Durable immunovirological control after sequential mogamulizumab and tucidinostat in relapsed or refractory adult T-cell leukemia/lymphoma

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Adult T-cell leukemia/lymphoma (ATLL) is an aggressive HTLV-1-associated T-cell neoplasm, and durable control of relapsed/refractory disease remains difficult without allogeneic hematopoietic stem cell transplantation. Mogamulizumab, an afucosylated anti-C-C chemokine receptor type 4 (CCR4) monoclonal antibody, and tucidinostat, an oral histone deacetylase inhibitor, have activity in this setting, but the immunovirological consequences of sequential CCR4-directed therapy and epigenetic modulation are unclear. We describe two patients with relapsed or refractory ATLL who achieved prolonged disease control after mogamulizumab/tucidinostat-based sequential therapy and underwent longitudinal monitoring of Tax301–309-specific CD8+ T cells, CD4/CD8 dynamics, HTLV-1 proviral DNA, and T-cell receptor (TCR) Vβ repertoire. Patient 1 had lymphoma-type ATLL with metabolic partial response after mogamulizumab plus EPOCH; tucidinostat was initiated 63 days after the final mogamulizumab dose. Tax301–309-specific CD8+ T cells increased from 0.03% at tucidinostat initiation to >0.8% during long-term follow-up, and disease control persisted for 32 months after tucidinostat initiation. Patient 2 had multiply relapsed ATLL and received four cycles of sequential mogamulizumab/tucidinostat, followed by rapid disappearance of circulating ATLL cells, normalization of soluble interleukin-2 receptor, and marked reduction of HTLV-1 proviral load from 565.7 copies/1,000 peripheral blood mononuclear cells to low levels. Disease control persisted for 17 months after treatment discontinuation. In both patients, TCR Vβ repertoire analysis showed memory CD8+ T-cell-predominant patterns, including expansion of a Vβ2 memory CD8+ T-cell population. These observations are hypothesis-generating and suggest that sequential tumor debulking, CCR4/Treg-axis modulation, and epigenetic treatment may create a context permissive for HTLV-1 antigen-specific cellular immune surveillance in selected patients with ATLL.