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4476 Targeting EBV Encoded Viral Kinases with GCV, AZT, Rituximab and Dexamethasone (GARD) Results in Durable Responses in Patients with CNS Lymphoproliferative DiseaseClinically Relevant Abstract

Program: Oral and Poster Abstracts
Session: 627. Aggressive Lymphomas: Clinical and Epidemiological: Poster III
Hematology Disease Topics & Pathways:
Research, adult, Lymphomas, non-Hodgkin lymphoma, Clinical Research, Combination therapy, Diseases, Immune Disorders, immunodeficiency, aggressive lymphoma, Therapies, Lymphoid Malignancies, survivorship, Study Population, Human
Monday, December 11, 2023, 6:00 PM-8:00 PM

Haley L. Klimaszewski, BS1, Christoph Weigel, PhD2, Selamawit Addissie, MD3, Sarah Schlotter, MPH4, Tounkara Fode, PhD5*, James P. Dugan, MD6, Bradley M. Haverkos, MD, MS, MPH7, Lynda Villagomez, MD8, Mark Lustberg, MD9*, Pierluigi Porcu, MD10, Timothy Voorhees, MD, MSCR11, Michael A Caligiuri, MD12, Christopher C. Oakes, PhD13,14,15, Ginny Bumgardner, MD, PhD16* and Robert Baiocchi, MD2,13

1College of Medicine, The Ohio State, Columbus, OH
2Division of Hematology, Department of Internal Medicine, The Ohio State University, Columbus, OH
3Department of Internal Medicine, John's Hopkins, Baltimore, MD
4College of Medicine, The Ohio State University, Columbus, OH
5Center for Biostatistics, The Ohio State University, Columbus, OH
6Malignant Hematology and Cellular Therapy Department, Novant Health Cancer Institute - Forsyth Medical Center, Winston-Salem, NC
7Division of Hematology, University of Colorado School of Medicine, Aurora, CO
8Department of Pediatrics, Division of Hematology and Oncology, The Ohio State University and Nationwide Children's Hospital, Columbus, OH
9Division of Infectious Disease, Department of Internal Medicine, Yale School of Medicine, New Haven, CT
10Division of Hematologic Malignancies and Hematopoietic Stem Cell Transplantation, Department of Medical Oncology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA
11Department of Hematology, James Comprehensive Cancer Center, The Ohio State University, Columbus, OH
12Department of Hematology & Hematopoietic Cell Transplantation, City of Hope National Medical Center, Los Angeles, CA
13Comprehensive Cancer Center, The James Cancer Hospital and Solove Research Institute, The Ohio State University, Columbus, OH
14Department of Biomedical Informatics, The Ohio State University, Columbus, OH
15Division of Hematology, Department of Internal Medicine, Comprehensive Cancer Center, The Ohio State University, Columbus, OH
16Comprehensive Transplant Center, Department of Surgery, The Ohio State University College of Medicine, Columbus, OH

Introduction: Epstein-Barr virus positive (EBV+) central nervous system lymphoproliferative diseases (CNS-LPD) are aggressive clinical conditions with poor prognosis. EBV+ CNS-LPD often occurs in the setting of immune suppression and comorbidities (solid organ transplant, autoimmunity). Treatment with high-dose methotrexate has increased survival but is not a viable option for all patients, highlighting the need for alternative treatments. Previous research has reported EBV+ CNS-LPD exhibits unique genetic and immunobiological signatures, however, few studies have reported on the epigenetic landscape. We have previously reported use of ganciclovir (GCV), zidovudine (AZT), rituximab and dexamethasone (GARD) regimen induced complete and durable responses in a cohort of 13 patients with primary CNS post-transplant lymphoproliferative disease (PCNS-PTLD). Here we present 24 patients (10 from prior cohort and 14 new) with EBV+ CNS-LPD treated with GARD. We extend follow-up time for the previous cohort and add molecular context to clinical observations. We performed DNA methylation and expression analysis of EBV viral kinases in available tumor samples and revealed unique viral epigenetic states leading to expression of antiviral drug targets in an array of EBV+ CNS-LPD.

