Characteristics of Patients with Central Nervous System Relapse in Veterans with Diffuse Large B-Cell Lymphoma within the Veterans Health Administration
Authors: Horowitz Amy M , Williams Madison H. , Williams Ryan A. , Blaize Jean Pierre , Ananth Snegha , Song Michael M. , Warnecke Brian , Pandya Abhishek , Djoufack Djoumessi Lakene Raissa , Nazarewicz Phillip , Espinoza-Gutarra Manuel Ricardo , Toro Juan J. , Lu Lindsey , Lucero Kana Tai , Whitehead Jennifer , Franklin Kathleen , Mader Michael , Nooruddin Zohra 
Published: November 2021

Abstract
Introduction
Around 2-5% of patients with diffuse large B-cell lymphoma (DLBCL) will experience central nervous system (CNS) relapse resulting in a poor prognosis. The Central Nervous System International Prognostic Index (CNS-IPI) is a validated risk model used to help identify DLBCL patients receiving R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone) chemotherapy who are at risk for CNS relapse. CNS prophylaxis is recommended for those with high-risk CNS-IPI scores; however, the role of CNS prophylaxis has been called into question given recent large datasets showing no impact on CNS relapse. The purpose of this study is to evaluate the characteristics of Veterans who experienced CNS relapse within the Veterans Healthcare Administration (VHA) and to validate the CNS-IPI risk stratification within this population.
Methods
Trained abstractors performed a retrospective chart review of 3287 lymphoma patients seen in the VHA nationwide between 01/01/2011 and 12/31/2017. Figure 1 describes the selection of the study cohort. We evaluated baseline patient and disease characteristics including CNS-IPI score, performance of diagnostic lumbar puncture (LP) and first-line chemotherapy regimen. Pathology reports to identify cell of origin (COO), and additional risk factors for CNS relapse present at the time of original diagnosis including HIV associated lymphoma, testicular lymphoma, and high-grade B-cell lymphomas (HGBLs) defined as double or triple-hit DLBCL were evaluated. We also assessed response to first-line treatment, type of CNS prophylaxis used, including number of doses, and time to CNS relapse.
Results
A total of 1621 patients met criteria for analysis. Patients were predominately male, white, had a median age of 67, and presented with advanced disease (Table 1). At the time of diagnosis, 81% of the cohort had an ECOG performance status of 0-2, 73% received a CHOP based regimen, and 52% were designated as having a high-risk CNS-IPI score. Patients were about twice as likely to have a germinal center B-cell (GCB) COO rather than activated B-cell (ABC), but the COO was unavailable for almost 30% of the cohort. About 6% of the patients were known to have HGBLs, but the "hit status" of around 65% of the patients was unknown. Diagnostic LP was performed in 10%, 14%, and 19% of patients in the low-, intermediate-, and high-risk CNS-IPI groups respectively.
The median follow-up time for the subjects in the study was 44 months. The low-risk group (12% of all patients analyzed), the intermediate-risk group (36%) and the high-risk group (52%) showed rates of CNS relapse of 1% (with a 95% CI: 0% to 2.4%), 2.4% (CI: 1.2% to 3.7%), and 2.4% (CI: 1.3% to 3.4%) respectively with no statistically significant difference across the risk groups (p=0.30). In patients with CNS relapse, only 35% of patients had a diagnostic LP. More than 90% of patients deemed high-risk for CNS relapse did not receive CNS prophylaxis. Among the 36 patients with CNS relapse, only 3 were given CNS prophylaxis at baseline (Table 2). Of the patients with CNS relapse, 75% of patients achieved a complete response with initial treatment. When categorized by the CNS-IPI score, there is no significant difference between intermediate- and high-risk based on type of CNS relapse, type of CNS prophylaxis used, response to first-line therapy, median time to relapse, median survival time, or median time from relapse to death. Those with CNS relapse had a shorter survival time compared to those with systemic relapse or no relapse (Figure 2).
Conclusions
When compared to the previously validated CNS-IPI study, there were fewer instances of CNS relapse in our patient population in the intermediate- and high-risk groups, however, about a quarter of the patients in these groups did not receive CHOP based therapy. Although there is published data demonstrating COO and HGBLs as contributing factors to CNS relapse, our data did not show any statistically significant difference in relapse rates. Potential limitations include that the study is a retrospective chart review of a predominately male veteran population. Our data suggests the CNS-IPI may not identify patients at risk for CNS relapse with adequate accuracy.
Figure 1 Figure 1.

Disclosures
Nooruddin: AstraZeneca: Research Funding.