The variability in global access to medications and treatment practices make it challenging to evaluate the benefits of contemporary therapies for patients with relapsed and refractory (R/R) mature T-cell and NK-cell lymphomas (MTCL and MNKCL). While numerous prognostic factors and models have been suggested to categorize the risk levels of patients with MTCL and MNKCL, they have primarily been developed for newly diagnosed patients. On the other hand, for the common subtypes of R/R MTCL and MNKCL patients, the identification of risk factors and subgroups that lead to variability in treatment outcomes and overall survival (OS) is still not well established. Thus, a new prognostic model is needed to further refine subgroups with varied outcomes in R/R patients.

We conducted an international retrospective cohort study of 925 patients with R/R MTCL and MNKCL diagnosed between Jan 2010 and Sept 2021 who received either “novel” single agent (SA) or cytotoxic chemotherapy (CC) for second line treatment from 13 institutions representing 10 countries. We first split our global cohort of 763 patients with second line treatment details into a training set (80%) and a testing set (20%). Among the 21 available demographics, histological, laboratory, radiologic non-treatment characteristics, we identified 11 variables on univariable analysis to be associated with inferior OS from the start of second-line treatment. Based on the step-by-step selection in multivariable Cox regression (MVC) and clinical considerations, our final model that combined 6 of the 11 features was chosen based on the highest Concordance index (C-index) among the models that incorporated covariates retaining an independent prognostic value (p £ 0.05 in the testing set. The six variables in the final model included age being greater than 60, primary refractory disease in contrast to relapsed, histological subtypes other than AITL, extranodal sites greater than 1, Ki-67 proliferation index (%) being 40 or greater, and absolute lymphocyte count around diagnosis being lower than Lower Limit of Normal (LLN).

We then created a new prognostic index for R/R TCL (PIRT) score to estimate OS from start of second-line treatment, which ranged from 0 to 6. We assigned a score of 1 to each unfavorable feature since the relative risks associated with each of these 6 factors are similar. When patients were initially categorized into 6 subgroups, we observed a clear declining trend of OS with an increasing score. Patients were stratified into 3 final risk group: low- (0-1 risk factor), intermediate- (2-3 risk factors), or high- (3-4 risk factors) groups, which showed notable similarity between their predicted and actual survival. In the training set, the median 3-yr OS for the low-risk group was 75.2% (95% CI: 29.7 - 85.2) vs intermediate-risk group (50.6%, 95% CI: 37.7 - 58.9) vs the high-risk group (16%, 95% CI: 7.7 - 26.9). The three risk groups were also segregated in the testing set with disparate 3-yr OS with low-risk (57.1%, 95% CI: 17.1 - 83.7) vs intermediate-risk (23.3%, 95% CI: 8.7 - 41.9) vs the high-risk (7.0%, 95% CI: 0.4 - 26.9). An analysis of 1000 bootstrapped testing sets showed that our PIRT score achieved a higher prediction probability with an average C-index of 0.7 (95% CI: 0.63 - 0.76) compared to IPI (0.56, 95% CI: 0.5 - 0.63) and PIT (0.59, 95% CI: 0.52 - 0.65). The paired t-tests between IPI vs. PIRT and PIT vs. PIRT scores confirmed the statistical significance of this performance difference. We also validated our prognostic model's survival prediction power in an independent multicenter study cohort and developed a web-based calculator for healthcare professionals to use: Website for PIRT Score Calculator

In summary, we developed a new prognostic scoring system for patients with R/R MTCL and MNKCL that was validated in training, testing and independent datasets that has enabled their segregation and has the potential to facilitate clinical decision.

