Early time-to-relapse as a predictor of survival in mature T-cell/NK-cell lymphomas: Results from the PETAL consortium
Abstract
Abstract INTRODUCTION We and others have demonstrated that patients with refractory nodal mature T-Cell lymphomas (nMTCL) have worse overall survival (OS) versus relapsed disease.1–3 Among patients who relapse, responses and OS in (nMTCL) remain poor with little data to tailor decision-making based on disease kinetics.1–9 Time-to-relapse (TTR) is a significant predictor of survival and decision-making tool among many other lymphomas,10–18 however a majority of nMTCL patients will relapse prior to 24 months.14 We aimed to characterize how TTR may affect survival and explore differential second-line (2L) therapy effects based on TTR subgroups. METHODS This was a global retrospective cohort study using multiple international cohorts: PETAL (n=1414) and GELL (n=487).1,3,19–21 Two separate independent cohorts validated TTR12 as an OS predictor: an observational U.S. multicenter cohort (n=138) and the phase 3 randomized trial of romidepsin-CHOP versus CHOP.22 Patients with PTCL-NOS, AITL/TFHL, or ALCL with a CR to 1L were included. Patients without progression or 2L within the study period were included as not having TTR12 per landmark methods,11,23–25 and were removed for sensitivity analyses. The primary objective was OS among nMTCL who relapsed or started 2L26 within 12m from 1L (TTR12) versus without TTR12 because nearly half of patients in our cohort and previous studies of nMTCL relapsed within 12m.6,14 The secondary objective was to compare OS among 2L novel agents (NA) versus chemotherapy (CC) in those with and without TTR12. Kaplan-Meier and Cox PH methods were used adjusting for a priori covariates.1,3 The primary analysis was a modified-landmark analysis (m-LM) with OS measured from relapse or 2L start (TTR12 group) or from 12m from 1L start (without TTR12 group) to death. Sensitivity analyses used standard 12m landmark (s-LM; excluded patients who died or lost-to-follow <12m),11,25 and time-dependent Cox (td-Cox; OS 1L start to death). For 2L analyses, OS was measured from 2L start to death. RESULTS A total 452 were included in the final cohort and for td-Cox, 428 in m-LM, and 388 in s-LM. Of the 452 total, 165 (36.5%) had TTR12, 181 (40%) relapsed ≥12m, and 106 (23.5%) never relapsed (total without TTR12: 287 [63.5%]). The median (range) age was 58 (18-89) and 60 (15-92), PTCL-NOS included 47.3% and 43.2%, AITL/TFHL included 35.8% and 32.1%, and ALCL included 16.4% and 24.7% of patients with TTR12 and without TTR12 respectively. Patients received similar frontline regimens and HSCT utilization was comparable. Demographics in the validation cohorts largely mirrored the primary cohort. Using m-LM, TTR12 conferred worse OS (aHR 2.14, 95%CI: 1.58-2.90; p<0.001) overall, irrespective of 1L HSCT or PIT score, and across prespecified subgroups (PTCL-NOS: aHR 2.32, 95%CI: 1.51-3.55; p<0.001, AITL/TFHL: aHR 1.92, 95%CI: 1.15-3.21; p=0.013, ALCL: aHR 3.34, 95%CI: 1.18-9.50; p=0.023, no 2L HSCT: aHR 2.27, 95%CI: 1.63-3.15; p<0.001). TTR12 patients who received any 2L HSCT had similar OS than those without TTR12 (aHR 1.85, 95%CI: 0.73-4.65; p=0.194). When excluding patients that did not relapse, TTR12 still showed poorer OS (aHR 1.60, 95%CI: 1.18-2.18; p=0.003). In the observational validation cohort, TTR12 patients had worse OS across all analyses in both univariate (HR 3.72, 95%CI 1.85-7.46; p<0.001) and multivariate models adjusting for covariates (aHR 3.60, 95%CI 1.77-7.34; p<0.001). In the phase 3 validation cohort, TTR12 patients also had worse OS (aHR 3.71, 95%CI 2.17-6.32; p<0.001). All results were consistent across s-LM and td-Cox sensitivity analyses. TTR12 predicted worse OS in parallel to, and compounding with, PIT score, with patients who had TTR12 and PIT≥2 exhibiting the worst OS. Patients with PIT score of 4 were at a significantly higher odds of developing TTR12 (OR 3.64, 95%CI 1.07-12.38; p=0.038). In TTR12 patients, 2L NA significantly improved OS versus CC (aHR 0.60, 95%CI: 0.37-0.97; p=0.038). In those without TTR12 who received 2L, there were no significant differences in OS with NA versus CC (aHR 0.82, 95%CI 0.51-1.32; p=0.407 CONCLUSION TTR12 consistently exhibited worse OS in nMTCL and highlighted differential responses to 2L, defining a unique risk group after 1L. TTR12 may be a novel endpoint for clinical trials and may better inform treatment decisions upon progression. Prospective validation and correlation with molecular alterations has been initiated and is the focus of the PETAL consortium.
