A multi-center, single-arm, phase 2 trial of dasatinib in T follicular helper cell lymphomas

T follicular helper cell lymphomas (TFHL) harbor activating T cell receptor (TCR) signaling mutations and epigenetic alterations, such as TET2 mutations. Here, we conduct a multi-center, single-arm, phase 2 trial of the tyrosine kinase inhibitor dasatinib in patients with relapsed/refractory TFHLs (jRCT2031190079). The primary outcome is the overall response rate (ORR) according to CT-based Lugano criteria 2014. Key secondary endpoints include ORR in RHOA-mutated patients and progression-free/overall survival. The main inclusion criteria consist of TFHL diagnosis and relapse following at least 1 prior chemotherapy regimen. Key exclusion criteria encompass central nervous system involvement, history of other malignancies, and receipt of chemotherapy or radiotherapy within 4 weeks. Nineteen patients are enrolled, with 18 receiving dasatinib and 17 evaluable for efficacy. Median age is 73 years, 50% are female, and angioimmunoblastic T cell lymphoma is the predominant subtype (n = 13). Dasatinib yields a 23.5% ORR, below the prespecified 30% endpoint. Treatment-related adverse events occur in 61.1% of patients (n = 11). Patients harboring TCR signaling mutations, especially those with RHOA p.G17V, achieve a 36.4% ORR, whereas no responses are observed in mutation-negative cases. Exploratory single-cell RNA sequencing reveals interferon-γ/tumor necrosis factor-enriched tumor microenvironments and peripheral expansion of cytotoxic T cell clones in responders. Conversely, early progression correlates with a high TET2 mutation burden in non-malignant immune cells, including CD8+ T cell subsets. While the primary outcome is below the prespecified endpoint, our exploratory findings implicate immune dysfunction involving TET2 mutations in limiting the therapeutic benefit of dasatinib. T follicular helper cell lymphomas (TFHL) depend on T cell receptor (TCR) signaling propagated by tyrosine kinases. Here, the authors conduct a phase 2 clinical trial of the tyrosine kinase inhibitor dasatinib in TFHL, not meeting the prespecified primary endpoint (ORR = 23.5%), but correlating response with TCR signaling mutations.