denotes an abstract that is clinically relevant.
denotes that this is a recommended PHD Trainee Session.
denotes that this is a ticketed session.Session: 627. Aggressive Lymphomas: Pharmacologic Therapies: Poster I
Hematology Disease Topics & Pathways:
Research, Clinical trials, Lymphomas, Clinical Research, Diseases, Aggressive lymphoma, Lymphoid Malignancies
HTLV-1 related adult T-cell leukemia-lymphoma (ATL) is generally fatal. While standard therapies may be transiently efficacious, patients usually relapse and die of their disease in the absence of allogeneic transplant, which is only curative in a portion of patients. Patients with acute type ATL have the worst outcome with median survival of < 8 months in the largest retrospective studies. Our pre-clinical work showed that belinostat (BEL), a pan-HDAC inhibitor, induces dose-dependent Tax expression and blocks HBZ protein expression resulting in apoptosis of ATL cells. The anti-ATL effects of BEL is augmented by AZT (zidovudine). Since the HTLV-1 promoter is regulated by HDACs, we hypothesized BEL would reactivate HTLV-1 in host cells of subjects treated with AZT+ interferon-α (AI) thus eliciting anti-HTLV-1/ATL immune responses. Thus, we conducted a phase 2 trial of AI-BEL for patients with aggressive ATL and leukemic involvement as a consolidation therapy (Clinicaltrials.gov NCT02737046).
Methods:
Eligibility criteria included adult patients with newly diagnosed or relapsed ATL with adequate organ function and ECOG PS ≤ 3 with active disease in peripheral blood without progressive disease after AI, steroids, or dose-reduced cytoreductive chemotherapy, or after standard chemotherapy given ≥ 2 weeks prior. The regimen consisted of up to eight 21-day cycles of intravenous belinostat 1,000 mg/m2 (Days 1-5), oral AZT 300 mg three times daily, and interferon-α (5-10 million units daily) or its pegylated forms (90-180 mcg weekly) followed by maintenance AZT and/or interferon up to at least month 12. The protocol included dose adjustment guidelines based on grade 4 hematologic events. The primary objectives were 1) evaluating safety, and 2) determining the regimen’s ability to induce a complete molecular response (CMR) in blood compartment based on disappearance of the dominant T-cell clone measured by multiplex PCR. Secondary objectives included determining overall response rate (ORR) and survival rates and investigating cytotoxic T-cell (CTL) responses in vivo.
Results:
A total of 18 patients with acute type ATL signed informed consent and were screened between December 2016 and June 2024. Fifteen patients (ages 31-75) from the Caribbean or South American origin were enrolled. Seven subjects (47%) had relapsed from prior therapies. Five patients showed signs of progressive disease after enrollment and before treatment initiation. Patients completed 1-8 cycles of BEL. Drug was dose-reduced or discontinued after grade 4 thrombocytopenia (47%) or grade 4 neutropenia (60%), or after progressive disease (n=4). Grade 1 or 2 nausea/vomiting occurred in 75% of subjects. Ten of 14 (71%) evaluable patients had a clinical benefit based on ORR of 57% (complete response, n=4, 29%; partial response n=4, 29%) or stable disease, (n=2, 14%). 3/13 subjects (23%) have achieved CMR in blood compartment, while 2 patients are still completing treatment and evaluations. The study is now closed to accruals after meeting primary endpoints. One subject who achieved a CMR continues to be without evidence of disease at 39 months while receiving maintenance pegylated interferon. The estimated median progression-free survival is approximately 5 months (95%CI 0.8, 16 months) and median overall survival 28 months (95%CI 7.1 months to not estimable). Immunophenotypic studies of serially collected PBMC samples demonstrated that there was a significant population of exhausted CD8+ T cells (PD-1+TIGIT+TOX+) in all baseline samples. Remarkably, only in patients who achieved deep hematologic responses, exhausted CD8+ T cells exhibited a transitional expansion phase before returning to a low baseline level, which coincided with the expansion of highly cytolytic CD8+ CTLs upon treatment response.
Conclusions:
AI-BEL can be efficacious in patients with aggressive ATL with circulating leukemic cells. Our results demonstrate that judicious use of HDAC inhibitors in combination with AZT-interferon-α can provoke sustained immunologic effects driven by CD8 T-cell responses against ATL resulting in deep hematologic responses. AI-BEL is relatively safe to administer; however, hematologic adverse events are expected, which may warrant dose and treatment schedule modifications. Our clinical data support testing such approach in larger studies including as upfront therapy for ATL.
Disclosures: Pongas: Eli Lilly: Current holder of stock options in a privately-held company; MEVOX LTD: Current equity holder in publicly-traded company; CRISPR Therapeutics: Current holder of stock options in a privately-held company; Amgen: Current holder of stock options in a privately-held company. Ramos: Acrotech Biopharma Inc.: Consultancy.
OffLabel Disclosure: Belinostat is a drug that is only approved for relapsed peripheral T-cell lymphoma, but not approved in combination with interferon-α and/or zidovudine for HTLV-1 related adult T-cell leukemia-lymphoma. Zidovudine and interferon-α are not approved drugs either, but they are recommended for ATLL leukemic subtype according to Adult T-Cell Leukemia-Lymphoma International Consensus Review panel and NCCN.
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