Article Details
Authors (99)
Mark Sorial
1Dana-Farber Cancer Institute, Boston, United States
Kenechukwu Aniagboso
2Massachusetts General Hospital, Boston, United States
Emily Buttermore
2Massachusetts General Hospital, Boston, United States
Matthew Lei
2Massachusetts General Hospital, Boston, United States
Ellen Kendall
2Massachusetts General Hospital, Boston, United States
Kristiana Nasto
2Massachusetts General Hospital, Boston, United States
Min Jung Koh
2Massachusetts General Hospital, Boston, United States
Jessy Xinyi Han
3Massachusetts Institute of Technology, Boston, United States
Leora Boussi
4Memorial Sloan Kettering Cancer Center, New York, United States
Luis Malpica
Brady Beltran
6Hospital Edgardo Rebagliati, Lima, Peru
Laura Korin
7Alexander Fleming Institute, Olivos, Argentina
German Stemmelin
8Hospital Británico de Buenos Aires, Buenos Aires, Argentina
Carlos Chiattone
4Department of Medicine, Santa Casa Medicine School, Sao Paulo, Brazil
Denisse Castro
6Hospital Edgardo Rebagliati, Lima, Peru
Fabiola Valvert
10Liga Nacional Contra el Cancer, Guatamala, Guatemala
Jule Vasquez
11Instituto Nacional de Enfermedades Neoplasicas, Lima, Peru
Henry Quintero
12Universidad Tecnológica de Pereira, Pereira, Colombia
Macarena Roa
13Hospital del Salvador, Santiago, Chile
Alfredo Quiroz
14Hospital Central IPS, Asuncion, Paraguay
Marialejandra Torres Viera
15Clinica Santa Sofia, Caracas, Venezuela
Luis Mario Villela Martinez
16Hospital Fernando Ocaranza, Hermosillo, Mexico
Ana Oliver
4CASMU, Montevideo, Uruguay
Cesar Augusto Samanez Figari
17Hematologic Malignancies Unit, Lima, Peru
Edith Julia
Vincent Camus
19Centre Henri Becquerel, Rouen, France
Catherine Thieblemont
15Assistance Publique–Hôpitaux de Paris, Hôpital Saint-Louis, Hémato-Oncologie and Université Paris Cité, Paris, France
Philippe Gaulard
Laurence de Leval
Franck Morschhauser
Centre Hospitalier Universitaire de Lille, Groupe de Recherche sur les formes Injectables et les Technologies Associées, Lille, France
Emmanuel Bachy
Omar Elghawy
2Division of Hematology and Oncology, University of Pennsylvania, Philadelphia, PA
Stefan Barta
25University of Pennsylvania, Philadelphia, United States
Jack Malespini
2Massachusetts General Hospital, Boston, United States
Kusha Chopra
2Massachusetts General Hospital, Boston, United States
Caroline MacVicar
2Massachusetts General Hospital, Boston, United States
Sean McCabe
2Massachusetts General Hospital, Boston, United States
Luke Peng
26Northeastern University, Boston, United States
Shambhavi Singh
2Massachusetts General Hospital, Boston, United States
Makoto Iwasaki
Ijeoma Eche-Ugwu
1Dana-Farber Cancer Institute, Boston, United States
Judith Gabler
2Massachusetts General Hospital, Boston, United States
Maria J Fernandez
27Beth Israel Deaconess Medical Center, Boston, United States
Alexander Disciullo
2Massachusetts General Hospital, Boston, United States
Josie Ford
2Massachusetts General Hospital, Boston, United States
Alexandra Lenart
2Massachusetts General Hospital, Boston, United States
Emmanuel Nwodo
2Massachusetts General Hospital, Boston, United States
Jeffrey Barnes
23Department of Hematology and Oncology, Harvard Medical School, Massachusetts General Hospital, Boston, MA
Min Ji Koh
2Massachusetts General Hospital, Boston, United States
Eliana Miranda
28University of Campinas, Sao Paulo, Brazil
Robert Stuver
3Lymphoma Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY
Mwanasha Merrill
1Dana-Farber Cancer Institute, Boston, United States
Eric Jacobsen
