Daratumumab in combination with GDP chemotherapy in CD38-positive relapsed/refractory peripheral T-cell lymphoma: a phase 2 study of the Fondazione Italiana Linfomi.

Peripheral T-cell lymphomas (PTCLs) are rare, aggressive malignancies with poor outcomes, particularly in the relapsed or refractory (R/R) setting. Given the frequent CD38 expression in PTCLs, this multicenter, open-label, single-arm phase II study (FIL_Dara-GDP; EudraCT 2018-002644-91) evaluated daratumumab, an anti-CD38 monoclonal antibody, combined with gemcitabine, dexamethasone, and cisplatin (D-GDP) in CD38-positive systemic PTCLs. The trial aimed to achieve a complete response (CR) rate of ≥ 40% after four cycles. Eligibility required ≥ 5% CD38-positive tumor cells and one or two prior treatment lines. The study was terminated early after the enrollment of eight of the planned 35 patients due to unacceptable hematologic and non-hematologic toxicities. Grade 4 thrombocytopenia and grade 3-4 neutropenia occurred in 75% and 63% of patients, respectively, with two toxicity-related deaths. No CRs were achieved, and the overall response rate was 13%. Median progression-free and overall survival at six months were 12.5% and 25%, respectively. The high hematological toxicity observed likely reflects the possible additive myelosuppressive effect of daratumumab to GDP in a pretreated PTCL population. Although daratumumab has shown therapeutic potential in T-cell malignancies, its combination with intensive chemotherapy appears unsuitable in this setting. Future studies should explore safer, targeted approaches to optimize CD38-directed therapy in PTCL.