved test. Regulators also approved an expanded indication for a companion diagnostic, the LeukoStrat CDx FLT3 mutation test, to include the use of geritinib and the detection of FLT3 mutations in this patient population.

In the international, double-blind, placebo-controlled, Phase 3 MORPHO trial, investigators sought to determine whether there is a clinical benefit to treating patients with FLT3-ITD mutant AML after transplantation with giritinib and whether MRD should be used to guide geritinib therapy in this setting. Allogeneic transplantation was performed within 1 year after first remission and any conditioning, donor, or graft-versus-host disease (GVHD) prophylaxis was allowed. On days +30 and +90 after transplantation, patients receiving transplantation (absolute neutrophil count ≥500, platelets ≥20K, transfusion independent) were required to be able to take oral medications and not have grade 2-4 acute GVHD requiring more than 0.5 mg/kg prednisone per day.

356 patients were randomized to receive maintenance gilitinib 120 mg orally daily or placebo for 24 months. Stratification factors included intensity of conditioning regimen (myeloablative vs. reduced intensity), time from transplantation to randomization (30-60 days vs. 61-90 days), and an MRD of at least 10-4 (present vs. absent in the enrollment sample). The primary endpoint isRFS, and secondary endpoints are overall survival (OS), the impact of MRD on RFS/OS before and after HCT, graft versus host-freeRFS (GRFS), event-free survival (EFS), recurrence-free mortality, acuteGVHD, chronicGVHD, and infection incidence.

Before transplantation, investigators found that 46% of patients had detectable MRD (MRD4, 21.1%; MRD5, 15.4%; MRD6, 9.6%). MRD was not detected in 52% of patients, and MRD analysis was not performed in 2% of patients. After transplantation and before randomization, 19.9% u200bu200bof patients had detectable MRD6 or higher, including 4.5% who had undetectable MRD levels before transplantation. A total of 52.8% of patients in the giltinib group completed 2 years of treatment compared with 53.9% in the placebo group; 17.4% discontinued due to adverse events (AEs), relapse (8.4%), discontinuation (7.3%), death (4.5%), graft-versus-host disease (2.8%), and other (6.7%). These ratios are 5.6%, 23.0%, 9.6%, 1.1%, 3.9% and 2.8% respectively.

Regarding baseline characteristics, the median age was53 years old (range 18-78 years). Sixty percent of patients received myeloablative conditioning therapy, and 60% received FLT3 inhibitor therapy before transplantation. In addition, 34.5% of patients had NPM1-mutated disease. A pre-transplant MRD of at least 10-4 was observed in 21.5% of patients, an MRD of at least 10-6 was observed in 47% of patients, and a pre- or post-transplant MRD of 10-6 or higher was observed in 51.5% of patients. Additional findings showed a hazard ratio for OS of 0.846 (95% CI, 0.554-1.293; P=.4394). Regardless of study treatment group, MRD6 patients enrolled before or after transplantation had worse OS than MRD-negative patients (HR, 0.514; 95% CI, 0.331-0.798; P=0.0025).

In addition,MRD status was found to affect both RFS (HR, 0.378; 95% CI, 0.208-0.688; P < 0.001) and OS (HR, 0.426; 95% CI, 0.217-0.839; P = 0.0109) of myeloablative pretreatment . In MRD-positive patients, myeloablative conditioning with gilitinib showed a RFS benefit (HR, 0.418; 95% CI, 0.213-0.818; P=0.0087) compared with MRD-negative patients (HR: 1.511; 95%CI: 0.538-4.247; P=0.482) . The sensitivity of randomization in the study was 10-6 (MRD6). The MRD eradication rate was 68.8% in the geritinib group and 43.6% in the placebo group, highlighting the potential of using FLT3-ITD to guide the management of these patients.

An RFS benefit with giltinib was observed at detectableMRD levels (10-4 at randomization to CRF, HR 0.23; 10-6 at randomization to CRF, HR 0.04) and prior use of a FLT3 inhibitor (HR 0.60). Myeloablative conditioning therapy was associated with improved OS and lower intensity conditioning (HR 0.529; 95% CI 0.346-0.808; P = 0.027), regardless 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, compared with the placebo group, the gilitinib group had higher grade 3 or higher treatment-related adverse events (61.2% and 25.4%, respectively), and higher grade 3 or higher treatment-related infections (32.6% and 21.5%, respectively). The geritinib group had greater grade 3 or greater myelosuppression (24.7%) than placebo (7.9%), decreased platelet count (15.2% and 5.6%, respectively), anemia (6.2% and 1.7%), increased alanine aminotransferase (3.4% and 2.2%), and increased creatine kinase (6.7% and 0%). Compared with placebo (6.8% and 7.9%, respectively), geritinibThe group also experienced more treatment-related dose interruptions (18.0%) and treatment-related discontinuations (15.2%).