The CNS relapse in T-cell lymphoma index predicts CNS relapse in patients with T- and NK-cell lymphomas

Abstract

Little is known about risk factors for central nervous system (CNS) relapse in mature T-cell and natural killer cell neoplasms (MTNKNs). We aimed to describe the clinical epidemiology of CNS relapse in patients with MTNKN and developed the CNS relapse In T-cell lymphoma Index (CITI) to predict patients at the highest risk of CNS relapse. We reviewed data from 135 patients with MTNKN and CNS relapse from 19 North American institutions. After exclusion of leukemic and most cutaneous forms of MTNKNs, patients were pooled with non-CNS relapse control patients from a single institution to create a CNS relapse-enriched training set. Using a complete case analysis (n = 182), including 91 with CNS relapse, we applied a least absolute shrinkage and selection operator Cox regression model to select weighted clinicopathologic variables for the CITI score, which we validated in an external cohort from the Swedish Lymphoma Registry (n = 566). CNS relapse was most frequently observed in patients with peripheral T-cell lymphoma, not otherwise specified (25%). Median time to CNS relapse and median overall survival after CNS relapse were 8.0 and 4.7 months, respectively. We calculated unique CITI risk scores for individual training set patients and stratified them into risk terciles. Validation set patients with low-risk (n = 158) and high-risk (n = 188) CITI scores had a 10-year cumulative risk of CNS relapse of 2.2% and 13.4%, respectively (hazard ratio, 5.24; 95% confidence interval, 1.50-18.26; P = .018). We developed an open-access web-based CITI calculator (https://redcap.link/citicalc) to provide an easy tool for clinical practice. The CITI score is a validated model to predict patients with MTNKN at the highest risk of developing CNS relapse.

Graphical abstract

Figure 1.

Flowchart of patient selection for study. Contributing sites are shown in supplemental Table 1.

Figure 2.

MTNKN subtypes with CNS relapse and outcomes. (A) Frequency of MTNKN subtypes is depicted with number of patients displayed above each bar. Kaplan-Meier estimates for PFS and OS after initial diagnosis are shown in panels B and C, respectively. Four patients were excluded from PFS calculation due to absence of data on time to initial progression. Cumulative incidence of CNS relapse and OS after CNS relapse are shown by reverse and standard Kaplan-Meier estimate in panels D and E-F, respectively. Median OS after CNS relapse is indicated by dashed line (F). For all Kaplan-Meier curves, hashmarks denote censored patients, and shading indicates 95% CI. AITL, angioimmunoblastic T-cell lymphoma; ALKu, ALK status unknown; ANKL, aggressive NK-cell lymphoma; ATLL, adult T-cell leukemia/lymphoma; CLD-NK, chronic lymphoproliferative disorder of NK-cells; HSTCL, hepatosplenic T-cell lymphoma; MEITL, monomorphic epitheliotropic intestinal T-cell lymphoma; T-IOL, T-cell intraocular lymphoma; T-LGL, T-cell large granular lymphocytic leukemia; T-PLL, T-cell prolymphocytic leukemia; TCL, T-cell lymphoma; TFH-TCL, T-follicular helper T-cell lymphoma.

Figure 3.

Cumulative incidence of CNS relapse stratified by CITI risk group. Cumulative incidence of CNS relapse in training set (A) and validation set (B) is depicted by reverse Kaplan-Meier curve, stratified by CITI risk group. Reverse Kaplan-Meier curve for validation set without scaled y-axis is shown in top-left panel inset. For all Kaplan-Meier curves, hashmarks denote censored patients, and shading indicates 95% CI. Log-rank P values for trend are shown above the Kaplan-Meier curves. Cumulative risk, HRs with 95% CI, and Holm-Bonferroni adjusted P values for pairwise risk group comparisons are depicted in tables beneath Kaplan-Meier curves. Low-risk groups were used as reference values for training and validation sets.