Background: Epstein-Barr Virus (EBV)-associated lymphoproliferative disorder (EBV-LPD) complicating allogeneic hematopoietic cell transplant (alloHCT) most frequently present as malignant, high grade, diffuse large B cell lymphomas (DLBCL) that do not respond to reduction in immune suppression. Rituximab induces remissions in approximately 55% of those with radiographically demonstrable disease. Median survival reported for rituximab-refractory EBV-LPD patients (pts) ranges from 16 - 56 days. There are few other treatment options.

EBV-cytotoxic T lymphocytes (CTLs) offer a possible treatment approach. We evaluated the efficacy and safety of EBV-CTLs have been evaluated in 2 clinical trials in alloHCT recipients with EBV+ disease.

Methods: As part of 2 ongoing clinical trials (95-024 and 11-130) 57 pts received EBV-CTLs derived from unrelated third-party donors (13 on 95-024 and 18 on 11-130) or primary stem cell donors (26 on 95-024). Fifty-one pts were treated for monomorphic DLBCL, 3 polymorphic, 1 NK/T cell lymphoma and 2 for viremia alone. Subjects on 11-130 (n = 18) had a median age of 52y, 8 were male, all had failed prior rituximab. Pts on 95-024 (n = 39) had a median age of 21y, 23 were male, and 28 had failed prior rituximab. Subjects in both studies received up to 5 cycles of EBV-CTL infusions; each cycle consisting of 1 or 2×106 cells/kg weekly for 3 weeks.

Results: Of the 18 recipients of 3rd party EBV-CTLs on 11-130, 9 pts had complete response (CR), 3 had partial response (PR) and 1 had stable disease (SD) for a response rate of 67% and non-progression rate of 72%. The median duration of CR+PR was 318d. Kaplan-Meier (KM) overall survival (OS) was 71.8% at 1 and 2y. KM progression-free survival was 66.7% at 1y.

Of 39 pts on 95-024, 23 had CR, 1 PR, and 3 had SD, for a response rate of 62% and non-progression rate of 69%. Strikingly, the 1y OS for rituximab-refractory pts in both studies was 50% and 49% for pts treated with 3rd party and transplant donor-derived EBV-CTLs, respectively.

Four patients on 11-130 and 6 patients on 95-024 died within 2 months of the first EBV-CTL infusion due to progression of EBVLPD (N = 6), leukemic relapse (N = 2), or other causes (N = 2); no death was considered related to treatment. EBV-CTLs had low toxicity: no pts developed cytokine release syndrome or GvHD requiring systemic therapy.

Conclusions: EBV-CTLs produce high response rates that are durable; pts who achieved CR had no relapses of EBV LPD. The OS in both studies far exceeded the survival reported for this patient population. EBV-CTLs had a favorable safety profile and were well tolerated.

Citation Format: Susan E. Prockop, Ekaterina Doubrovina, Karim Baroudy, Farid Boulad, Ramzi Khalaf, Esperanza B. Papadopoulos, Craig Sauter, Victoria Szenes, Stephanie Suser, Gloria Wasilewski, Julianna Ruggierio, Richard J. O'Reilly. Epstein-Barr virus-specific cytotoxic T lymphocytes for treatment of rituximab-refractory Epstein-Barr virus-associated lymphoproliferative disorder. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr CT107. doi:10.1158/1538-7445.AM2015-CT107

©2015 American Association for Cancer Research.
2015