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.

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Journal
Nature Communications
Published
2026-10-05
DOI
https://doi.org/10.1038/s41467-026-78100-z
Primary Topic
Lymphoma Diagnosis and Treatment
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article
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article

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

Hideki Goto, Kenichi Makishima, Mamiko Sakata‐Yanagimoto, Koichi Hashimoto et al.
Nature Communications
Lymphoma Diagnosis and Treatment
article

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

Hideki Goto, Kenichi Makishima, Mamiko Sakata‐Yanagimoto, Koichi Hashimoto, Futoshi Yoshino, Kensuke Usuki, Satoshi Kimura, Kosei Matsue, Takahide Ara, Koji Izutsu, Emiko Sakaida, Naoki Kurita, Kenichi Yoshida, Dai Maruyama, Motoko Yamaguchi, Yoshiaki Abe, Kengo Takeuchi, Atsushi Uehara, Christian Steidl, Masahiko Gosho, Sakurako Suma, Noriko Fukuhara, Tatsuhiro Sakamoto, Tomohiro Kaneta, Seishi Ogawa, Yasuhito Suehara, Shigeru Chiba, Ken Ohmachi, Naoya Nakamura, Keiichiro Hattori, Mitsutaka Nishimoto, Hidekazu Nishikii, Hirokazu Nagai, Yuko Hashimoto, Manabu Fujisawa, Takashi Terauchi, Naoto Keino, Hiroyuki Hosokawa
article en

Abstract

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.

Nature Communications
BC Cancer Agency (CA), Fukushima Medical University (JP), Tokai University (JP), University of Tsukuba (JP), Chiba University (JP), Mie University (JP), Tohoku University (JP), Kyoto University (JP), National Cancer Centre Japan (JP), Tohoku University Hospital (JP), Chiba University Hospital (JP), Kameda Medical Center (JP), University of Tsukuba Hospital (JP), Tokai University Hospital (JP), The Cancer Institute Hospital (JP), Hokkaido University Hospital (JP), Fukushima Medical University Hospital (JP), Nagoya Medical Center (JP), Japanese Foundation For Cancer Research (JP), Osaka Metropolitan University (JP), Teikyo University Hospital, Mizonokuchi, Teikyo University (JP), Kindai University (JP)
Openalex Percentile: Top 12%
Lymphoma Diagnosis and Treatment
DOIOpen Access PDFOpenAlex
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