Hypomethylating agents or chemotherapy in combination with venetoclax and gilteritinib for FLT3-mutated Acute Myeloid Leukemia Free

BACKGROUND Triplet therapies with hypomethylating agents (HMA), venetoclax, and second-generation FLT3 inhibitors have demonstrated promising efficacy in early phase clinical trials for newly diagnosed (ND) or relapsed/refractory (R/R) FLT3-mutated acute myeloid leukemia (FLT3-m AML). Herein, we report our clinical experience with venetoclax and gilteritinib combination regimens for newly diagnosed or R/R FLT3-m AML outside clinical trials.

METHODS We have conducted a retrospective, single-center study. The patients were older than 18 years, had FLT3-m AML, and received venetoclax and gilteritinib-containing regimens. Data collection and treatment regimens were approved by the Vilnius University Hospital Santaros Klinikos Hematology Board and Vilnius Regional Biomedical Research Ethics Committee.

Three different remission induction regimens were used: AzaVenGilt (azacitidine 75 mg/m² (days 1-7) + venetoclax 400 mg (days 1-14) + gilteritinib 80/120 mg (days 1-14)), DecVenGilt (decitabine 20 mg/m² (days 1-5) + venetoclax 400 mg (days 1-14) + gilteritinib 80/120 mg (days 1-14)), or ACTIVE+Gilt (actinomycin D 12.5 mcg/kg (days 1-3) + cytarabine 20 mg/m2 (days 1-10) + venetoclax 600 mg + gilteritinib 80/120 mg (days 4-18). The first bone marrow analysis was performed on day 14 with G-CSF initiation in MLFS patients. The number of venetoclax and gilteritinib days was adapted individually based on the toxicity (stopping prior day 14 in case of life-threatening adverse events) or continued up to day 21 or 28 if MLFS was not achieved on day 14. After 1 or 2 induction cycles, consolidation with alloSCT was implemented in eligible responders, whereas alloSCT-ineligible patients continued maintenance with individually dosed triplets every 6-8 weeks: miniAzaVenGilt (azacitidine 75 mg/m² (days 1-5 or 1-7) + venetoclax 400 mg (days 1-7 or 1-14) + gilteritinib 80 mg (days 1-7 or 1-14) or miniDecVenGilt (decitabine 20 mg/m² (days 1-3 or 1-5) + venetoclax 400 mg (days 1-7 or 1-14) + gilteritinib 80 mg (days 1-7 or 1-14), or miniACTIVE+Gilt (cytarabine 20 mg/m² (days 1-5 or 1-10) + venetoclax 600mg (days 1-7) + gilteritinib 80mg (days 1-7 or 1-14).

We collected patient and disease-related characteristics, treatment schedules, CR+CRp, ORR (CR+CRp+MLFS), and MRD negativity (multiparameter flow cytometry) rates, time to neutrophil and platelet recovery, day 30, day 60 mortality, OS, and RFS.

RESULTS We enrolled 39 patients (22 female) with FLT3-m AML. 23 % (8/39) had ND and 77 % (31/39) had R/R disease. The median age was 65 (36-88) years (77 (65-88) in ND and 64 (34-87) in the R/R). 59 % (23/39) had an ECOG status of 0-1, whereas 41% (16/39) were ECOG 2 or 3. FLT3-ITD mutations were identified in 69 % (27/39), 21 % (8/39) had FLT3-TKD mutations, and 10 % (4/39) had both.

ND patients were treated with either AzaVenGilt (88 %, 7/8) or DecVenGilt (12 %, 1/8) induction triplets. R/R patients received ACTIVE+Gilt induction (97%, 30/31) or AzaVenGilt (3 %, 1/31). Gilteritinib was dosed at 80 mg (46%, 18/39) or 120 mg (54 %, 21/39). The median duration of Gilteritinib and Venetoclax during Cycle 1 was 15 days (7-28) and 14 days (7-28), respectively.

The ORR was 95 % for all patients (100 % (8/8) in ND and 94 % (29/31) in the R/R). The CR+CRp rate was 82 % for all patients (100 % (8/8) in ND and 77 % (24/31) in the R/R). MRD negativity was confirmed in 50 % (16/32). All responses were achieved after the first treatment cycle. The median time to neutrophil (>1x10⁹/l) and platelet (>100x10⁹/l) recovery in responders was 25 days (14-59) and 23 days (14-54), respectively. 41 % (16/39) of patients were bridged to alloSCT (80 % (16/20) of 1st alloSCT-eligible patients).

The median OS was 24.9 months (8.6-41.2) for all patients (not reached in ND and 17 months (7.5-41.2) in the R/R). The median RFS was 8.2 months (3.8-40.5) for all patients (not reached in ND and 17 months (2.3-40.5) in the R/R). The 12 and 24-month OS probabilities were 59 % and 52 % for all patients, respectively. The 12 and 24-month RFS probabilities were 49.5 % and 41.8 % for all patients, respectively.

Day 30 and day 60 mortality rates were 3 % (1/39) and 10 % (4/39), respectively.

CONCLUSIONS Frontline triplets with HMA, venetoclax, and gilteritinib, as well as the salvage quadruplet with actinomycin D, cytarabine, venetoclax, and gilteritinib, demonstrate high antileukemic efficacy and a manageable safety profile for FLT3-m AML patients in the clinical practice setting.