8Lymphoma Program, Department of Pharmacy, Dana-Farber Cancer Institute, Boston, MA
Martina Manni
29University of Modena and Reggio Emilia, Modena, Italy
Monica Civallero
29University of Modena and Reggio Emilia, Modena, Italy
Tetiana Skrypets
30IRCCS Istituto Tumori Giovanni Paolo II, Bari, Italy
Athina Lymboussaki
29University of Modena and Reggio Emilia, Modena, Italy
Massimo Federico
10CHIMOMO Department, University of Modena and Reggio Emilia, Modena, Italy
Yu Ri Kim
Jin Seok Kim
10Yonsei University College of Medicine, Severance Hospital, Seoul, Korea
Jae Yong Cho
31Gangnam Severance Hospital, Yonsei University School of Medicine, Seoul, Korea
Thomas Eipe
32Tata Memorial Centre, Mumbai, India
Tanuja Shet
Epari Sridhar
32Tata Memorial Centre, Mumbai, India
Alok Shetty
32Tata Memorial Centre, Mumbai, India
Saswata Saha
32Tata Memorial Centre, Mumbai, India
Manju Sengar
32Tata Memorial Centre, Mumbai, India
Hasmukh Jain
11Hematolymphoid Unit, Department of Medical Oncology, Tata Memorial Centre, Homi Bhabha National Institute, Mumbai, India
Carrie Van Der Weyden
Peter MacCallum Cancer Centre, Melbourne, Australia
H. Miles Prince
15Clinical Hematology, Epworth HealthCare and University of Melbourne, Melbourne, VIC, Australia
Ramzi Hamouche
34Yale Cancer Center, New Haven, United States
Tinatin Muradashvili
34Yale Cancer Center, New Haven, United States
Francine Foss
Marianna Gentilini
35IRCCS Azienda Ospedaliero-Universitaria di Bologna Istituto di Ematologia “Seràgnoli”, Balogna, Italy
Beatrice Casadei
35IRCCS Azienda Ospedaliero-Universitaria di Bologna Istituto di Ematologia “Seràgnoli”, Balogna, Italy
Pier Luigi Zinzani
12IRCCS Azienda Ospedaliero-Universitaria di Bologna, Istituto di Ematologia “Seràgnoli,” Dipartimento di Scienze Mediche e Chirurgiche, Università di Bologna, Bologna, Italy
Takeshi Okatani
16Department of Hematology, Hiroshima Red Cross Hospital and Atomic-bomb Survivors Hospital, Hiroshima, Japan
Noriaki Yoshida
37Radiation Effects Research Foundation, Hiroshima, Japan
Sang Eun Yoon
Won-Seog Kim
17Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
Girisha Panchoo
39University of Cape Town and Groote Schuur Hospital, Cape Town, South Africa
Zainab Mohamed
39University of Cape Town and Groote Schuur Hospital, Cape Town, South Africa
Estelle Verburgh
18Department of Medicine, University of Cape Town and Groote Schuur Hospital, Cape Town, South Africa
Jackielyn Cuenca Alturas
40King Abdulaziz Medical City, Jeddah, Saudi Arabia
Mubarak Al Mansour
40King Abdulaziz Medical City, Jeddah, Saudi Arabia
Maria Elena Cabrera
20Hematology Department, Hospital del Salvador, University of Chile, Santiago, Chile
Govind Bhagat
Helen Ma
43University of California, Irvine, VA Long Beach Health System, Long Beach, United States
Ahmed Sawas
42Columbia University Irving Medical Center, New York, United States
Dhruv Mistry
2Massachusetts General Hospital, Boston, United States
Khyati Kariya
2Massachusetts General Hospital, Boston, United States
Forum Bhanushali
2Massachusetts General Hospital, Boston, United States
Maya Krishnan
2Massachusetts General Hospital, Boston, United States
Erica Lee
2Massachusetts General Hospital, Boston, United States
Owen O'Conner
44University of Virginia, Charlottesville, United States
Enrica Marchi
1University of Virginia Comprehensive Cancer Center, University of Virginia, Charlottesville, VA
Devavrat Shah
Changyu Shen
Salvia Jain
2Jon and Jo Ann Hagler Center for Lymphoma, Massachusetts General Hospital Cancer Center, Boston, MA