Outpatient Low-Dose Venetoclax Plus Azacitidine Vs. Intensive Chemotherapy for Newly Diagnosed Fit Patients with Acute Myeloid Leukemia in a Limited Resource Setting

Introduction: venetoclax plus azacitidine (Ven/Aza) is the standard-of-care in patients with newly diagnosed acute myeloid leukemia (AML) who are unsuitable candidates for intensive chemotherapy (IC), prompting questions related to whether it should be used for candidates fit for IC (FIT). Access to novel agents in low- and middle-income countries (LMIC) is limited, however, in a previous phase 2 study (NCT05048615), we demonstrated that using venetoclax concomitantly with strong CYP3A4 inhibitors like itraconazole could be a practical approach to reduce the venetoclax dose and diminish treatment-related costs without compromising treatment response. We sought to compare FIT patients for IC with newly diagnosed AML who received either low-dose Ven/Aza or traditional IC as first-line treatment to evaluate survival outcomes in LMIC.

Methods: we retrospectively included all newly diagnosed adult patients with AML suitable for IC treated in our center from August 2016 to March 2023. Since the COVID-19 pandemic, we have used Ven/Aza as a standard first-line therapy in an effort to reduce early mortality and to allow outpatient induction for all patients with AML. Low-dose Ven/Aza was administered as follows: venetoclax 100 mg QD fixed dose plus itraconazole 100 mg BID for 21 days per cycle, and azacitidine 100 mg SC fixed dose QD or 7 days, 1-2 cycles. IC patients received 7+3 or intermediate dose cytarabine plus 3 days of mitoxantrone. Consolidation with intermediate dose cytarabine was given following remission in both groups. Baseline characteristics were registered and compared. We evaluated induction complications, complete response (CR/CRi), 30 and 60-day early death (ED), allogeneic hematopoietic stem cell transplantation (HCT), event-free survival (EFS), and overall survival (OS). Multivariate Cox regression for OS was performed.

Results: 83 patients were included, the median age at diagnosis was 44 years (IQR, 32-56), 27 received Ven/Aza (56% received 2 cycles), and 56 IC. Patients who received Ven/Aza were older, had a higher risk disease, and had a longer time between diagnosis and treatment. Patients who received Ven/Aza had a lower incidence of febrile neutropenia, need for transfusions, and less than half required hospitalization during induction; 30- and 60-day mortality was reduced 2.4 and 3-fold in Ven/Aza vs IC although statistical significance was not reached. There were no differences in the rate of CR/CRi between groups (Table 1). After achieving CR/CRi, the IC group had a higher incidence of being relapsed however the median EFS was not different with 7.7 months (95% CI 5.9-9.6) for Ven/Aza vs. 8.5 months (95% CI 6.6-10.5) for IC (p=0.53). Median OS was 10 months (95% CI 5.8-14.1) for Ven/Aza vs 9 months for IC (95% CI 6.6-11.3) (p=0.33) (Figure 1). Patients who received Ven/Aza followed by HCT had the best outcomes with a 2-year OS of 80% vs. 35.5% of those who received IC plus HCT. An OS landmark analysis for patients alive at or beyond 5 months (median time from diagnosis to HCT) showed prolonged survival in HCT vs. not transplanted patients (16 vs 11 months, p=0.035), irrespective of their induction arm. In the multivariate analysis, HCT (HR 0.05, 95% CI 0.007-0.5) and a need for cytoreduction (HR 8.7, 95% CI 1.2-59.6) were the only predictors of OS.

Conclusion: in this single-center study, AML patients treated in a limited resource setting with low-dose Ven/Aza had similar complete response and survival to IC with reduced complications and shorter hospital stay, despite being older with higher risk disease. This induction treatment is a low-cost but effective option in a LMIC environment and could be considered an alternative option, even in suitable candidates for IC, especially with access to HCT.