Background:North American Adult T-cell leukemia/lymphoma (NA-ATLL) is an aggressive HTLV-1–associated malignancy with median survival of less than one year. Interferon-alpha/Zidovudine in combination with other chemotherapy regimens showed efficacy in acute and chronic subtypes of ATLL. Our group investigated, for the first time, Venetoclax, a BCL-2 inhibitor therapeutic activity in T-cell malignancies, together with the antiretroviral combinations such as IFN-α2a and Bictegravir/Emtricitabine/Tenofovir alafenamide (Biktarvy) against HTLV-1. We evaluated the efficacy of Venetoclax alone or in combination with Biktarvy in ATLL cases.
Methods:In preclinical and clinical study, we evaluated Venetoclax alone and in combination with IFN-α2a/Biktarvy in NA-ATLL patient-derived cell lines and refractory ATLL cases.
Objectives:
To assess the efficacy and resistance mechanisms of Venetoclax-based combinations with IFN-α2a/Biktarvy in refractory NA ATLL cases.
Results:NA-ATLL cell lines were sensitive to both venetoclax alone or in combination with IFN-α2a/Biktarvy (IC₅₀ = 1–10 µM). Mechanistically, BH3 profiling confirmed apoptotic priming, and reduction in HTLV-1 HBZ and Tax expression, and Caspase-3/PARP-1 was also observed. Additionally, ferroptosis was not observed, as confirmed by GPX4 expression and BODIPY-C11 lipid peroxidation assays. RNA-seq study specified up-regulation of compensatory survival pathways, including MAPK/PI3K, suggesting potential mechanisms of venetoclax resistance. Clinically, venetoclax combinations were well tolerated and overall response rate was 75% (1 CR, 5 PRs), including one durable complete remission enabling AlloSCT. Considerably, TP53 mutations (50%) were associated with inferior outcomes (median OS 40 vs. 255 days).
Conclusion:Our preclinical and clinical findings provide a strong rationale for combining IFN-α2a/Biktarvy and Venetoclax in NA-ATLL and merits further research to enhance effectiveness and elucidate mechanisms of Venetoclax resistance.
