Utility of the Central Nervous System International Prognostic Index (CNS-IPI) in Patients with Primary Mediastinal B-Cell Lymphoma Treated with Rituximab-Containing Chemoimmunotherapy

Introduction: Central nervous system (CNS) relapse is a rare, but devastating event in primary mediastinal B-cell lymphoma (PMBCL). Historically, CNS recurrence occurred in ~2% of patients. However, large scale studies in the rituximab era have not been performed and there is limited information on specific risk factors. The CNS-international prognostic index (CNS-IPI) is a validated CNS risk model for diffuse large B-cell lymphoma (DLBCL) incorporating 6 risk factors, including the standard IPI factors, in addition to renal and/or adrenal involvement. The CNS-IPI risk can identify a high-risk group (≥4 risk factors) with a CNS relapse risk of ≥10%. However, as a separate entity, PMBCL was not included.

Methods: All patients (pts) age ≥18 years with a new clinico-pathological diagnosis of PMBCL, treated with curative intent rituximab (R)-containing chemoimmunotherapy, between January 1, 2001 and December 31, 2022 were identified through the BC Cancer Centre for Lymphoid Cancer Database. The CNS-IPI, incorporating age (>60 years), stage (III/IV), ECOG performance status (PS) (≥2), number of extranodal sites (>1), elevated LDH, and renal/adrenal involvement, was determined to stratify pts into low risk (0-1 factors), intermediate risk (2-3 factors), and high risk (≥4 factors) groups. The cumulative incidence of CNS relapse was estimated using a competing risk analysis with the R package cmprsk, accounting for death from any cause as a competing event.

Results: In total, 244 pts were identified. The median age at diagnosis was 36 years (range 17-84) and 136 (55.7%) were female. The median size of the anterior mediastinal mass was 11 cm (range 5-20 cm). By the CNS-IPI risk factors, 21 (8.6%) pts were age >60 years, 95 (38.9%) had stage III/IV disease, 87/236 (36.9%) had PS ≥2 (missing n=8), 83 (34.0%) had >1 extranodal site, 180/239 (75.3%) had an elevated LDH (missing n=5), and 13 (5.3%) patients had renal and/or adrenal involvement. The CNS-IPI for 233 pts with all factors available was: 0-1, n=95 (38.9%); 2-3, n=100 (41%); 4+ factors n=38 (15.6%). In total, 33 (13.5%) pts received dose adjusted (DA) EPOCH-R, and the remaining pts received R-CHOP, 8 of which had R-CHOP x 3/R-ICE x3 as part of a clinical trial. 69 (28.3%) pts received radiotherapy post systemic therapy. Three pts with renal/adrenal involvement had high dose methotrexate prophylaxis, 1 of whom also received intrathecal chemotherapy. With a median duration of follow up for alive pts of 91 months (range 5-263), 6 (2.5%) had a CNS relapse, with a median time to CNS relapse from diagnosis of 9.9 months (range 5.1-56.9) and 5-year (5 y) estimated cumulative incidence of CNS relapse of 2.7% (95% confidence interval (CI) 1.1%, 5.7%). Five pts with CNS relapse had isolated parenchymal involvement, 1 of whom developed systemic relapse later during CNS treatment, and the remaining pt had leptomeningeal disease concurrent with systemic relapse.

The 5 y cumulative incidence of CNS relapse was 2.1% (95% CI 0.7%, 5.0%) and 6.8% (95% CI 1.1%, 19.8%) in the R-CHOP and DA-EPOCH-R treatment groups, respectively, p=0.075. By the CNS-IPI, 14.7% (31/211) of pts treated with R-CHOP, and 21.2% (7/33) of pts treated with DA-EPOCH-R were high-risk (p=0.337) and renal/kidney involvement occurred in 11/200 (5.5%) and 2/31 (6.4%), by treatment group respectively (p=0.84). The 5 y cumulative incidence of CNS relapse was 0%, 1.7% (95% CI 0.1%, 7.9%), and 13.2% (95% CI 4.7%, 26.0%) in the low, intermediate, and high-risk CNS-IPI groups, respectively (p<0.0001). Four of the cases with CNS relapse had renal/adrenal involvement at diagnosis, which translated into a 5 y cumulative incidence CNS recurrence risk of 30.8% (95% CI 8.7%, 57%) vs. 1.1% (95% CI 0.2%, 3.9%) (p<0.00001) for those with and without renal/adrenal involvement, respectively.

Conclusion: The risk of CNS relapse in PMBCL is overall low and comparable to estimates reported in the pre-rituximab era, which likely reflects the poor penetrance of rituximab across the blood-brain barrier. Like in DLBCL, the CNS-IPI appears to stratify pts and identifies a high-risk group in PMBCL with a CNS relapse rate of approximately 10%. However, this appears to largely driven by renal/adrenal involvement, which represents a very high-risk site. These data provide a benchmark to compare the impact of ongoing studies incorporating PD1 inhibitors and other novel therapies in frontline therapy.