EBV Positive DLBCL Is Effectively Treated with Commercial CAR T Cell Therapy but Is Associated with Higher Rates of Severe Immune Effector Cell Associated Neurologic Syndrome (ICANS): A Single Institution Experience
Authors: Nikolaenko Liana , Herrera Alex F. , Budde Elizabeth , Song Joo Y. , Shouse Geoffrey 
Published: November 2021

Abstract
Introduction:
CAR T-cell therapy (CART) has revolutionized the treatment landscape of aggressive B cell lymphoma (aBCL) in the relapsed/refractory (r/r) setting, including high-risk groups such as high grade B cell lymphoma (HGBCL), primary refractory disease, and chemo-resistant relapses. To date, however, there has been no data reported, on the outcomes of patients with Epstein-Barr virus positive (EBV+) DLBCL, NOS. EBV+ DLBCL, NOS is a high-risk group of aBCL characterized by the incorporation of EBV into the malignant cells, with the chronic inflammation associated with EBV infection being thought to contribute to DLBCL pathogenesis. It has been shown to be less responsive to standard chemotherapy with high relapse rates and overall poor prognosis. In the present study, we analyze outcomes and toxicities of patients with EBV+ DLBCL, NOS treated with CD19CART.
Methods:
We retrospectively analyzed charts of patients treated with commercially available CD19CAR T-cell products for the treatment of aBCL at City of Hope (COH) between April 2018 and March 2021. EBV status was determined by immunohistochemical stains from EBER in situ hybridization on paraffin embedded tissues. Patients were included in the analysis if they had positive or negative EBER staining, referred as EBV+ or EBV-, respectively. The investigation was approved by the COH IRB. Cytokine release syndrome (CRS) and immune effector cell associated neurologic syndrome (ICANS) were graded using ASTCT criteria (Lee et al. BBMT 2019). Demographics were analyzed with descriptive statistics. Univariate analysis was performed by Chi Square test.
Results:
Seventy-three patients had tumor samples that were evaluable for analysis, 92% (n=67) were negative for EBER and 8% (n=6) were positive for EBER. In the entire cohort, the median age was 62 years (range, 21-90), and included 18% (n=13) transformed follicular lymphoma, 73% (n=53) DLBCL, NOS, and 10%(n=7) DH. The median number of prior lines of therapy was 2 (range, 2-6) and 15% (n=11) patients had prior autologous stem cell transplant.
Comparing the EBV+ patients to the EBV-, the CR rate was 67% (n=4) vs 58% (n=34), with 16% (n=1) PR vs 27% (n=15) (ORR 83% vs 74%). With a median follow up of 17.0 months (range, 3.6-38.3), 33% (n=2) of EBV+ patients had progressed vs 42% (n=28). In the EBV+ DLBCL, NOS group, 3 CR patients had absence of detectable EBV PCR in the peripheral blood at the time of CART; 1 CR patient did not have clinical indication for EBV viral load (VL) evaluation (EBV PCR not measured); 1 PR and 1 PD patients had detectable viremia. At the time of analysis, 31% (n=21) of EBV- patients died vs 33% (n=2) of EBV+ patients, both with non-CR response to CAR T and persistent EBV VL during therapy. In terms of toxicity, overall CRS rates were similar with 83% (n=5) in the EBV+ patients and 86% (n=58) in EBV- patients. Although overall incidences of ICANS were similar between the two groups (50% [n=3] vs 45% [n=30]), grade 3 ICANS was higher in EBV+ patients (50% [n=3]) than in EBV- patients( 7.5% [n=5]; p = 0.02). EBV VL did not correlate with CRS or neurotoxicity.
Conclusion:
We present a retrospective analysis of EBV+ DLBCL, NOS patients treated with CART at our institution. Based on our analysis, despite the limited number of cases, the CART is an effective therapy for EBV+ DLBCL,NOS with response rates similar to what has been reported in the literature for other aBCL groups. Responses appear to be improved if EBV VL is undetectable at the time of CART. Interestingly, we demonstrate a statistically significant higher rates of grade 3 ICANS in patients with EBV+ DLBCL,NOS. Our data suggests that close monitoring for ICANS during CART should be considered in EBV+ DLBCL patients with early therapeutic intervention to prevent severe toxicity. Further investigation of a larger cohort of EBV+ DLBCL patients, as well as a deeper analysis of inflammatory markers and EBV viremia in these patients undergoing CART may provide further insight to response and toxicity profile.

Disclosures
Nikolaenko: Rafael Pharmaceuticals: Research Funding; Pfizer: Research Funding. Herrera: Seagen: Consultancy, Research Funding; AstraZeneca: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; Takeda: Consultancy; ADC Therapeutics: Consultancy, Research Funding; Merck: Consultancy, Research Funding; Bristol Myers Squibb: Consultancy, Research Funding; Tubulis: Consultancy; Kite, a Gilead Company: Research Funding; Karyopharm: Consultancy; Gilead Sciences: Research Funding. Budde: Mustang Bio, Inc: Research Funding; Gilead: Consultancy; Merck, Inc: Research Funding; AstraZeneca: Research Funding; Amgen: Research Funding; IGM Biosciences: Research Funding; Roche: Consultancy; BeiGene: Consultancy; Novartis: Consultancy. Shouse: Kite Pharma: Speakers Bureau; Beigene: Honoraria.