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. 2025 Feb 11;9(3):583-602.
doi: 10.1182/bloodadvances.2024014674.

Global outcomes and prognosis for relapsed/refractory mature T-cell and NK-cell lymphomas: results from the PETAL consortium

Jessy Xinyi Han  1 , Min Jung Koh  2 , Leora Boussi  3 , Mark Sorial  4 , Sean M McCabe  4 , Luke Peng  5 , Shambhavi Singh  6 , Ijeoma Julie Eche-Ugwu  7   8   9 , Judith Gabler  4 , Maria J Fernandez Turizo  8 , Caroline T MacVicar  4 , Aditya Garg  4 , Alexander Disciullo  4 , Kusha Chopra  4 , Alexandra Lenart  4 , Emmanuel Nwodo  4 , Jeffrey Barnes  4   9 , Min Ji Koh  2   4 , Eliana Miranda  10 , Carlos Chiattone  11 , Robert Stuver  12 , Steven M Horwitz  12 , Mwanasha Merrill  7 , Eric Jacobsen  7   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 , Epari Sridhar  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 , Josie Ford  4 , Maria Elena Cabrera  29 , Amy Ku  30 , Govind Bhagat  30 , Helen Ma  31 , Ahmed Sawas  30 , Khyati Maulik Kariya  4 , Makoto Iwasaki  4 , Forum Bhanushali  4 , Owen A O'Connor  32 , Enrica Marchi  32 , Changyu Shen  33 , Devavrat Shah  1 , Salvia Jain  4   9   34
Affiliations

Global outcomes and prognosis for relapsed/refractory mature T-cell and NK-cell lymphomas: results from the PETAL consortium

Jessy Xinyi Han et al. Blood Adv. .

Abstract

Variances in global access to drugs and treatment practices make it challenging to understand the benefit of contemporary therapies in patients with relapsed and refractory (R/R) mature T-cell and natural killer-cell lymphomas (MTCL and MNKCL). We conducted an international retrospective cohort study of 925 patients with R/R MTCL and MNKCL. In peripheral T-cell lymphoma-not otherwise specified and anaplastic lymphoma kinase-negative anaplastic large cell lymphoma (ALK- ALCL), patients with relapsed lymphoma demonstrated a superior median overall survival (OS) relative to refractory from the time of second-line treatment. We identified several independent predictors of OS for R/R lymphoma including age >60 years, primary refractory disease, histological subtype other than angioimmunoblastic T-cell lymphoma (AITL), extranodal sites >1, Ki67 ≥40%, and absolute lymphocyte count less than the lower limit of normal. A multivariable model incorporating these formed the basis for a prognostic index for R/R TCL, in which patients are stratified into low-risk (0-1 risk factor), intermediate-risk (2-3 risk factors), or high-risk (≥4 risk factors) groups, which were associated with 3-year OS of 57.14%, 23.3%, and 7%, respectively. Patients received either a "novel" single agent (SA; 35%) or cytotoxic chemotherapy (CC; 60%) for their second-line treatment. Higher progression-free survival was observed with SA over CC for the entire cohort with a higher 3-year OS in AITL and ALK- ALCL. Among the SA, small-molecule inhibitors demonstrated OS advantage relative to CC in AITL. Our results highlight continued efficacy of novel drugs globally and the potential of a new prediction model in informing heterogeneous prognosis within the R/R population of MTCL and MNKCL.

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Conflict of interest statement

