PB1860: HIGH EFFICACY OF HYPOMETHYLATING AGENTS PLUS VENETOCLAX COMBINATION THERAPY IN ELDERLY PATIENTS AML PATIENTS UNFIT FOR INTENSIVE CHEMOTHERAPY: A REAL-LIFE EXPERIENCE.

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Topic: 4. Acute myeloid leukemia - Clinical Background: The combination therapy with hypomethylating agents (HMAs) decitabine (DAC) or 5-azacitidine (AZA) plus the BCL-2 inhibitor venetoclax (VES) has recently emerged as an effective therapy for patients (pts) with newly diagnosed acute myeloid leukemia (AML) unfit for intensive chemotherapy. Response rates ranged between 54 to 68% in clinical trials. However, this therapy may induce severe marrow-suppression with infections and bleeding, that could affect the outcome of these pts. Aims: Aim of this study was to analyze efficacy and safety of HMA+VEN efficacy in an unselected cohort of elderly/ unfit AML pts treated at a single institution. Methods: 39 consecutive newly diagnosed AML pts treated with HMA (25 DAC and 14 AZA) + VEN from Feb 2020 to Jan 2023 were included. Median age at diagnosis was 78 yrs (range: 64-84) wit 9 pts ≥ 80 yrs. Median CIRS-geriatric comorbidity score was 7 (range: 0-18), with the most common system affected being “vascular” (26/39 pts). Secondary AML was diagnosed in 25 pts (64%), while 15/39 (38%) had a cytogenetic-molecular high-risk AML. The drug schedule for DAC was 20 mg/sqm daily for 5 days, for AZA was 75 mg/sqm daily for 7 days every 4 weeks; VEN starting dose was 400 mg daily (dose reduced to 25% in case of combination with azoles fungal prophylaxis) 14 to 28 days every 4 weeks (treatment duration was modulated on hematological toxicity and was stopped at complication onset). Results: A total of 359 HMA+VEN cycles were administered, with a mean of 9.2 cycles/pts. VEN was started at 1st or 2nd HMA cycle. 327/359 cycles (91%) were given on an out-patient basis. In all, 38 pts were evaluable for response (1 patient was lost to follow-up). The Overall Response Rate (ORR=CR+PR) was 89%, with 79% CR and 10% PR; 63% of CR were molecular CR, with negative MRD. CR was obtained after a mean of 2.1 cycles. Eight out of 34 responsive pts (24%) relapsed after a mean of 7.6 cycles, and all died for progressive disease. Although the small samples size, we found no differences in terms of pts age, rate of CR, time to CR and rate of relapse according to HMA used (DAC or AZA). The median follow up was 11.1 months (range: 1-37); at last follow-up 25 pts (64%) are still alive and 14 (36%) had died. The 1-year OS probability from the start of therapy was 69%. The main cause of death was disease progression (93%). The most common toxicities were myelosuppression (100%) and documented infectious complications (67%), the most frequent being pneumonia and neutropenic fever; infectious complications happened after a mean of 2.4 cycles. Thirteen pts (33%) were hospitalized for complications, with complete recovery in all cases. Summary/Conclusion: Considering the advanced age and the comorbidity index of the population and the rate of high-risk disease (65% secondary AML), these real-life data confirm the excellent performance of the HMA+VEN regimen, highlighting the emerging role of this combination in the management of elderly pts with untreated AML (ORR 89%, 1-year OS 69%). The outcome of combination therapy is significantly better than single agent HMA therapy (DAC ORR around 35% in real-life experiences). Infectious complications remain a major problem (67%) but, if prevented with prophylaxis and adequately treated, do not seem to affect outcome. Keywords: Hypomethylating agents, AML, Venetoclax

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