Early Results Suggest Gilteritinib Plus Chemotherapy Safe, Effective for AML

Keith Pratz, MD

A new ongoing study shows that gilteritinib in combination with induction and consolidation chemotherapy is well tolerated in patients with newly diagnosed acute myeloid leukemia (AML).

The oral FMS-like tyrosine kinase 3 (FLT3) inhibitor also demonstrated antileukemic responses in patients with mutated FLT3 regardless of anthracycline type or gilteritinib administration dosing schedule.

These findings were presented at the American Society of Hematology (ASH) 2020 Annual Meeting.

Keith Pratz, MD, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, and colleagues conducted a 4-part, open label, phase I study to assess the safety and efficacy of gilteritinib plus 7+3 induction and high-dose cytarabine consolidation chemotherapy. They also evaluated the effects of gilteritinib as single-agent manteinance therapy.

The 4-Part Study

In part I of the study, Pratz and team administered 40-200 mg/d gilteritinib and ≤2 cycles of induction to successive cohorts of 3-6 patients. Induction included 100 mg/m²/d of intravenous cytarabine and 12 mg/m²/d of intravenous idarubicine.

Gilteritinib was administered on days 1-3; cytabarine, days 1-7; and idarubicine, days 1-3.

In part 2, 33 patients—of which at least 15 had mutated FLT3—received 120 mg/m²/d gilteritinib and ≤2 cycles of the part 1 induction schedule.

In part 3, the investigators stratified patients (n = 14) 1:1 to receive treatment from part 2 or treatment that replaced idarubicin with 90 mg/m²/d of daunorubicin.

And finally, in part 4, 12 patients received the same part 3 daunorubicin treatment. However, in the second cycle, the investigators reduced daunorubicin dosing to 45 mg/m²/d.

During consolidation, patients were administered ≤3 cycles of 1.5 g/m² every 12 hours on days 1, 3, and 5. At the same time, they received the induction dose of gilteritinib — for those in parts 1-3, they were administered on days 1-14; those in part 4 were administered on days 1-56.

As maintenance therapy, gilteritinib was administered once daily in 28-day cycles for up to 26 cycles. This phase is ongoing.

The Results

Thus, a total of 80 patients were allocated to treatment—with 79 being included in the safety set. Of this total, 59 years was the mean age, and the majority were male (62.0%). Median follow-up for overall survival was 35.8 months.

Furthermore, at the end-of-induction time point, 44 (55.7%) patients had mutated FLT3 across all dose groups.

Pratz and colleagues indicated that the maximum tolerated dose was 120 mg/d, which 38 (48.1%) of patients achieved for gilteritinib.

“Serious treatment-related adverse events (AEs) and AEs leading to discontinuation of gilteritinib occurred in 12.7% (n=10) and 5.1% (n=4) of patients, respectively,” they reported. “One (1.3%) death occurred across all treatment phases.”

Grade ≥3 nonhematologic adverse events occurred in ≥10% of patients. These events included increased alanine aminotransferase (13.9%), pneumonia (13.9%), sepsis (11.4%), and bacteremia (11.4%).

Further, complete remission was achieved by 81.8% of patients across all dose groups. Of this total, 81.6% received 120 mg/d of gilteritinib. There was no noted impact of anthracycline choice on complete remission rate—although, the investigators acknowledged the low number of patients in these cohorts.

In FLT3-muated patients who experienced complete remission, the median duration of remission was 14.1 months (95% CI, 4.0-29.9). The median duration of disease-free survival was 15.3 months.

“The survival probability (95% CI) in all [FLT3-muated] patients at weeks 8, 12, 26, 52, and 104 were 97.7% (84.6%–99.7%), 95.3% (82.5%–98.8%), 92.9% (79.6%–97.7%), 83.1% (67.7%–91.5%), and 71.8% (54.6%–83.4%), respectively,” the investigators continued.

Looking ahead

In light of these findings, Pratz and team indicated their initiation of randomized clinical trials that will compare induction and consolidation chemotherapy plus gilteritinib with midostaurin in AML patients with mutated FLT3.

The study, “A Phase 1 Study of Gilteritinib in Combination with Induction and Consolidation Chemotherapy in Patients with Newly Diagnosed AML: Final Results,” was presened at ASH 2020.