Conflict-of-interest disclosure: C.C. treports honoraria and consultancy fees from Roche, AbbVie, Janssen, AstraZeneca (AZ), Eli Lilly and Company (Lylli), and Takeda. S.M.H. reports consultancy fees from ONO Pharmaceuticals, Tubulis, Abcuro Inc, Cimieo Therapeutics, Auxilius Pharma, Secura Bio, Shoreline Biosciences, Inc, and Yingli Pharma Limited; research funding from Affimed, Celgene, ADC Therapeutics, Millenium, CRISPR Therapeutics, Seattle Genetics, and Verastem/Secura Bio; and consultancy fees and research funding from Daiichi Sankyo, Trillium Therapeutics, Kyowa Hakko Kirin, and Takeda. E.J. reports research funding from Celgene, Pharmacyclics, and Hoffmann-LaRoche; honoraria and research funding from Merck; honoraria from Daiichi, Bristol Myers Squibb (BMS), and Bayer; and patents and royalties with UpToDate. H.J. reports research funding from ImmunoACT, Zydus Pharmaceuticals, and Intas Pharmaceuticals. C.V.D.W. reports ending employment in the past 24 months and membership on an entity's board of directors or advisory committees of Cartherics Pty Ltd. H.M.P. reports speakers bureau fees from Takeda, Merck, Mallinkrodt, and Mundipharma. F.F. reports honoraria from Secura Bio, Daiichi Sankyo, Kyowa, Conjupro, and Astex; and speakers bureau fees from Seagen and Acrotech. B.C. reports membership on an entity's board of directors or advisory committees in Kite-Gilead, AbbVie, Janssen, Celgene-BMS, BeiGene, and Takeda; and speakers bureau fees from Kite-Gilead, AbbVie, Janssen, Novartis, Lilly, and Roche. P.L.Z. reports membership on an entity's board of directors or advisory committees in Servier, Celltrion, Sandoz, Gilead, Secura Bio, Janssen-Cilag, BMS, Novartis, Antibody-drug conjugate (ADC) Therapeutics, Incyte, AstraZeneca, Merck Sharp & Dohme (MSD), EUSA Pharma, Takeda, Roche, Kyowa Kirin, and BeiGene; speakers bureau fees from Servier, Celltrion, Gilead, Janssen-Cilag, BMS, Novartis, Incyte, AstraZeneca, MSD, Takeda, Roche, EUSA Pharma, Kyowa Kirin, and BeiGene; and consultancy fees from Novartis, MSD, and EUSA Pharma. W.-S.K. reports research funding from Sanofi, BeiGene, Boryong, Roche, Kyowa Kirin, and Donga. E.V. reports research funding from MSD. C.S. reports current employment with Biogen Digital Health. E. Marchi reports research funding from Merck, Celgene/BMS, Astex Pharmaceutical/Myeloid Pharmaceuticals, and Dren Bio; membership on an entity's board of directors or advisory committees in Dren Bio; and other interests including data safety monitoring committee fees from Everest Clinical Research. S.J. reports consultancy fees from Mersana Therapeutics, Myeloid Therapeutics, SIRPant Immunotherapeutics, and Abcuro Inc; membership on an entity's board of directors or advisory committees in Mersana Therapeutics, Myeloid Therapeutics, SIRPant Immunotherapeutics, Abcuro Inc, Secura Bio, Daiichi Sankyo, and CRISPR Therapeutics; and research funding from Daiichi Sankyo, SIRPant Immunotherapeutics, Acrotech Limited Liability Company (LLC), and Abcuro Inc. The remaining authors declare no competing financial interests.

