Mogamulizumab Shows Significant Activity with Tolerable Toxicity in a Real-World North American Adult T-Cell Leukemia/Lymphoma (ATLL) Cohort

Adult T-cell leukemia/lymphoma (ATLL) is a rare hematologic malignancy of CD4+ T-cells that is associated with a dismal prognosis in most cases. ATLL affects people who had prior infection with human T cell lymphotropic virus 1 (HTLV-1), an oncogenic retrovirus that is endemic to many parts of the world, including the Caribbean, Latin America, countries in West Africa, and Japan. There are limited treatment options for ATLL, and bone marrow transplants are often the only curative measure. There are no FDA-approved targeted treatments for ATLL and there is a dire need for the evaluation of novel agents in this disease. Here, we evaluate the use of mogamulizumab in a real-world cohort of relapsed/refractory ATLL.

Mogamulizumab is a monoclonal antibody that targets the chemokine receptor CCR4, which is expressed by malignant T-cells in ATLL and is FDA-approved for the treatment of adult patients with relapsed cutaneous T-cell lymphoma. Importantly, mogamulizumab showed promising results in relapsed/refractory CCR4-positive ATLL in Japanese patients and has been approved by the Japanese regulatory agency for relapsed disease.

We showed previously that North American ATLL (NA-ATLL) has a distinct transcriptional and genomic profile which we believe may be linked to the worse outcomes we have observed clinically. A single arm clinical trial of mogamulizumab versus investigator's choice chemotherapy was performed in NA-ATLL with an overall response rate of 11% and 0% in the mogamulizumab and chemotherapy arms, respectively.

Nine patients with relapsed/refractory ATLL from our center were treated with mogamulizumab. The median age at the first infusion of mogamulizumab was 63 years old (range 42-77), and 67% of our cohort was Black/African American. Five patients had acute/leukemic ATLL per Shimoyama classification and the other four had the lymphomatous type. Two patients had one prior line of treatment, one patient had two prior lines, and six had three or more prior therapies. Our primary objectives were to determine the progression-free survival and overall survival of the patients in this cohort. Progression was based on imaging, clinical, or pathologic progression of disease. We also compared overall survival of our mogamulizumab patients to a group of matched historical control ATLL patients. We also looked at the adverse events associated with mogamulizumab in our cohort.

Here we report for first time the use of mogamulizumab in a real-world cohort of relapsed ATLL patients treated at different stages of their disease. We observed an overall response rate of 55.6% with two complete responses, three partial responses, and four patients who had disease progression despite mogamulizumab. The adverse events that we observed include febrile reactions after infusion in two of our patients and fatigue in one patient. Overall, mogamulizumab was well-tolerated. Notably, we also observed prolonged survival in two of our patients after discontinuation of treatment. Interestingly, in one of these cases, clonal evolution was observed with loss of a pathogenic mutation and a significantly prolonged overall survival was documented. We also observed that the overall survival in our cohort was significantly higher than in the clinical trial of mogamulizumab versus investigator's choice chemotherapy. In our long-term survivors, mogamulizumab was combined with Peg-IFN/Biktarvy, venetoclax, and lenalidomide. Compared to our historical control group, OS in the mogamulizumab-treated group was 309 days versus an OS of 33 days in our control group (p-value=0.0013).

Overall, our data supports the use of mogamulizumab in heavily pre-treated ATLL patients. Further studies, using mogamulizumab alone or in combination with other agents, are necessary to elucidate the role of this agent in ATLL.

Shastri:Gilead, Rigel, Kymera: Consultancy; NACE & PeerView: Honoraria; Jassen: Consultancy; Kymera: Research Funding; Ryvu therapeutics: Research Funding; Geron: Speakers Bureau. Konopleva:Menarini Group: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: clinical trials, Research Funding; Immune Oncology: Membership on an entity's Board of Directors or advisory committees; Redona: Consultancy; Sellas: Consultancy; Dark Blue Therapeutics: Membership on an entity's Board of Directors or advisory committees; Boehringer: Consultancy; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: clinical trials, Research Funding; Janssen: Consultancy, Other: clinical trials; F. Hoffmann-LaRoche: Consultancy, Membership on an entity's Board of Directors or advisory committees; Cellectis: Other: Clinical Trials; Rafael Pharmaceutical: Research Funding; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bakx Therapeutics: Membership on an entity's Board of Directors or advisory committees; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: clinical trials, Research Funding; Legend Biotech: Consultancy; Precision Biosciences: Research Funding; Pfizer: Other: clinical trials; Sanofi Aventis: Consultancy, Other: clinical trials, Research Funding; Reata Pharmaceutical: Other: IP; Allogene: Research Funding; AstraZeneca: Consultancy, Other: clinical trials, Research Funding; ImmunoGen: Research Funding; MEI Pharma: Consultancy, Research Funding; Vincerx: Consultancy, Membership on an entity's Board of Directors or advisory committees; Auxenion GmbH: Membership on an entity's Board of Directors or advisory committees. Bazarbachi:Caribou: Honoraria; Amgen: Honoraria; Roche: Honoraria, Research Funding; Pfizer: Research Funding; Jansen: Honoraria, Research Funding; Takeda: Honoraria; Biologix: Research Funding. Janakiram:BMS: Honoraria, Research Funding; JANNSEN: Honoraria, Research Funding; FATE THERAPEUTICS: Research Funding; LEGEND: Honoraria, Research Funding.