Gilteritinib Induces Encouraging Responses in Newly Diagnosed FLT3-Mutated AML

Keith W. Pratz, MD

Gilteritinib (Xospata), in combination with induction and consolidation chemotherapy, generated responses in patients with newly diagnosed acute myeloid leukemia (AML), including those with FLT3 mutations, according to data from a phase 1 trial (NCT02236013).¹

Findings presented at the 10th Annual Meeting of the Society of Hematologic Oncology showed that among all evaluable patients with AML (n = 78), the composite complete remission (CRc) rate was 79.7%. Specifically, the CR rate was 54.4%, the CR with incomplete hematologic recovery (CRi) rate was 21.5%, and the CR with incomplete platelet recovery (CRp) was 3.8%. Among evaluable patients with FLT3 mutations (n = 44), the CRc, CR, CRi, and CRp rates were 90.9%, 70.5%, 13.6%, and 6.8%, respectively.

Additionally, patients in the overall population who received at least 80 mg of gilteritinib per day (n = 69) achieved a median overall survival (OS) of 1176 days (95% CI, 661–not estimable [NE]). Patients with FLT3 mutations administered at least 80 mg of gilteritinib per day (n = 41) experienced a median OS of 1397 days (95% CI, 936-NE). The median OS for the FLT3-negative population (n = 26) was 998 days (95% CI, 392-NE).

The 26-week, 1-year, and 2-year OS rates were 92.4%, 82.1%, and 69.2%, respectively, among patients with FLT3 mutations. Those rates were 79.2%, 75.0%, and 53.8%, respectively, in the FLT3-negative population.

“Gilteritinib in combination with induction and consolidation chemotherapy was well-tolerated in patients with AML, in both the overall population and those with FLT3 mutations,” lead study author Keith W. Pratz, MD, director of the Leukemia Program and an associate professor of Medicine at the Hospital of the University of Pennsylvania, and colleagues, wrote in a poster presentation. “Favorable antileukemic responses were observed in terms of CR and OS, particularly in the FLT3-mutated population.”

FLT3 mutations are the most common genetic alterations in AML, occurring in approximately 30% of patients. FLT3 ILD and point mutations are associated with increased risk of relapse, a shorter time to relapse, and poorer OS.

In November 2018, the FDA approved gilteritinib for the treatment of adult patients with FLT3 mutation—positive relapsed/refractory AML.²

This phase 1 study aimed to assess the safety, tolerability, and efficacy of gilteritinib in combination with intensive chemotherapy in patients with newly diagnosed AML. Patients were required to be at least 18 years of age with newly diagnosed AML and have an ECOG performance status of 2 or less. The presence of a FLT3 mutation was not required.

Key exclusion criteria included a diagnosis of acute promyelocytic leukemia or AML with good-risk cytogenetics; the presence of BCR-ABL–positive leukemia; or active malignant tumors or myelodysplastic syndrome.

Dose escalation of gilteritinib was examined in part 1 of the study to determine the maximum tolerated dose (MTD). Remission induction featured 3 days of idarubicin and 7 days of cytarabine, plus 14 days of gilteritinib at doses of 20 mg, 40 mg, 80 mg, 120 mg, or 200 mg, given on days 4 through 17 for up to 2 cycles. Consolidation treatment included high-dose cytarabine plus the same dose of gilteritinib given daily for the first 14 days of each cycle for up to 3 cycles. Finally, patients received maintenance gilteritinib daily for 28 days for up to 26 cycles.

Patients enrolled in the dose expansion stage in part 2 received gilteritinib at 120 mg a day, with induction, consolidation, and maintenance following the same treatment pattern as part 1.

In part 3 of the study, the gilteritinib dosing schedule during induction was modified to begin with the completion of chemotherapy, running from days 8 through 21. Patients were split into 2 cohorts, one receiving induction chemotherapy with 3 days of idarubicin and 7 days of cytarabine, and the other receiving 3 days of daunorubicin and 7 days of cytarabine. Consolidation and maintenance followed the same treatment pattern as parts 1 and 2.

In part 4 of the study, patients followed the same treatment cycle as the daunorubicin cohort in part 3, except that gilteritinib was administered up to 56 consecutive days during consolidation.

A total of 79 patients were administered a study drug, including 78 who received gilteritinib. The median age was 59 years (range, 23-77), and 62.8% of patients were male. The median body mass index and body surface area was 28.4 kg/m2 (range, 18.1-48.1) and 2.0 m2 (range, 1.1-2.8).

Furthermore, 56.4% of patients harbored FLT3 mutations, 42.3% of patients had FLT3-ITD mutations, and 41% of patients had FLT3 wild-type disease.

Additional data showed that while censoring for hematopoietic stem cell transplantation, the median disease-free survival (DFS) for all participants with non-missing values (n = 63) was 460 days (95% CI, 288-970). Among patients with FLT3 mutations (n = 40), the median DFS was 460 days (95% CI, 150-970), and FLT3-negative population (n = 22) experienced a median DFS of 288 days (95% CI, 23-971).

Study authors noted that anthracycline choice did not substantially impact CRc rate or toxicity. Moreover, patients who achieved a CRc while receiving at least 120 mg of gilteritinib per day had a mutational clearance of FLT3-ITD after consolidation of 84.6%.

The MTD of gilteritinib was established at to be 120 mg per day, and dose-limiting toxicities occurred in 15 of 78 (19.2%) patients given gilteritinib. Adverse effects (AEs) led to the discontinuation of gilteritinib in 24.4% of patients.

Grade 3 or higher treatment-emergent AEs (TEAEs) were reported in 93.6% of patients. The most common grade 3 or higher TEAEs included febrile neutropenia (66.7%), decreased platelet count (23.1%), decreased neutrophil count (21.8%), decreased white blood cell count (21.8%), thrombocytopenia (20.5%), neutropenia (17.9%), anemia (15.4%), pneumonia (15.4%), increased ALT (14.1%), bacteremia (11.5%), and sepsis (11.5%).

“These results support ongoing randomized trials testing this approach against current standards,” study authors concluded.

References

1. Pratz KW, Cherry M, Podoltsev NA, et al. A phase 1 study of gilteritinib in combination with induction and consolidation chemotherapy in patients with newly diagnosed acute myeloid leukemia: final study results. Presented at: 10th Annual Meeting of the Society of Hematologic Oncology; September 28-October 1, 2022; Houston, TX. Abstract AML-256.
2. FDA approves gilteritinib for relapsed or refractory acute myeloid leukemia (AML) with a FLT3 mutation. News release. FDA. November 28, 2018. Accessed October 4, 2022. https://bit.ly/3EgYyUF