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

Journal: British journal of haematology
Published Date: May 1, 2025

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.

Authors

  • Mark N Sorial
    Massachusetts General Hospital Cancer Center, Boston, Massachusetts, USA.
  • Jessy Xinyi Han
    Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.
  • Min Jung Koh
    Georgetown University School of Medicine, Washington, DC, USA.
  • Leora Boussi
    Department of Hematology and Medical Oncology, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
  • Sijia Li
    Department of Nephrology, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Southern Medical University, Guangdong, 510000, China.
  • Rui Duan
    Department of Biostatistics and Epidemiology, University of Pennsylvania, Philadelphia, PA, USA.
  • Junwei Lu
    School of Electrical and Automation Engineering, Nanjing Normal University, Nanjing 210042, China.
  • Matthew M Lei
    Massachusetts General Hospital Cancer Center, Boston, Massachusetts, USA.
  • Caroline T MacVicar
    Massachusetts General Hospital Cancer Center, Boston, Massachusetts, USA.
  • Jessica Freydman
    Massachusetts General Hospital Cancer Center, Boston, Massachusetts, USA.
  • Jack Malespini
    Massachusetts General Hospital Cancer Center, Boston, Massachusetts, USA.
  • Kenechukwu N Aniagboso
    Massachusetts General Hospital Cancer Center, Boston, Massachusetts, USA.
  • Sean M McCabe
    Massachusetts General Hospital Cancer Center, Boston, Massachusetts, USA.
  • Luke Peng
    Department of Radiation Oncology, Johns Hopkins University School of Medicine, Baltimore, MD.
  • Shambhavi Singh
    Massachusetts General Hospital Cancer Center, Boston, Massachusetts, USA.
  • Makoto Iwasaki
    Massachusetts General Hospital Cancer Center, Boston, Massachusetts, USA.
  • Ijeoma Julie Eche-Ugwu
    Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
  • Judith Gabler
    Massachusetts General Hospital Cancer Center, Boston, Massachusetts, USA.
  • Maria J Fernandez Turizo
    Department of Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA.
  • Aditya Garg
    Massachusetts General Hospital Cancer Center, Boston, Massachusetts, USA.
  • Alexander Disciullo
    Massachusetts General Hospital Cancer Center, Boston, Massachusetts, USA.
  • Kusha Chopra
    Massachusetts General Hospital Cancer Center, Boston, Massachusetts, USA.
  • Josie Ford
    Massachusetts General Hospital Cancer Center, Boston, Massachusetts, USA.
  • Alexandra Lenart
    Massachusetts General Hospital Cancer Center, Boston, Massachusetts, USA.
  • Emmanuel Nwodo
    Massachusetts General Hospital Cancer Center, Boston, Massachusetts, USA.
  • Jeffrey Barnes
    Massachusetts General Hospital Cancer Center, Boston, Massachusetts, USA.
  • Min Ji Koh
    Massachusetts General Hospital Cancer Center, Boston, Massachusetts, USA.
  • Eliana Miranda
    University of Campinas - UNICAMP, Hematology and Hemotherapy Center, Statistical and Data Center, Sao Paulo, Sao Paulo, Brazil.
  • Carlos Chiattone
    Department of Medicine, Santa Casa Medicine School, Sao Paulo, Brazil.
  • Robert Stuver
    Lymphoma Service, Medical Oncology, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
  • Mwanasha Merrill
    Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
  • Eric Jacobsen
    Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
  • Martina Manni
    Department of Medical and Surgical Sciences for Children and Adults, University of Modena and Reggio Emilia, Modena, Italy.
  • Monica Civallero
    CHIMOMO Department, University of Modena and Reggio Emilia, Modena, Italy.
  • Tetiana Skrypets
    Hematology and Cell Therapy Department, IRCCS Istituto Tumori Giovanni Paolo II, Bari, Italy.
  • Athina Lymboussaki
    Department of Medical and Surgical Sciences for Children and Adults, University of Modena and Reggio Emilia, Modena, Italy.
  • Massimo Federico
    CHIMOMO Department, University of Modena and Reggio Emilia, Modena, Italy.
  • Yuri Kim
    Department of Nutritional Science and Food Management, Ewha Womans University, Seoul, 03760, Korea.
  • Jin Seok Kim
    Department of Medicine, Gangnam Severance Hospital, Yonsei University School of Medicine, Seoul, Republic of Korea.
  • Jae Yong Cho
    Department of Medicine, Gangnam Severance Hospital, Yonsei University School of Medicine, Seoul, Republic of Korea.
  • Thomas Eipe
    Tata Memorial Centre, Homi Bhabha National Institute, Mumbai, India.
  • Tanuja Shet
