Safety and Efficacy of Venetoclax, Cytarabine and Metformin for Relapsed-Refractory and Induction-Ineligible Acute Myeloid Leukemia

Background: Venetoclax-based combinations have improved outcomes in acute myeloid leukemia (AML) for newly diagnosed (ND) patients ineligible for induction chemotherapy. In relapsed-refractory (RR) AML, patients often lack options that provide sustained remissions, and no regimen that incorporates venetoclax in this setting is currently approved. Diverse mechanisms have been associated with venetoclax resistance, and novel combinations are needed. Metformin, a widely used antidiabetic biguanide, inhibits complex I of the mitochondrial electron transport chain. Numerous in vitro studies have shown potential synergistic effects with venetoclax in AML through, among other mechanisms, reduction in oxidative phosphorylation (OXPHOS). Metformin-induced OXPHOS inhibition may also increase sensitivity to cytarabine, which is an integral part of cytotoxic regimens for ND and RR AML, and has been approved in combination with venetoclax for ND induction-ineligible AML. In this scenario, we report the preliminary safety and efficacy analysis of reduced-exposition venetoclax, cytarabine and metformin (VenCM) for RR and ND induction-ineligible AML. Methods: This analysis included 25 patients from public hematology centers in Brazil. Diagnosis and treatment response were according to ELN 2022 recommendations. MRD assessment was performed by multiparametric flow cytometry. In cycle 1, patients received venetoclax (200 mg on day 1, 400 mg on days 2-10), cytarabine (100 mg/m2, SC once daily, days 1-10) and metformin (850 mg every 8 hours, days 1-10). From cycle 2 onwards, patients in remission received 5 days of treatment. Use of azole antifungals was permitted, and venetoclax dose was reduced by 50% and 75% with concomitant fluconazole or voriconazole, respectively. Patients with incomplete hematologic recovery had progressive cytarabine dose reductions in succeeding cycles. Treatment interruption for allogeneic hematopoietic stem cell transplantation (HSCT) was allowed, including reinitiation in the event of relapse. Results: As of July 15, 2024, 13 ND induction-ineligible and 12 RR AML patients received one or more cycles of the combination. No patients were excluded from this analysis. Median age was 64 years (range: 24-82) and 72% were women. Median ECOG was 2 (range: 0-3), 7 patients (28%) had secondary AML, and 1 patient had therapy-related AML (4%). ELN risk category was intermediate in 11 patients (65%) and adverse in 6 (35%). Among RR AML patients, previous exposure to cytarabine, anthracyclines, fludarabine, hypomethylating agents and venetoclax was observed in 100%, 92%, 17%, 17% and 33% respectively. All patients had peripheral blood blast clearance by day 10 of cycle 1, including 6 patients (4 ND and 2 RR AML) with leukocyte counts above 25,000 per mm3 at treatment initiation (median: 121,905, range: 36,730 - 167,710). Concomitant azoles were used in 22 patients (fluconazole: 80%; voriconazole: 8%). Eight patients (32%) developed treatment-emergent grade 1-2 diarrhea, and 2 (8%) had grade 1-2 increased aminotransferase levels (8%). Tumor lysis syndrome, lactic acidosis or hypoglycemia were not observed. No grade 3-5 non-hematological toxicity was observed. Overall response rate was 88% (1 patient with no response, 2 non-evaluable for response due to early mortality). Among ND AML patients, composite complete response (CCR) was 69% (CR = 46%, CRh = 15%, CRi = 8%) and 3 patients had partial response (23%). MRD negativity was observed in 44%, achieved after a median of 2 cycles (range: 1-2). Among RR AML patients, CCR was 83% (CR = 33%, CRh = 8%, CRi = 42%), and MRD negativity was achieved in 60%, after a median of 2 cycles (range: 1-3). Four RR AML patients underwent HSCT and currently remain MRD negative. With a median follow-up time of 5 months, 2 RR and 1 ND patient relapsed after a median of 4 cycles (range: 3-8). Overall survival at 6 months was 68% (ND AML: 62%; RR AML: 75%). Sepsis was the main cause of death (75%), including 3 patients with invasive fungal infections without access to prophylaxis with voriconazole or posaconazole. Conclusions: In a limited resource setting, VenCM for ND induction-ineligible and RR AML was safe and potentially effective, especially in patients with RR disease. Further experience from additional patients and longer-term follow up is needed to gain more insight into the role of metformin when combined with cytarabine and venetoclax.