Introduction: The prognosis of newly diagnosed FLT3-mutated adult acute myeloid leukemia (AML) has recently improved by the combination of standard chemotherapy with FLT3 inhibitors, midostaurin or quizartinib. Nevertheless, once the disease relapses or if the disease is primarily refractory, the prognosis is poor. Conventional salvage chemotherapy ineffectively provides only 20% response rates and median overall survival (mOS) of 5.6 months. FLT3 inhibitor, gilteritinib, has showed higher response rates of 21.1% complete remission (CR) and 54.3% composite complete remission (CRc = CR + CR with incomplete neutrophil or platelet recovery). While its mOS of 9.3 months represents a meaningful improvement over traditional salvage therapies, it remains suboptimal. More effective salvage modalities are needed for obtaining higher therapeutic efficacy and improving survival. Japan Adult Leukemia Study Group (JALSG) has conducted a multicenter phase 2, single-arm study investigating sequential administration of gilteritinib following MEC chemotherapy in adult patients with relapsed/refractory (R/R) FLT3-mutated AML (JALSG-RR-FLT3-AML220).

Study Design and Methods: Eligibility criteria included patients with FLT3-mutated (FLT3-ITD or FLT3-TKD) R/R AML aged equal to or older than 20 years. The treatment regimen consisted of 13 cycles (28 days per cycle, total of 1 year). The first cycle was the remission induction treatment that comprised the administration of MEC (mitoxantrone 8 mg/m2 intravenous infusion, days 1-3; etoposide 100 mg/m2 intravenous infusion, days 1-5; cytarabine 100 mg/m2 continuous intravenous infusion, days 1-7) followed by gilteritinib (120 mg/day orally, day 8-28). Gilteritinib (120 mg/day, days 1-28) alone was administered in 2-13 cycles as maintenance treatment. Allogeneic hematopoietic stem cell transplantation (HSCT) was permitted during the treatment period. Gilteritinib resumption was allowed after HSCT under certain conditions. The follow-up period was 1 year after the completion of the treatment. The primary endpoint was the CR rate during the treatment period. The secondary endpoints included CRc, CR with partial hematologic recovery (CRh), overall response rate (ORR), the time to CR or CRc, the duration of CR or CRc, CR prior to transplantation, OS, relapse-free survival, transfusion independency, and adverse events. Comprehensive genetic analysis, Variant allele frequencies of FLT3-ITD/TKD and NPM1, plasma FLT3 ligand concentrations, and the plasma inhibitory activity were also determined. The study aimed to enroll 42 patients. This study is registered with Japan Registry of Clinical Trials (jRCTs041200067).

Results: Between November 2020 and May 2024, 42 patients were enrolled in Japan. Among them, 41 patients were included in the full analysis set. The median age was 51 years (range: 20-80), with 23 males and 18 females. FLT3-ITD and FLT3-TKD mutations were identified in 36 and 5 patients, respectively. 21 patients had relapsed disease, and 20 had primary refractory disease. Four patients received prior treatment with an FLT3 inhibitor, and 11 patients had undergone allo-HSCT before enrollment. As the primary endpoint, the CR rate was 48.8% (20/41; 80% credible interval: 39.0-58.7). As the secondary endpoint, the CRc rate was 87.8% (95% confidence interval [CI ]: 73.8-95.9). Among patients undergoing allo-HSCT (n=25), the CR rate prior to transplantation was 44.0% (95% CI: 24.4–65.1), and the CRc rate was 76.0% (95% CI: 54.9–90.6). In contrast, for those who did not undergo transplantation (n=16), the CR and CRc rates were 18.8% (95% CI: 4.1–45.7) and 81.3% (95% CI: 54.4–96.0). At a median follow-up of 20.4 months (range: 0.2-46.0), mOS was 32.2 months (95% CI: 11.5–NE), and the median relapse-free survival (RFS) among patients who achieved CRc was 29.3 months (95% CI: 8.7–NE). Adverse events occurred in 40 patients (97.6%). The most common grade 3-4 adverse events were anemia (90.2%), neutropenia (97.6%), thrombocytopenia (92.7%), and febrile neutropenia (92.7%). No early deaths occurred within the first 30 days of treatment.

Conclusions: Sequential administration of MEC chemotherapy followed by gilteritinib demonstrated high rates of CR and CRc and manageable toxicity in patients with R/R FLT3-mutated AML. The high therapeutic efficacy of this combination was supported by the high CR rate achieved prior to HSCT. Moreover, the treatment was well tolerated, with no early deaths observed.

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2025
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