Résumé
Background:
North American ATLL (NA-ATLL) is a highly aggressive HTLV-I-associated T-cell malignancy with a dismal prognosis. Venetoclax has shown activity in other T-cell malignancies, alone or in combination with hypomethylating agents (HMA), AZT (Zidovudine) with Interferon-alpha has been the backbone of acute ATLL treatment for the past three decades. While AZT-monotherapy was the first treatment to show benefit for HIV infection and in the treatment of HTLV-I induced ATLL along with interferon, combination therapy, such as the fixed-dose combination tablet Bictegravir-Emtricitabine-Tenofovir alafenamide 50mg-200mg-25mg (Biktarvy) is superior and has become standard of care for HIV treatment. There is preclinical evidence that these agents have activity against HTLV-I. Here, we evaluated the efficacy of Venetoclax alone or in combination with Biktarvy in patient-derived ATLL cell lines and the clinical use in the treatment of chemotherapy refractory ATLL patients.
Methods:
Preclinical: Japanese patient-derived ATLL cell lines [ATL43T (−)] (J-ATLL) as well as our own NA patient-derived ATLL cell lines [Pt-4a, Pt-5a, Pt-6a, Pt-15a] were used. We evaluated the inhibitory activity of Venetoclax, Biktarvy and their synergistic effect against J-ATLL and NA-ATLL cell lines.
Clinical: We treated 8 ATLL (6 acute and 2 lymphomatous per Shimoyama classification) patients with disease refractory to 2 or more lines of chemotherapy with Venetoclax along with hypomethylating agents or with PEG-Interferon and Biktarvy.
Results:
Preclinical: We observed that both the J-ATLL and NA-ATLL cells are sensitive to BCL-2 inhibitors (Venetoclax & Sonrotoclax) with IC50s in the 1-10uM range. Additionally, Biktarvy demonstrated a significant inhibitory effect on ATLL cells; with more efficacy against J-ATLL cell line (IC50=8uM) as compared to NA-ATLL cell lines (IC50 =16uM). To determine synergy between drugs we tested the combination of Decitabine (hypomethylating agent)-Venetoclax as well as between Biktarvy-Venetoclax. At the concentrations tested (range 0.5uM-32uM), we did not observe in-vitro synergy between Decitabine-Venetoclax. We did observe synergy between Venetoclax-Biktarvy showing also a robust inhibitory effect at lower inhibitory concentration compared to either agent alone.
Clinical: Venetoclax combinations (HMA: 4, ICE regimen: 2, PEG-IFN/Biktarvy: 2) were well tolerated in a heavily pretreated population. The main adverse effects observed were: cytopenias (80%), fatigue (90%), and infections/sepsis (60%). The overall response rate was 75% (1 CR; 5 partial responses, and 2 progressive diseases). TP53 mutations were detected in 50% (4/8) of this cohort and were associated with a worse prognosis and shorter duration of responses than the TP53 wild-type cases [mean overall survival TP53 mutant: 40 days (26-52 days); TP53 wild-type: 255 days (82-642)]. There was a significant difference between these two subgroups with a log-rank test p-value of 0.0027. Deploying HMA resulted in resensitization to chemotherapy in cases that were refractory before (2/8 patients). Importantly, we observed a complete response in a chemotherapy-refractory patient with uncontrollable hypercalcemia and lymphocytosis by combining PEG-IFN alpha, Biktarvy, and Venetoclax. At relapse, most cases displayed clonal evolution and acquisition of additional mutations, revealing the great genomic plasticity of ATLL cells. Notably, Shimoyama subtype change was observed in 3 cases as well.
Conclusion: Venetoclax is active in established preclinical models of J-and NA-ATLL. Furthermore, it shows a synergistic effect with Biktarvy but, unexpectedly, not with decitabine. In our heavily pretreated and chemotherapy-refractory cohort, we observed promising activity with an ORR of 75% (historical ORR of 20%) with Venetoclax combinations including a sustained complete remission in a patient who proceeded to allogeneic stem cell transplantation. TP53 mutated patients had poorer responses. Given the encouraging preclinical and clinical activity of this agent, a prospective clinical trial is being developed using these agents.
Shastri:Kymera: Research Funding; Gilead, Rigel, Kymera: Consultancy; Jassen: Consultancy; NACE & PeerView: Honoraria; Ryvu therapeutics: Research Funding; Geron: Speakers Bureau. Feldman:Stelexis: Consultancy. Bazarbachi:Roche: Honoraria, Research Funding; Takeda: Honoraria; Caribou: Honoraria; Amgen: Honoraria; Pfizer: Research Funding; Jansen: Honoraria, Research Funding; Biologix: Research Funding. Janakiram:JANNSEN: Honoraria, Research Funding; BMS: Honoraria, Research Funding; LEGEND: Honoraria, Research Funding; FATE THERAPEUTICS: Research Funding. Verma:Clinstreet: Current equity holder in private company; Bioconvergent health: Current equity holder in private company; Prelude: Research Funding; Bristol Myers Squib: Research Funding; Curis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Halia: Research Funding; Calico: Membership on an entity's Board of Directors or advisory committees; Stelexis: Current equity holder in private company, Membership on an entity's Board of Directors or advisory committees. Konopleva:Rafael Pharmaceutical: Research Funding; Dark Blue Therapeutics: Membership on an entity's Board of Directors or advisory committees; MEI Pharma: Consultancy, Research Funding; Pfizer: Other: clinical trials; AstraZeneca: Consultancy, Other: clinical trials, Research Funding; Auxenion GmbH: Membership on an entity's Board of Directors or advisory committees; Sellas: Consultancy; Redona: Consultancy; Sanofi Aventis: Consultancy, Other: clinical trials, Research Funding; Cellectis: Other: Clinical Trials; Reata Pharmaceutical: Other: IP; F. Hoffmann-LaRoche: Consultancy, Membership on an entity's Board of Directors or advisory committees; Legend Biotech: Consultancy; Janssen: Consultancy, Other: clinical trials; Bakx Therapeutics: Membership on an entity's Board of Directors or advisory committees; Boehringer: Consultancy; Immune Oncology: Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: clinical trials, Research Funding; Precision Biosciences: Research Funding; ImmunoGen: Research Funding; Menarini Group: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: clinical trials, Research Funding; Vincerx: Consultancy, Membership on an entity's Board of Directors or advisory committees; Allogene: Research Funding; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: clinical trials, Research Funding.
Decitabine and Venetoclax has been used in other T cell malignancies and ATLLBIKTARVY has been used to treat other retroviral infections