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Multicenter Study
. 2025 Jun;206(6):1664-1677.
doi: 10.1111/bjh.20063. Epub 2025 May 1.

Forecasting optimal treatments in relapsed/refractory mature T- and NK-cell lymphomas: A global PETAL Consortium study

Mark N Sorial  1   2 Jessy Xinyi Han  3 Min Jung Koh  4 Leora Boussi  5 Sijia Li  6 Rui Duan  6 Junwei Lu  6 Matthew M Lei  1 Caroline T MacVicar  1 Jessica Freydman  1 Jack Malespini  1 Kenechukwu N Aniagboso  1 Sean M McCabe  1 Luke Peng  7 Shambhavi Singh  1 Makoto Iwasaki  1 Ijeoma Julie Eche-Ugwu  2   8   9 Judith Gabler  1 Maria J Fernandez Turizo  8 Aditya Garg  1 Alexander Disciullo  1 Kusha Chopra  1 Josie Ford  1 Alexandra Lenart  1 Emmanuel Nwodo  1 Jeffrey Barnes  1   9 Min Ji Koh  1   3 Eliana Miranda  10 Carlos Chiattone  11 Robert Stuver  12 Mwanasha Merrill  2 Eric Jacobsen  2   9 Martina Manni  13 Monica Civallero  14 Tetiana Skrypets  15 Athina Lymboussaki  13 Massimo Federico  14 Yuri Kim  16 Jin Seok Kim  16 Jae Yong Cho  16 Thomas Eipe  17 Tanuja Shet  17 Sridhar Epari  17 Alok Shetty  17 Saswata Saha  17 Hasmukh Jain  17 Manju Sengar  17 Carrie Van Der Weyden  18 Henry Miles Prince  18 Ramzi Hamouche  19 Tinatin Muradashvili  19 Francine Foss  19 Marianna Gentilini  20   21 Beatrice Casadei  20 Pier Luigi Zinzani  20   21 Takeshi Okatani  22 Noriaki Yoshida  23 Sang Eun Yoon  24 Won-Seog Kim  24 Girisha Panchoo  25 Zainab Mohamed  26 Estelle Verburgh  27 Jackielyn Cuenca Alturas  28 Mubarak Al-Mansour  28 Maria Elena Cabrera  29 Amy Ku  30 Govind Bhagat  30 Helen Ma  31 Ahmed Sawas  32 Khyati Maulik Kariya  1 Forum Bhanushali  1 Arushi Meharwal  1 Dhruv Mistry  1   17 Maria Kosovsky  1 Mesrob Yeterian  33 Owen A O'Connor  34 Enrica Marchi  34 Changyu Shen  35 Devavrat Shah  3 Salvia Jain  1   9   36
Affiliations
Multicenter Study

Forecasting optimal treatments in relapsed/refractory mature T- and NK-cell lymphomas: A global PETAL Consortium study

Mark N Sorial et al. Br J Haematol. 2025 Jun.

Abstract

There is no standard of care in relapsed/refractory T-cell/natural killer-cell lymphomas. Patients often cycle through cytotoxic chemotherapy (CC), epigenetic modifiers (EM) or small molecule inhibitors (SMI) empirically. Ideal therapy at each line remains unknown. We conducted a retrospective, multiple intervention, 'target-trial' using the PETAL global cohort. Patients received front-line CC, then second and third line (2L and 3L) with either CC again, EM or SMI (12 possible treatment scenarios). Overall survival (OS; 2L or 3L to death) was compared across treatment sequences using Cox, reinforcement learning and synthetic intervention methods adjusting for age, histology, primary refractory disease, prognostic index for T-cell lymphoma (PIT) score, response to 2L, and receipt of 2L transplant consolidation. Five hundred and forty received 2L (EM = 101, SMI = 45, CC = 394), and 290 received 3L (EM = 65, SMI = 44, CC = 181). 2L SMI then 3L EM improved OS (adjusted hazard ratio [aHR]: 0.29, 95% confidence interval [CI]: 0.11-0.74; p = 0.010) versus 2L-3L CC-CC, and consistently across most other sequential strategies. In 2L stability analyses, benefit was notable with 2L SMI in angioimmunoblastic T-cell lymphoma (vs. CC: aHR: 0.23, 95% CI: 0.10-0.4; p < 0.001); vs. EM: aHR: 0.32, 95% CI: 0.12-0.82; p = 0.020), and both SMI and EM in PIT-stratified high-risk groups (SMI: aHR: 0.40, 95% CI: 0.21-0.76; p = 0.005; EM: aHR: 0.60, 95% CI: 0.39-0.92; p = 0.020) versus 2L CC. Results were consistent across all other independent stability and causal inference analyses providing a treatment selection framework.

Keywords: cytotoxic chemotherapy; epigenetic modifiers; machine learning; mature T‐cell and NK‐cell lymphomas; molecular therapeutics.