Methods: We conducted an IRB-approved, retrospective review of patients with EBV+ CNS-LPD treated with GARD at The Ohio State University Wexner Medical Center between 1998-2022. Patient information was extracted from the electronic medical record. Treatment consisted of two-week induction of twice daily IV GCV/AZT (5mg/kg and 1,500 mg) IV dexamethasone (10-40mg), and weekly rituximab (375mg/m2). After induction, dexamethasone was tapered, and GCV/AZT was switched to maintenance oral dosing of 450mg valganciclovir twice daily and 300mg of AZT twice daily. Rituximab was administered on days 1, 8, 15, and 22. Two-year overall survival (OS), five-year OS, and overall response rate were assessed. Available CNS-LPD biopsy samples were obtained, and expression of EBV lytic genes BZLF1, BXLF1 (thymidine kinase), and BGLF4 (protein kinase) were measured via qRT-PCR. Mass spectrometry based EpiTYPER assay was used to report the percentage of DNA CpG methylation in the gene promoters for viral BZLF1, BXLF1, BGLF4 and LMP1 genes. Biopsies from 17 patients with systemic PTLD with no CNS involvement were used for comparison.

Results: 24 patients with EBV+ CNS-LPD were identified. 21 (87.5%) patients were diagnosed with a primary CNS-LPD (PCNS-LPD). Of the PCNS-LPD, 14 patients were PCNS-PTLD, 4 were receiving immunosuppression for autoimmune conditions, 1 patient had type 2 diabetes and two had no known history of immunosuppression. The remaining three patients had systemic PTLD with secondary CNS involvement. Diffuse large B-cell lymphoma was the most common histology (11; 45.8%) followed by grade 3 lymphomatoid granulomatosis (5; 20.8%), B-cell LPD (5;20.8%), polymorphic PTLD (2;8.3%) and one large cell lymphoma of ambiguous lineage. All patients were HIV negative. EBER was positive in all biopsies and EBV PCR of cerebrospinal fluid was positive in patients without biopsy. Sixteen patients (66.7%) achieved a completed response, with an overall response rate of 83%. Two-year OS was 62.5% (95% CI, 45.8-85.2%) and five-year OS was 52.8% (95% CI, 35.7%-77.9%). Five CNS-LPD brain biopsies were available for analysis. qRT-PCR of biopsy specimens showed expression of LMP1, BXLF1, and BGLF4, but not BZLF1. Expression of BGLF4 was significantly higher (p=1.35e-5) in CNS-LPD when compared to systemic EBV+ PTLD. EpiTYPER data showed significantly decreased promoter methylation for viral kinases BXLF1 and BGLF4 (p=0.0281, p=0.0089).

Conclusions: We have shown that GARD regimen shows efficacy in the treatment of EBV+ CNS-LPD, with 62.5% two-year OS and 52.8% five-year OS. Our results provide the molecular basis for expression of lytic viral kinases BXLF1 and BGLF4 in CNS-LPD by showing that both genes exhibit decreased promotor methylation. This expression of viral kinases in CNS-LPD supports the mechanistic rationale of this antiviral approach and could be further investigated as a predictive biomarker. Overall, this research highlights unique epigenetic features of EBV in CNS-LPD that support the use of antiviral, specifically the GARD regimen, in EBV+ CNS-LPD.

Disclosures: Dugan: Abbvie: Consultancy, Speakers Bureau; Novartis: Consultancy, Speakers Bureau; Sobi: Speakers Bureau; Rigel: Speakers Bureau; Bristol-Meyer-Squibb: Speakers Bureau. Haverkos: Viracta Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees. Porcu: BioGene: Membership on an entity's Board of Directors or advisory committees; Kyowa: Consultancy; Kymera: Membership on an entity's Board of Directors or advisory committees; Dren-Bio, ADCT, Lilly-Loxo, Viracta, Innate Pharma: Membership on an entity's Board of Directors or advisory committees; Ono: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Kyowa, Daiichi, Viracta, Dren Bio, Innate Pharma: Consultancy; Kyowa, Daiichi, Viracta, Dren Bio, Innate Pharma, Ono: Honoraria; Teva: Research Funding; Innate Pharma: Research Funding. Voorhees: Incyte: Research Funding; AstraZeneca: Research Funding; Novartis: Consultancy; Recordati: Consultancy, Research Funding; Morphosys: Research Funding. Baiocchi: Prelude Therapeutics: Consultancy; EUSA: Consultancy; Viracta: Membership on an entity's Board of Directors or advisory committees; Atara Biotherapeutics: Membership on an entity's Board of Directors or advisory committees.

OffLabel Disclosure: Zidovudine (AZT) is an antiviral, nucleoside analog reverse transcriptase inhibitor, used in the treatment of HIV.

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