Mogamulizumab Combinations in Patients with Relapsing/Refractory Adult T-Cell Leukemia/Lymphoma (r/r ATLL)
Authors: Srinivasan Maya D. , Dittus Christopher , El-Jawahri Areej , Jain Salvia , Shelton Anthony , Sloan John Mark 
Published: December 2024

Background:
Adult T-cell Leukemia Lymphoma (ATLL) is a highly aggressive, T-lymphocyte malignancy etiologically linked to the Human T-cell Lymphotropic Virus Type 1 (HTLV-1) infection with a dismal prognosis. Advances to frontline management have afforded better disease control, and multi-agent chemotherapy regimens followed by consolidative allogeneic transplant presents a potential path to cure. Many patients cannot proceed to transplant due to limited donor availability, primary refractory disease, sociocultural barriers, and significant comorbidities. Without transplant, relapse occurs and is characterized by highly chemo-refractory and lethal disease course, with median survival limited to 4-6 months.
ATLL impacts the global population with heterogeneous clinical manifestations and variable therapeutic response amongst clinical and geographical subtypes. No standard regimen has been established for treatment of relapsed or refractory (r/r) ATLL, and no FDA approved targeted treatment for relapsed disease exists. Response to salvage chemotherapy is unsatisfactory. There is minimal data on outcomes with national and societal guideline-recommended targeted agents within the US ATLL population. Additionally, guideline-recommended targeted agents for r/r ATLL are extrapolated from international populations representing differing ATLL subtypes and disease biology. There is little data or knowledge of outcomes in non-study populations to support treatment decisions in the relapsed/refractory setting.
Mogamulizumab, a humanized monoclonal antibody that exploits C-C chemokine receptor type 4 (CCR4) overexpression of ATLL tumor cells and Treg cells via antibody dependent cellular cytotoxicity (ADCC), demonstrated improved survival in r/r ATLL in an initial Japanese study with variable outcomes in a larger international multi-center trial. Lenalidomide exerts pleiotropic immunomodulatory effects and has a potential synergistic role by augmenting NK cell activity and number. Mogamulizumab and lenalidomide each have demonstrable activity in r/r ATLL but are insufficient as monotherapies.
Approach to r/r ATLL remains an unanswered and important question. We describe our experience with mogamulizumab +/- lenalidomide in the r/r ATLL setting.
Methods: A retrospective chart review of patients with r/r ATLL treated with mogamulizumab at Boston Medical between January 2018 and January 2024 was conducted. Five patients (5) currently included at time of abstract.
Results: All patients had acute r/r ATLL with stage IV disease; 1 patient with leptomeningeal involvement. Median age was 65 (range 30-69), 4 of 5 were female, and all were Afro-Caribbean. All patients received BV-CHEP in the frontline setting, with ≥1 cycle of intrathecal methotrexate. Prior to relapse, 3 of 5 patients achieved a complete response with frontline treatment, 1 had progressive disease, and 1 had a partial response. No patients were able to proceed to consolidative transplant following frontline therapy due to either lack of available donor, primary refractory disease, or medical comorbidities and complications with conditioning. Patients had relapsed disease within an average of 3.15 months (median 1.47 months), (range 23 days - 10.40 months) of initial treatment. At relapse, all patients received mogamulizumab +/- lenalidomide. Median overall survival upon initiating mogamulizumab was 9.9 months (range 2.9 - NR). Toxicities included fatigue, Grade 2 and 3 infections, Grade 2 rash, and 1 instance of Grade 3 peripheral eosinophilia.
Conclusions: In this retrospective study of patients with r/r ATLL, mogamulizumab demonstrated effective disease control even in aggressive, primary chemotherapy refractory disease. Mogamulizumab in combination with lenalidomide was generally well tolerated, achieving disease control for up to one year, and importantly offering CNS activity. There were no treatment-related toxicities that required its discontinuation. Our study provides support for a prospective study for the combination regimen.