Disclosures

Sorial:Daiichi Sankyo: Research Funding; SecuraBio: Research Funding; The Dedham Group: Consultancy; MJH Life Sciences: Honoraria. Stuver:Pfizer: Research Funding. Horwitz:Auxilius Pharma, Abcuro Inc., Corvus, Daiichi Sankyo, DrenBio, Farallon Capital Management, L.L.C., Kyowa Hakko Kirin, March Bio, Neovii Pharmaceuticals AG, ONO Pharmaceuticals, Pfizer, SecuraBio, SymBio, Treeline Bio and Takeda Pharmaceuticals.: Consultancy; Auxilius Pharma, Abcuro Inc., Corvus, CTI BioPharma Corp, Daiichi Sankyo, DrenBio, Kyowa Hakko Kirin, March Bio, ONO Pharmaceuticals, Pfizer, SecuraBio, SymBio and Takeda Pharmaceuticals.: Honoraria; ADC Therapeutics, Affimed, Celgene, Crispr Therapeutics, Daiichi Sankyo, Kyowa Hakko Kirin, Takeda, Seattle Genetics, Trillium Therapeutics, and SecuraBio.: Research Funding. Jacobsen:AstraZeneca: Consultancy; Merck: Consultancy; Pharmacyclics: Consultancy; F. Hoffman-LaRoche: Consultancy; Novartis: Consultancy; Takeda: Consultancy; Ascerta: Consultancy. Kim:Roche: Other: All authors received support for third-party writing assistance, furnished by Akshaya Srinivasan, PhD, CMPP, of Nucleus Global, an Inizio company, and funded by F. Hoffmann-La Roche Ltd, Basel, Switzerland.. Van Der Weyden:Kyowa Kirin: Consultancy. Prince:AbbVie: Research Funding; Takeda: Honoraria; Mallinckrodt: Honoraria; Johnson and Johnson: Honoraria; Amgen: Honoraria; Kyowa Kirin: Honoraria; Bristol Myers Squibb: Honoraria; GSK: Honoraria. Zinzani:MSD, EUSAPHARMA, NOVARTIS: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; SECURA BIO, ADC Therap, Sandoz: Membership on an entity's Board of Directors or advisory committees; CELLTRION, GILEAD, JANSSEN-CILAG, BMS, SERVIER, ASTRAZENECA, TAKEDA, ROCHE, KYOWA KIRIN, Incyte, Beigene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Kim:Kyowa-Kirin: Research Funding; Boryong: Research Funding; BeiGene: Research Funding; Sanofi: Research Funding; F. Hoffmann-La Roche Ltd: Research Funding; Donga: Research Funding. Verburgh:MSD: Research Funding; Takeda: Honoraria; Roche: Honoraria; NIH: Research Funding; CANSA: Research Funding; South African Stem Cell Transplantation Society: Membership on an entity's Board of Directors or advisory committees. Ford:Moderna: Current equity holder in publicly-traded company. Sawas:Flatiron Health Inc.: Current Employment, Current equity holder in publicly-traded company; Seagen: Honoraria; Lilly: Honoraria; Kite: Honoraria; Daiichi: Honoraria. O'Connor:Merck: Research Funding; BMS: Research Funding; Acrotec: Honoraria, Other: Advisor; Myeloid Therapeutics: Current equity holder in publicly-traded company, Honoraria; Dren Bio: Current equity holder in publicly-traded company; Kymera: Current equity holder in publicly-traded company, Honoraria, Other: Scientific advisory board. Marchi:Dren Bio: Consultancy, Research Funding; Seagen: Honoraria; Kymera Therapeutics: Consultancy, Research Funding; U.S. Patent Application Serial No. 18/701,581: Patents & Royalties: U.S. Patent Application Serial No. 18/701,581; Kyowa Kirin: Honoraria; Vittoria Biotherapeutics: Consultancy; Everest Clinical Research: Consultancy; Acrotech: Honoraria; Celgene/BMS: Research Funding; Merck: Research Funding. Shen:Biogen Digital Health: Current Employment. Jain:Kyowakirin: Research Funding; Acrotech: Membership on an entity's Board of Directors or advisory committees, Research Funding; 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; Mersana Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Daiichi Sankyo: Membership on an entity's Board of Directors or advisory committees, Research Funding; SecuraBio: Membership on an entity's Board of Directors or advisory committees, Research Funding; Myeloid Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Crispr therapeutics: Membership on an entity's Board of Directors or advisory committees.

Off Label Disclosure:

There is no established standard of care in relapsed or refractorymature T and NK cell neoplasms. Agents reported in thisobservational study may have been used off-label as part of clinicalpractice.

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2024
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