S132: updated results of ven-a-qui study: a phase 1-2 trial to assess the safety and efficacy of triplets for newly diagnosed unfit aml patients: azacitidine or low-dose cytarabine with venetoclax and quizartinib

Background: Venetoclax (VEN) combined with Azacitidine (AZA) or Low Dose Cytarabine (LDAC) has emerged as new therapeutic option for unfit acute myeloid leukemia (AML) patients (pts), but primary resistance and relapses occur in the vast majority. We hypothesize that adding an oral FLT3 inhibitor could improve outcomes in this setting. Aims: To explore the safety and efficacy of VEN-AZA or VEN-LDAC in combination with Quizartinib (QUI) (VEN-A-QUI trial; EUDRACT2020-000406-28), in phase 1-2 clinical trial. Methods: Newly diagnosed pts older than 70 years and/or older than 65 years unfit for intensive induction, including secondary AML with or without prior exposure to HMAs were eligible. The phase 1 consisted of 2 parallel arms (VEN-AZA-QUI and VEN-LDAC-QUI) dose escalating in 3 + 3 cohorts to set dose limiting toxicities (DLTs) and establish the recommended phase 2 dose (RP2D). The phase 2 comprised randomized 1:1 assignment of 60 patients (12 FLT3-ITD+) to VEN-AZA-QUI vs. VEN-LDAC-QUI, comparing the CR/CRi rate of both arms. Secondary objectives were OS and event-free survival (EFS). Results: Interim analysis in February 2023, including 77 pts from 11 Spanish institutions, 16 in phase 1 and 61 in phase 2. The median age of the phase 1 was 74 years (70-88), previous MDS and/or MPN in 10 pts (62%), and 7 pts (44%) received previous HMAs. 9 patients were treated with AZA triplet and 7 with LDAC. RP2D of QUI was 60 mg in AZA arm and 40 mg in LDAC arm. DLTs in LDAC arm were a brain hemorrhage after more than 40 days of thrombocytopenia at dose of 60 mg. For both triplets, the safety committee recommended performing an early (day 14-21) bone marrow assessment in cycle 1, leading to VEN interruption in case of aplastic marrow. No grade ≥3 related extra-hematological adverse events were noted. CR+CRh+CRi was achieved in 7 pts (44%), PR 2 (12%), stable disease 3 (19%), and induction death 4 (25%). The phase 2 included 61 pts (30 LDAC and 31 AZA), 12 of them FLT3-ITD+. The median age of LDAC arm was 75.5 years (69-79), previous MDS and/or MPN in 10 pts (33%), and 8 pts (27%) received previous HMAs. The median age of AZA arm was 74 years (69-84), previous MDS and/or MPN in 12 pts (39%), and 8 pts (26%) received previous HMAs. Overall, CR+CRi+CRh was observed in 26 pts (43%), PR 8 (13%), morphological leukemia free state (MLFS) 7 (11%), and induction death 10 (16%) (CR+CRh+CRi+MLFS was 54%). No differences in CR+CRi+CRh between arms (LDAC 40% vs AZA 45%), but induction death was more frequent in LDAC (20%) vs AZA (13%). Due to substantial myelotoxicity, a protocol amendment reduced VEN to 7 days after achieving response (CR+CRh+CRi+MLFS). Median follow-up at data cut-off was 14.4 months. The median OS was not reached (NR) (CI 9.7-NR), without significant differences between LDAC and AZA (11.6 months, CI 5.6-NR vs median NR, CI 9,6-NR; Fig 1A). Median EFS was similar between LDAC (6.5 months; CI 2.3-NR),and AZA (8.0 months, CI 3.8-NR). FLT3-ITD+ pts had better OS and EFS than wild type (median NR vs. 11.9 months, p=0.04, Fig 1B; and NR vs. 4.3 months, p=0.09, respectively). HMA naïve pts had better OS than previously exposed (median NR vs. 8.4 months, p=0.06, Fig 1C). Summary/Conclusion: Triplets (VEN-AZA-QUI or VEN-LDAC-QUI) for newly diagnosed unfit AML pts could be feasible with substantial VEN reduction. FLT3-ITD+ pts and HMA naïve have not reached median OS. Final analyses with more follow-up will clarify the potential benefit of these triplets.Keywords: Elderly, Venetoclax, flt3 inhibitor, Acute myeloid leukemia