Biomarkers point to which lymphoma patients respond to dasatinib

Researchers at the University of Tsukuba have identified biomarkers that appear to predict which patients with T-follicular helper cell lymphoma (TFHL) benefit from dasatinib, a leukemia drug repurposed for this rare and hard-to-treat cancer. The findings come from a physician-initiated, multicenter Phase II clinical trial conducted across 13 institutions in Japan, with results published in Nature Communications.

TFHL is a subtype of peripheral T-cell lymphoma associated with a poor prognosis and limited treatment options after relapse. The disease is characterized by specific molecular abnormalities, including frequent activation of the T-cell receptor (TCR) signaling pathway. In earlier Phase I studies, the research team showed that dasatinib, originally developed to treat leukemia, suppresses this abnormal TCR signaling and demonstrated promising clinical activity in patients with TFHL.

In the new Phase II trial, the team evaluated the efficacy and safety of dasatinib and sought factors associated with treatment response. They performed comprehensive genetic analyses of tumor tissue and blood samples, together with single-cell transcriptomic profiling, in 17 patients with relapsed or refractory disease.

The analysis revealed a clear pattern among responders. Clinical responses were observed in patients whose tumors carried mutations related to TCR signaling. These patients also exhibited clonal expansion of CD8-positive effector T cells, which play a key role in eliminating tumor cells, along with enhanced antitumor immune activity.

In contrast, patients with a high burden of clonal hematopoiesis-associated mutations were less likely to benefit from treatment and showed impaired antitumor immune responses. Clonal hematopoiesis is an age-related phenomenon in which hematopoietic stem cells acquire somatic mutations and expand clonally, and its presence appears to blunt the immune environment that dasatinib seems to rely on.

According to the researchers, these results suggest that both the genetic characteristics of the tumors and the surrounding immune microenvironment influence the therapeutic efficacy of dasatinib. Response, in other words, depends not only on what drives the cancer cells themselves but also on the state of the immune cells recruited to fight them.

The identified biomarkers may help guide patient selection and inform treatment strategies in future studies, and could support the development of therapies targeting the tumor immune microenvironment. The results also provide new insights into the potential role of clonal hematopoiesis in shaping antitumor immunity, a question of growing interest well beyond this single lymphoma subtype.

The study, titled “A multi-center, single-arm, phase 2 trial of dasatinib in T follicular helper cell lymphomas,” was published in Nature Communications. As a single-arm Phase II trial in a small patient group, its findings will require validation in larger studies before biomarker-guided selection becomes standard practice, but they offer a concrete step toward more precise treatment of a disease with few options after relapse.

The work was supported by Grants-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, and Science of Japan, by multiple AMED programs including the Moonshot Research and Development Program and CREST, and by several private foundations including the Takeda Science Foundation and the Japan Leukemia Research Fund.

Subject of Research: Biomarkers predicting dasatinib response in relapsed or refractory T-follicular helper cell lymphoma

Article Title: Predictive biomarkers for dasatinib therapy identified in relapsed or refractory T-follicular helper cell lymphoma

Article References: Predictive biomarkers for dasatinib therapy identified in relapsed or refractory T-follicular helper cell lymphoma. Original publication (Bibliographic details unavailable.)

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Keywords: dasatinib, T-follicular helper cell lymphoma, peripheral T-cell lymphoma, biomarkers, Phase II trial, clonal hematopoiesis, TCR signaling, CD8-positive T cells, tumor immune microenvironment, University of Tsukuba, Nature Communications, single-cell transcriptomics