    Tata Memorial Centre, Homi Bhabha National Institute, Mumbai, India.
  • Sridhar Epari
    Department of Pathology, Tata Memorial Centre, Mumbai 400012, India.
  • Alok Shetty
    Tata Memorial Centre, Homi Bhabha National Institute, Mumbai, India.
  • Saswata Saha
    Tata Memorial Centre, Homi Bhabha National Institute, Mumbai, India.
  • Hasmukh Jain
    Adult Haematolymphoid Disease Management Group, Tata Memorial Centre, Mumbai, Maharashtra, India.
  • Manju Sengar
    Adult Haematolymphoid Disease Management Group, Tata Memorial Centre, Mumbai, Maharashtra, India.
  • Carrie Van Der Weyden
    Sir Peter MacCallum Department of Hematology and Oncology and University of Melbourne, Parkville, Australia.
  • Henry Miles Prince
    Sir Peter MacCallum Department of Hematology and Oncology and University of Melbourne, Parkville, Australia.
  • Ramzi Hamouche
    Department of Hematology, Yale Cancer Center, New Haven, Connecticut, USA.
  • Tinatin Muradashvili
    Department of Hematology, Yale Cancer Center, New Haven, Connecticut, USA.
  • Francine Foss
    Department of Hematology, Yale Cancer Center, New Haven, Connecticut, USA.
  • Marianna Gentilini
    IRCCS Azienda Ospedaliero-Universitaria di Bologna Istituto di Ematologia "Seràgnoli", Bologna, Italy.
  • Beatrice Casadei
    IRCCS Azienda Ospedaliero-Universitaria di Bologna Istituto di Ematologia "Seràgnoli", Bologna, Italy.
  • Pier Luigi Zinzani
    IRCCS Azienda Ospedaliero-Universitaria di Bologna Istituto di Ematologia "Seràgnoli", Bologna, Italy.
  • Takeshi Okatani
    Department of Hematology, Hiroshima Red Cross Hospital and Atomic-bomb Survivors Hospital, Hiroshima, Japan.
  • Noriaki Yoshida
    Department of Clinical Studies, Radiation Effects Research Foundation, Hiroshima, Japan.
  • Sang Eun Yoon
    Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea.
  • Won-Seog Kim
    Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea.
  • Girisha Panchoo
    Department of Pathology, University of Cape Town and Groote Schuur Hospital, Cape Town, South Africa.
  • Zainab Mohamed
    Department of Radiation Oncology, University of Cape Town and Groote Schuur Hospital, Cape Town, South Africa.
  • Estelle Verburgh
    Department of Medicine, University of Cape Town and Groote Schuur Hospital, Cape Town, South Africa.
  • Jackielyn Cuenca Alturas
    Department of Medicine, King Abdulaziz Medical City, Jeddah, Saudi Arabia.
  • Mubarak Al-Mansour
    Department of Medicine, King Abdulaziz Medical City, Jeddah, Saudi Arabia.
  • Maria Elena Cabrera
    Hematology Department, Hospital del Salvador, University of Chile, Santiago, Chile.
  • Amy Ku
    Department of Pathology and Cell Biology, Columbia University Irving Medical Center, New York, New York, USA.
  • Govind Bhagat
    Columbia University Medical Center, Department of Medicine - Celiac Disease Center, New York, USA; Columbia University Medical Center, Department of Pathology and Cell Biology, New York, USA.
  • Helen Ma
    University of California, Irvine, VA Long Beach Health System, Long Beach, California, USA.
  • Ahmed Sawas
    Division of Hematology/Oncology, Department of Medicine, Columbia University Irving Medical Center, New York, New York, USA.
  • Khyati Maulik Kariya
    Massachusetts General Hospital Cancer Center, Boston, Massachusetts, USA.
  • Forum Bhanushali
    Massachusetts General Hospital Cancer Center, Boston, Massachusetts, USA.
  • Arushi Meharwal
    Massachusetts General Hospital Cancer Center, Boston, Massachusetts, USA.
  • Dhruv Mistry
    Massachusetts General Hospital Cancer Center, Boston, Massachusetts, USA.
  • Maria Kosovsky
    Massachusetts General Hospital Cancer Center, Boston, Massachusetts, USA.
  • Mesrob Yeterian
    Department of Medicine, New York Presbyterian Brooklyn Methodist Hospital, New York, New York, USA.
  • Owen A O'Connor
    Program for T-Cell Lymphoma Research, University of Virginia, Charlottesville, Virginia, USA.
  • Enrica Marchi
    Program for T-Cell Lymphoma Research, University of Virginia, Charlottesville, Virginia, USA.
  • Changyu Shen
    School of Materials Science and Engineering, Key Laboratory of Materials Processing and Mold (Zhengzhou University), Ministry of Education, Zhengzhou University, Zhengzhou 450001, China.
  • Devavrat Shah
    Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.
  • Salvia Jain
    Massachusetts General Hospital Cancer Center, Boston, Massachusetts, USA.

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