Updated Results from a Phase I/II Study of the Triplet Combination of Azacitidine, Venetoclax and Gilteritinib for Patients with FLT3-Mutated Acute Myeloid Leukemia

Background: FLT3 mutations are associated with a poor prognosis in both newly diagnosed (ND) and relapsed/refractory (R/R) acute myeloid leukemia (AML). Gilteritinib is a potent oral FLT3 inhibitor that improves response rates and overall survival (OS) in R/R FLT3-mutated AML. While a hypomethylating agent (HMA) plus venetoclax is standard of care for older/unfit patients (pts) with ND FLT3-mutated AML, remission durations are relatively short and FLT3-driven relapses are common. We therefore designed a phase I/II study to evaluate the triplet regimen of azacitidine, venetoclax and gilteritinib in pts with FLT3-mutated AML.

Methods: In this phase I/II study, pts with either R/R FLT3­-mutated AML or ND FLT3-mutated AML who were unsuitable for intensive chemotherapy were eligible. Either FLT3-ITD and/or TKD mutations were allowed. Pts were required to have a performance status ≤3, total bilirubin ≤2.5 x ULN, ALT/AST ≤3 x ULN, and creatinine clearance ≥30 mL/min. In cycle 1, pts received azacitidine 75 mg/m² SC/IV on days 1-7, venetoclax on days 1-28, and gilteritinib on days 1-28. Gilteritinib dose ranged from 80mg to 120mg daily during the phase I dose escalation (3+3 design). Bone marrow was performed on day 14 and if blasts were <5% or the marrow was insufficient/aplastic, then both venetoclax and gilteritinib were held (ND cohort) or only venetoclax was held (R/R cohort). For cycles 2 and beyond, azacitidine 75 mg/m² SC/IV was given for 5 days, venetoclax was given for 7 days and gilteritinib was given continuously.

Results: Between 12/2019 and 6/2022, 40 pts were treated (21 ND pts and 19 R/R pts). Baseline characteristics of the 2 cohorts are shown in Table 1. The median age for both the ND and R/R cohorts was 68 years (range, 18-82 for ND cohort; 19-90 for R/R cohort). One pt <60 years of age (age 18) was enrolled in the ND cohort due to severe COVID-19 pneumonia at the time of AML diagnosis. In the ND cohort, 14 (67%) had a FLT3-ITD and 7 (33%) had a FLT3 TKD mutation; in the R/R cohort, 8 (42%) had a FLT3-ITD, 7 (37%) had a FLT3-TKD, and 4 (21%) had both mutations. In the R/R cohort, the median number of prior therapies was 2 (range, 1-5), 8 (42%) had received prior HMA plus venetoclax, 5 (26%) had received prior FLT3 inhibitor (including 1 pt who had received prior gilteritinib), and 5 (26%) had undergone prior hematopoietic stem cell transplant (HSCT).

Ten R/R pts were treated in the phase I cohort (6 at 80mg of gilteritinib and 4 at 120mg). Based on a superior safety and efficacy profile, the 80mg daily dose was chosen as the phase II dose for further study.

In the ND cohort, all pts responded, with 20 (95%) achieving CR and 1 (5%) achieving MLFS as best response. On the day 14 bone marrow, all pts achieved either morphologic remission with <5% blasts (n=15) or had an insufficient/aplastic marrow (n=6). Seventeen pts (81%) achieved flow measurable residual disease (MRD) negativity and 19 pts (90%) cleared the FLT3 mutation using a PCR assay with sensitivity of 10^-2. Four pts (19%) proceeded to HSCT in first remission. No pts died in the first 60 days of treatment. Overall, 3 pts have relapsed (1 FLT3-positive at relapse, 1 FLT3-negative at relapse, and 1 who relapsed with extramedullary-only disease) after a median response duration of 6.8 months, and 3 pts have died (1 after relapse, 1 from post-HSCT complications, and 1 due to sepsis while in CR). With a median follow-up of 10.0 months, the 6-month OS rate is 95% and the estimated 1-year OS rate is 80% (Figure 1A).

In the R/R cohort, 14 pts (74%) responded: 4 (21%) achieved CR, 3 (16%) achieved CRi, and 7 (37%) achieved MLFS. Among responders, 43% achieved MRD negativity by flow and 50% achieved FLT3 clearance by PCR. Four pts (29% of responding pts) proceeded to HSCT. Among the 14 responding pts, 7 relapsed (3 after HSCT and 4 who were not transplanted), 3 died in remission, 1 is alive and in remission post-HSCT, and 3 are alive in ongoing remission without HSCT. With a median follow-up of 24.1 months, the median OS is 5.8 months and the 1-year OS rate is 27%. Outcomes were superior for those who had not received prior HMA plus venetoclax or gilteritinib (median OS: 10.5 months vs. 4.8 months; 1-year OS rate: 41% vs. 11%; P=0.11) (Figure 1B).

Conclusions: The combination of azacitidine, venetoclax and gilteritinib is effective in pts with FLT3-mutated AML. OS in the ND cohort compares favorably with historical expectations of FLT3-mutated AML treated with HMA plus venetoclax without a FLT3 inhibitor.