| Abstrakt: |
Objectives HTLV-1 related adult T-cell leukemia-lymphoma (ATLL) is generally fatal. Standard therapies are only transiently efficacious, as patients usually relapse and die of their disease. Belinostat is a pan-HDAC inhibitor that blocks HBZ and induces dose-dependent Tax expression and apoptosis (augmented by zidovudine) in patient-derived ATLL cells. We hypothesized belinostat would reactivate HTLV-1 in host cells of subjects treated with zidovudine (+/-interferon-a) thus eliciting anti-HTLV-1/ATLL immune responses. Thus, we designed a phase 2 trial of belinostat with zidovudine (+/-interferon-a) as consolidation for patients with aggressive leukemic ATLL (Clinicaltrials.gov NCT02737046). Methods The regimen consists of up to eight 21-day cycles of intravenous belinostat 1,000 mg/m2 (Days 1-5), oral zidovudine 300mg three times daily, and optional interferon-a (5-10 million units daily, or pegylated form 180 mcg weekly) followed by maintenance zidovudine (+/-interferon-a) up to month 12. The primary objectives are to evaluate safety and complete molecular response (CMR) rates by measuring T-cell receptor clonality by multiplex PCR in blood compartment. Secondary objectives include measuring response rates, effect on HTLV-1 proviral load (PVLs), cytotoxic T-cell (CTL) responses, and molecular effects of belinostat in ATLL cells in vivo. Results 9 patients with acute type ATLL have been treated so far and completed a maximum of 6 cycles. Treatment was dose-reduced or discontinued after recurring grade 3 or 4 hematologic toxicities (expected events) (n = 5), or after progressive disease (PD) (n = 3). Clinical activity has been observed in 7 of 9 patients with at least 2 confirmed CMRs. Four patients achieved CMR in peripheral blood and bone marrow compartments lasting up to 27 months. Molecular, PVL, and CTL activity assays are in progress. Conclusions CMR can be achieved in patients with acute type ATLL treated with belinostat and zidovudine-interferon-a, supporting our main hypothesis that judicious use of HDAC inhibitors may provoke sustained immune responses against ATLL. [ABSTRACT FROM AUTHOR] |
