Relapsed/refractory (R/R) mature T and natural killer (NK)-cell lymphomas (TNKL) are aggressive blood cancers often resistant to frontline therapies. A team of Mass General Brigham researchers found that patients with these lymphomas had improved survival rates when treated with small molecule inhibitors as second-line therapy, followed by epigenetic modifiers as third-line therapy. Results of the study are published in the British Journal of Haematology.
“Our robust study design, multiple stability analyses, and independent machine learning models using the PETAL global dataset, all pointed to the same conclusion: targeted therapies and epigenetic modifiers consistently showed benefit over chemotherapy for patients with relapsed/refractory T-cell/NK-cell lymphomas,” said lead author Mark Sorial, PharmD, BCOP, a researcher in the Mass General Cancer Center, a member of the Mass General Brigham healthcare system.
RR TNKLs are notoriously difficult to treat, and patients living with these cancers have poor prognoses. To date, there is no established treatment protocol for this condition. Instead, health professionals must choose among several second-line options such as cytotoxic chemotherapies, epigenetic modifiers, and small molecule inhibitors, without clear evidence to guide their decision-making.
Led by senior author and founding member of the PETAL consortium, Salvia Jain, MD, at MGH, PETAL Investigators performed a retrospective sequential treatment cohort study using data from the Peripheral T-cell lymphoma (PETAL) Consortium including patients who first received upfront cytotoxic chemotherapy. Sorial then sorted patient data based on those who received second- and third-line treatments, including chemotherapy again, epigenetic modifiers, or small molecule inhibitors, analyzing overall survival across treatment groups. The study ultimately compared 12 possible treatment paths for second- and third-line therapies with 540 and 290 patients receiving second and third-line therapies, respectively.
Study outcomes showed that using small molecule inhibitors as second-line therapies followed by epigenetic modifiers significantly improved survival compared to other sequences. Survival benefits were especially pronounced among high-risk groups and patients with angioimmunoblastic T-cell lymphoma.
“These results support the earlier use of these novel therapies, prioritize further research of these drug classes, and provide a framework for examining survival effects with sequential treatments in other cancers,” said Sorial. “They also highlight that targeted signaling inhibitors like duvelisib warrant ongoing clinical investigation in this patient population with limited treatment options.”
Cancer research is a foundational pillar in the care we provide patients at Mass General Brigham. Research, along with the power of the system’s strengths in innovation, education, and community engagement, will allow Mass General Brigham Cancer to deliver integrated cancer care for all, putting health equity at the center of that support. The vision is to provide a comprehensive, integrated and research-informed approach to cancer care, helping patients navigate their entire journey of care, from prevention and early detection to treatment and survivorship.
Authorship: In addition to Sorial and Jain, Mass General Brigham authors include Matthew M Lei, Caroline T. MacVicar, Jessica Freydman, Shambhavi Singh, Makoto Iwasaki, Kusha Chopra, Josie Ford, Alexandra Lenart, Jeffrey Barnes, and Salvia Jain. Additional authors include Jessy Xinyi Han, Min Jung Koh, Leora Boussi, Sijia Li, Rui Duan, Junwei Lu, Ijeoma Julie Eche-Ugwu, Maria J. Fernandez Turizo, Eliana Miranda, Carlos Chiattone, Robert Stuver, Eric Jacobsen, Martina Manni, Monica Civallero, Tetiana Skrypets, Massimo Federico, Yuri Kim, Manju Sengar, Carrie Van Der Weyden, Henry Miles Prince, Francine Foss, Marianna Gentilini, Beatrice Casadei, Pier Luigi Zinzani, Takeshi Okatani, Noriaki Yoshida, Sang Eun Yoon, Won-Seog Kim, Zainab Mohamed, Estelle Verburgh, Mubarak Al-Mansour, Maria Elena Cabrera, Govind Bhagat, Helen Ma, Mesrob Yeterian, Owen A. O’Connor, Enrica Marchi, Changyu Shen, and Devavrat Shah.
Disclosures: Sorial discloses research funding from Secura Bio and Daiichi Sankyo. Disclosures for additional authors can be found in the paper.
Funding: This work was supported by Secura Bio, Daiichi Sankyo, Kyowa Kirin, and Acrotech Biopharma, and Center for Lymphoma Research Funds. Jain is supported by the National Cancer Institute K08 Career Development Award (K08CA230498) and MGH Lymphoma Research Funds. Jacobsen is supported by the Reid Family Fund for Lymphoma Research.
Paper cited: Sorial MN, Han JX, Koh MJ, Boussi L, Li S, Duan R, et al. Forecasting optimal treatments in relapsed/refractory mature T- and NK-cell lymphomas: A global PETAL Consortium study. Br J Haematol. 2025;00:1–14. https://doi. org/10.1111/bjh.20063
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