Italian Real-World Experience of Gilteritinib Monotherapy in Patients with Relapsed/Refractory FLT3-Mutated Acute Myeloid Leukemia: Preliminary Results

Background
The FMS-like tyrosine kinase 3 internal tandem duplication (FLT3-ITD) mutation is associated with a poor prognosis in patients with acute myeloid leukemia (AML). Gilteritinib, an oral FLT3 inhibitor, is the first approved monotherapy for relapsed or refractory (R/R) FLT3-mutated AML, demonstrating a survival benefit. The ADMIRAL phase 3 trial showed that gilteritinib monotherapy was superior to standard treatments, including intensive or non-intensive chemotherapy and hypomethylating therapy with azacitidine. However, real-world data on the efficacy and safety of gilteritinib in clinical practice are limited.

Methods
This study included adult patients (aged >18 years) with R/R AML harboring FLT3 mutations who received salvage therapy with gilteritinib. A retrospective, multicenter, observational study was conducted across 22 Italian centers, identifying 200 patients treated with gilteritinib monotherapy. The treatment period spanned from January 24, 2018, under an early-access program, and from May 31, 2020, as approved by the Italian Drug Agency (AIFA). The study protocol received approval from the ethics committees of all participating centers. This preliminary analysis focuses on 149 patients. Treatment response, event-free survival (EFS) and overall survival (OS) were assessed according to the European LeukemiaNet (ELN) 2017 criteria.

Results
A total of 149 patients with relapsed (n=107) or refractory (n=42) FLT3-mutated AML treated with gilteritinib monotherapy were included in the analysis. Among the refractory patients, 79% were resistant to a single line of therapy, while 21% were resistant to two or more lines. The median age of the patients was 62 years (range: 18-87 years). According to the ELN 2017 classification, 21% of patients had favorable-risk, 36% had intermediate-risk, and 43% had adverse-risk genetic aberrations at initial diagnosis. FLT3 mutations were present at AML diagnosis in 125 patients (84%), while 24 patients (16%) acquired the mutation during the disease course. Among those with FLT3 mutations at diagnosis, 107 out of 125 patients (86%) had FLT3-ITD mutation, 10 patients (8%) had FLT3-TKD mutation, and 8 patients (6%) had both FLT3-ITD and TKD mutations. Additionally, 28% of cases had a concurrent NPM1 mutation. Gilteritinib was administered as a monotherapy to 78 patients (53%), while 71 patients (47%) underwent additional allogeneic hematopoietic stem cell transplantation (alloHCT): 39 patients (26%) received gilteritinib at relapse post-alloHCT, and 32 patients (21%) used gilteritinib as a bridge to transplant. The median number of gilteritinib cycles was four (range: 1-39). In terms of treatment response, 50% of patients achieved complete remission or complete remission with incomplete hematologic recovery (CR/CRi), 13% achieved a partial response, and 33% had progressive or refractory disease. The median duration of response was four months (range: 1-40 months). With a median follow-up of 16.5 months (range: 2.1-67.9 months), the median overall survival (OS) and event-free survival (EFS) for the entire cohort were 10.6 months and 4.64 months, respectively. Patients who received only gilteritinib had a median OS of 7.1 months. The best survival outcomes were observed in patients who underwent alloHCT after gilteritinib treatment, with a median OS of 15.5 months. Similarly, the median EFS was lowest in the gilteritinib-only cohort (4.64 months), with improved outcomes in the group undergoing transplant (6.58 months).

Conclusions
These real-world data align with the results of the ADMIRAL trial, demonstrating that gilteritinib monotherapy is a valuable treatment option for patients with relapsed or refractory FLT3-mutated AML. Notably, patients who underwent allogeneic hematopoietic stem cell transplantation after gilteritinib treatment showed improved survival outcomes, highlighting the potential of gilteritinib as an effective bridge to transplant. Further analysis on complete cohort of 200 patients is ongoing to validate these findings and provide more comprehensive insights into the clinical benefits of gilteritinib in this setting.