Development of a Novel Prognostic Score for Relapsed/Refractory Mature T-Cell and NK-Cell Lymphomas (PIRT): Results from a Global Peripheral T-Cell Lymphoma (PETAL) Consortium
Authors: Koh Min Jung , Han Jessy Xinyi , Boussi Leora , Sorial Mark N , McCabe Sean M , Peng Luke , Singh Shambhavi , Eche-Ugwu Ijeoma Julie , Gabler Judith , Fernandez Turizo Maria J. J. , MacVicar Caroline , Garg Aditya , Disciullo Alexander , Chopra Kusha , Lenart Alexandra W , Nwodo Emmanuel , Barnes Jeffrey A. , Koh Min Ji , Miranda Eliana , Chiattone Carlos , Stuver Robert , Horwitz Steven , Merrill Mwanasha H. , Jacobsen Eric D. , Kim Jin Seok , Kim Yu Ri , Cho Jae Yong , Eipe Thomas , Shet Tanuja , Sridhar Epari , Shetty Alok , Saha Saswata , Jain Hasmukh , Sengar Manju , Van Der Weyden Carrie , Prince H. Miles , Hamouche Ramzi , Muradashvili Tinatin , Foss Francine M. , Gentilini Marianna , Casadei Beatrice , Zinzani Pier Luigi , Okatani Takeshi , Yoshida Noriaki , Yoon Sang Eun , Kim Won Seog , Panchoo Girisha , Mohamed Zainab , Verburgh Estelle , Alturas Jackielyn Cuenca , Al Mansour Mubarak , Ford Josie G , Manni Martina , Civallero Monica , Skrypets Tetiana , Federico Massimo , Cabrera Maria Elena , Ku Amy , Bhagat Govind , Ma Helen , Sawas Ahmed , Kariya Khyati , Iwasaki Makoto , Bhanushali Forum , O'Connor Owen A. , Marchi Enrica , Shen Changyu , Shah Devavrat , Jain Salvia 
Published: December 2024

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.