Figures

None
Graphical abstract
Figure 1.
Figure 1.
Study flowchart CONSORT diagram.
Figure 2.
Figure 2.
OS for relapsed and primary refractory (R/R) patients with MTCL and MNKCL stratified by histological subtype comparing relapsed vs primary refractory disease. (A-E) Kaplan-Meier curves show OS estimates since the start of second-line treatment for patients with PTCL-NOS (A), AITL (B), ENKTCL (C), ALK+ ALCL (D), and ALK– ALCL (E). Results depicted apply to the global data set of 763 patients for whom information on the start of second-line treatment was available. P values calculated by log-rank test. Prim. Refrac., primary refractory.
Figure 3.
Figure 3.
Cox proportional hazards regression analysis for OS from risk-defining events of patients with relapsed and primary refractory (R/R) MTCL and MNKCL. Forest plot of univariable and multivariable analysis for risk factors associated with survival. (A) Univariable analysis performed systematically on 21 clinically relevant factors on the global training and test data sets and C-index reported. The 6 features used in the final multivariable model are highlighted in red. (B) Final multivariable model selected based on the highest training C-index among the models that incorporated covariates retaining an independent prognostic value (P ≤ .05). Included covariates were age >60 years, primary refractory, not AITL subtype, >1 extranodal site involvement, Ki67 ≥40%, and ALC less than LLN. ALC, absolute lymphocyte count; β2M, beta-2 microglobulin; CRP, C-reactive protein; ECOG, Eastern Cooperative Oncology Group; IgG, Immunoglobulin G; LLN, lower limit of normal; Tx, treatment; ULN, upper limit of normal.
Figure 4.
Figure 4.
Risk stratification and OS by number of PIRT risk factors in the training, test, and validation cohorts. (A-B) Risk stratification and OS by number of PIRT score risk factors in the training cohort. (C-D) OS by PIRT score categorized risk group in the test and validation cohorts.
Figure 5.
Figure 5.
OS for relapsed and primary refractory (R/R) patients with MTCL and MNKCL stratified by histological subtype comparing second-line treatment with CC vs “novel” SA. Kaplan-Meier curves show OS estimates since the start of second-line treatment for patients with PTCL-NOS (A), AITL (B), ENKTCL (C), ALK+ ALCL (D), and ALK– ALCL (E). Results depicted apply to the global data set of 763 patients for whom information on start dates of second-line treatment was available. P values calculated by log-rank test.
Figure 5.
Figure 5.
OS for relapsed and primary refractory (R/R) patients with MTCL and MNKCL stratified by histological subtype comparing second-line treatment with CC vs “novel” SA. Kaplan-Meier curves show OS estimates since the start of second-line treatment for patients with PTCL-NOS (A), AITL (B), ENKTCL (C), ALK+ ALCL (D), and ALK– ALCL (E). Results depicted apply to the global data set of 763 patients for whom information on start dates of second-line treatment was available. P values calculated by log-rank test.
Figure 6.
Figure 6.
Survival for relapsed and primary refractory (R/R) patients with MTCL and MNKCL who had response to second-line treatment (complete response + partial response + stable disease) comparing second-line treatment with CC vs “novel” SA with and without HSCT. Kaplan-Meier curves show survival estimates. (A) PFS since the start of second-line treatment to the start of third-line therapy, death, or lost to follow-up without counting HSCT as an event or a censoring event. (B) PFS since the start of second-line treatment to the start of third-line therapy, death, or lost to follow-up but counting HSCT as an event. (C) PFS since the start of second-line treatment to transplant, start of third-line therapy, death, or lost to follow-up with the counting of HSCT as a censoring event. (D) OS since the start of second-line treatment to death or lost to follow-up, stratified by HSCT vs no HSCT. Results depicted apply to the global data set of 397 patients for whom information on the start of second-line treatment was available and had response to second-line treatment. P values calculated by log-rank test.
Figure 7.
Figure 7.
OS for relapsed and refractory (R/R) patients with MTCL and MNKCL stratified by histological subtype comparing second-line treatment with CC or a “novel” SA, which includes EM, ADC, AF, SMI, or a mAb. Kaplan-Meier curves show OS estimates since start of second-line treatment for patients with PTCL-NOS (A), AITL (B), ENKTCL (C), ALK+ ALCL (D) and, ALK– ALCL (E). Results depicted apply to the global data set of 763 patients for whom information on the start of second-line treatment was available. P values calculated by log-rank test. mAb, monoclonal antibody.
Figure 7.
Figure 7.
OS for relapsed and refractory (R/R) patients with MTCL and MNKCL stratified by histological subtype comparing second-line treatment with CC or a “novel” SA, which includes EM, ADC, AF, SMI, or a mAb. Kaplan-Meier curves show OS estimates since start of second-line treatment for patients with PTCL-NOS (A), AITL (B), ENKTCL (C), ALK+ ALCL (D) and, ALK– ALCL (E). Results depicted apply to the global data set of 763 patients for whom information on the start of second-line treatment was available. P values calculated by log-rank test. mAb, monoclonal antibody.
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