Pb1846: management of patients treated with venetoclax with hypomethylating agents: long-term incidence of cytopenias and infections

Topic: 4. Acute myeloid leukemia - Clinical Background: Since the publication of the pivotal VIALE-A study in 2020, the combination of venetoclax, and hypomethylating agents (VenHMA) has become the standard frontline treatment in patients diagnosed with acute myeloid leukemia (AML) ineligible for intensive chemotherapy. Most patients achieve response during the first two cycles; incidence of severe adverse events and early death is well-characterized in the initial period. Afterwards, hematological cytopenias and need of dose reduction are frequent events, though real impact on the long-term management and incidence of infections are mostly unknown. Aims: To describe the incidence of hematological cytopenias and other adverse events (AE) in patients diagnosed with AML and treated with VenHMA who continued treatment for at least 3 cycles. Methods: We performed a retrospective analysis of all consecutive patients diagnosed with AML, treated with VenHMA and receiving at least three cycles of treatment at Hospital Clinic of Barcelona from March 2019 to January 2023. Patients included in clinical trials were excluded from this study. Adverse events were determined according to the Common Terminology Criteria for Adverse Events, version 4.03. Additionally, a paired samples Wilcoxon test was used to analyze mean difference during evolution. Results: Forty-one patients were included. Baseline characteristics are displayed in Table 1. Median age was 73 years, and AML with myelodysplasia-related changes (35%) was the most common diagnosis. Twenty-two patients (54%) received treatment in a refractory/relapsed AML status, including 6 patients in a molecular positive relapse/persistence status after previous chemotherapy.. Median number of cycles administered was 8 (range 3-28) and median follow-up was 13.3 months (range 4-37). At first day of cycle 3 (C3D1), overall response rate was 78% and 7% obtained a response during cycle 3. One patient achieved a CR afterwards. ECOG PS 0-1 rate was in 82% of patients at C3D1. Main AEs and dose reduction during treatment are displayed in table 2 and image 1. Hematological cytopenias were were the most frequent AEs, with 95% (39/41), 56% (23/41) and 70% (29/41) of patients presenting G3-4 neutropenia, anemia, and thrombocytopenia, respectively. Twenty-three out of 25 patients receiving at least 6 cycles had reduced their initial dose, with a median of 2 reduction steps/patient during follow-up (range 1-4).. G-CSF was administered to 85% of the patients, with a median use of 5 cycles (range 1-15). Transfusion independence rate was 84% (21/25) at C6D1. Although the high rate of cytopenia during treatment cycles, mean Hb, absolute neutrophil count (ANC) and platelet count showed a progressive rise at each cycle start (paired samples Wilcoxon test C1D1-C6D1, Hb: p=0.01, ANC: p=<0.01, Platelet count p=0.12) (Figure 2). Although neutropenia rate was high, only 7 patients (17%) presented a G3-4 infection after C3D1, with 4 requiring a hospital admission (1 due to COVID-19 and 1 fungal infection after progressive disease). Only one cardiovascular event was observed (namely, an atrial fibrillation episode). No patient discontinued treatment due to AEs after C3D1. Summary/Conclusion: The incidence of hematological cytopenias, especially neutropenia, and subsequent dose reduction are common during long-term treatment of AML patients with VenHMA. Nonetheless, the infection rate is low, and most patients achieved transfusion independence. This high myelotoxicity might probably lead to shorten the recommended schedule duration of VenHMA in the future.Keywords: Acute myeloid leukemia, Venetoclax, Infection, Pancytopenia