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Conflict of interest statement

CONFLICT OF INTEREST DISCLOSURE STATEMENT

Sorial: Secura Bio: Research Funding, Daiichi Sankyo: Research Funding. Chiattone: ROCHE, ABBVIE, JANSSEN, AZ, LYLLI, TAKEDA: Honoraria; ROCHE, ABBVIE, JANSSEN, AZ, LYLLI, TAKEDA: Consultancy. Horwitz: ONO Pharmaceuticals: Consultancy; Affimed: Research Funding; Tubulis: Consultancy; Abcuro Inc.: Consultancy; Daiichi Sankyo: Consultancy, Research Funding; Celgene: Research Funding; Cimieo Therapeutics: Consultancy; Auxilius Pharma: Consultancy; Trillium Therapeutics: Consultancy, Research Funding; Kyowa Hakko Kirin: Consultancy, Research Funding; SecuraBio: Consultancy; Shoreline Biosciences, Inc.: Consultancy; Takeda: Consultancy, Research Funding; Yingli Pharma Limited: Consultancy; ADC Therapeutics: Research Funding; Millenium: Research Funding; Crispr Therapeutics: Research Funding; Seattle Genetics: Research Funding; Verastem/SecuraBio: Research Funding. Jacobsen: Celgene: Research Funding; Merck: Honoraria, Research Funding; Pharmacyclics: Research Funding; Hoffman-LaRoche: Research Funding; Daiichi: Honoraria; BMS: Honoraria; Bayer: Honoraria; UpToDate: Patents & Royalties. Jain: ImmunoACT: Research Funding; Zydus Pharmaceuticals: Research Funding; Intas Pharmaceuticals: Research Funding. Van Der Weyden: Cartherics Pty Ltd: Ended employment in the past 24 months, Membership on an entity’s Board of Directors or advisory committees. Prince: Takeda: Speakers Bureau; Merck: Speakers Bureau; Mallinkrodt: Speakers Bureau; Mundipharma: Speakers Bureau. Foss: SecuraBio: Honoraria; Daiichi Sankyo: Honoraria; Kyowa: Honoraria; Conjupro: Honoraria; Astex: Honoraria; Seagen: Speakers Bureau; Acrotech: Speakers Bureau. Casadei: Kite-Gilead: Membership on an entity’s Board of Directors or advisory committees, Speakers Bureau; Abbvie: Membership on an entity’s Board of Directors or advisory committees, Speakers Bureau; Janssen: Membership on an entity’s Board of Directors or advisory committees, Speakers Bureau; Novartis: Speakers Bureau; Lilly: Speakers Bureau; Roche: Speakers Bureau; Celgene-BMS: Membership on an entity’s Board of Directors or advisory committees; Beigene: Membership on an entity’s Board of Directors or advisory committees; Takeda: Membership on an entity’s Board of Directors or advisory committees. Zinzani: SERVIER: Membership on an entity’s Board of Directors or advisory committees, Speakers Bureau; SANDOZ: Membership on an entity’s Board of Directors or advisory committees; CELLTRION: Membership on an entity’s Board of Directors or advisory committees, Speakers Bureau; GILEAD: Membership on an entity’s Board of Directors or advisory committees, Speakers Bureau; SECURA BIO: Membership on an entity’s Board of Directors or advisory committees; JANSSEN-CILAG: Membership on an entity’s Board of Directors or advisory committees, Speakers Bureau; BMS: Membership on an entity’s Board of Directors or advisory committees, Speakers Bureau; NOVARTIS: Consultancy, Membership on an entity’s Board of Directors or advisory committees, Speakers Bureau; ADC THERAPEUTICS: Membership on an entity’s Board of Directors or advisory committees; INCYTE: Membership on an entity’s Board of Directors or advisory committees, Speakers Bureau; MSD: Consultancy, Membership on an entity’s Board of Directors or advisory committees, Speakers Bureau; ASTRAZENECA: Membership on an entity’s Board of Directors or advisory committees, Speakers Bureau; TAKEDA: Membership on an entity’s Board of Directors or advisory committees, Speakers Bureau; ROCHE: Membership on an entity’s Board of Directors or advisory committees, Speakers Bureau; EUSAPHARMA: Consultancy, Membership on an entity’s Board of Directors or advisory committees, Speakers Bureau; KYOWA KIRIN: Membership on an entity’s Board of Directors or advisory committees, Speakers Bureau; BEIGENE: Membership on an entity’s Board of Directors or advisory committees, Speakers Bureau. Kim: Sanofi, Beigene, Boryong, Roche, Kyowa-kirin, Donga: Research Funding. Shen: Biogen Digital Health: Current Employment. Marchi: Merck: Research Funding; Celgene/BMS: Research Funding; Astex Pharmaceutical/Myeloid Pharmaceuticals: Research Funding; Dren Bio: Membership on an entity’s Board of Directors or advisory committees, Research Funding; Everest Clinical Research: Other: Data Safety Monitoring Committee. Jain: Mersana Therapeutics: Consultancy, Membership on an entity’s Board of Directors or advisory committees; Myeloid Therapeutics: Consultancy, Membership on an entity’s Board of Directors or advisory committees; SecuraBio: Membership on an entity’s Board of Directors or advisory committees; SIRPant Immunotherapeutics: Consultancy, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Abcuro, Inc: Consultancy, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Daiichi Sankyo: Membership on an entity’s Board of Directors or advisory committees, Research Funding; Crispr Therapeutics: Membership on an entity’s Board of Directors or advisory committees; Acrotech LLC: Research Funding.

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