Clinical Outcomes of Solid Organ Transplant Patients with Epstein-Barr Virus-Driven (EBV +) Post-Transplant Lymphoproliferative Disorder (PTLD) Who Fail Rituximab Plus Chemotherapy: A Multinational, Retrospective Chart Review Study

Abstract

Introduction: Post-transplant lymphoproliferative disorder (PTLD) is a rare and often aggressive disease in the setting of immunosuppression following solid organ transplant (SOT). Epstein-Barr virus (EBV) infection of B cells is responsible for about 50% of cases, either due to reactivation of the virus after transplantation or primary EBV infection. Although there is no approved therapy for patients (pts) with PTLD, guidelines include reduction of immunosuppression (RIS) as a part of initial treatment and may be sufficient for pts with early lesions. Rituximab, either as monotherapy or in combination with chemotherapy (CT), is used in addition to RIS as initial treatment. Pts with EBV + PTLD following SOT who fail rituximab plus CT have poor outcomes with limited treatment options. There are ongoing clinical studies investigating innovative therapies to address unmet needs in these pts. Published data on clinical outcomes of these pts remain limited and not well documented. We aimed to characterize the outcomes for pts diagnosed with EBV + PTLD following SOT who fail initial rituximab plus CT in a multi-national real-world setting. Methods: We conducted a large multinational, multicenter, retrospective chart review study of pts with EBV + PTLD following allogeneic hematopoietic cell transplantation (HCT) or SOT who received rituximab or rituximab plus CT between January 2000‒December 2018 and were refractory (failed to achieve complete response [CR] or partial response [PR]) or relapsed at any point after such therapy. Treatment response was assessed either by clinical diagnosis, radiographic/imaging, biopsy/cytology, or a combination of such assessments. Data were collected from 29 centers across North America (United States and Canada) and the European Union. Study population was aligned to the ongoing investigational trial (Clinicaltrials.gov Identifier: NCT03394365). This analysis includes pts with EBV + PTLD following SOT who were refractory/relapsed to rituximab plus CT. The Kaplan-Meier method was utilized to estimate the overall survival (OS). Results: A total of 86 pts with EBV + PTLD following SOT who failed rituximab plus CT were included in the analysis; 65 (75.6%) pts were refractory while 21 (24.4%) relapsed after initial response of CR or PR. Median age at PTLD diagnosis was 43 years (range 1‒78) and median time to PTLD onset from transplant was 1.7 years (range 0.1‒27.9). Median follow up time was 12.9 months from the date of PTLD diagnosis. PTLD histological subtypes were 66 (76.7%) monomorphic, 18 (20.9%) polymorphic, and 2 (2.3%) early lesions. The most common PTLD subtype was diffuse large B-cell lymphoma (DLBCL) (58, 67.4%). Of the 86 pts, 49 (57%) received CT following rituximab monotherapy while 37 (43%) pts received CT concurrently with rituximab. Overall, 63 (73.3%) pts died. PTLD-specific mortality was observed in 41 (65.1%) pts, treatment-related mortality in 10 (15.9%) pts, mortality due to organ rejection/failure in 2 (3.2%) pts, mortality due to other causes in 7 (11.1%) pts, and mortality due to unknown causes in 3 (4.8%) pts. Median OS was 15.5 months (95% confidence interval [CI]: 8.3‒22.9) from PTLD diagnosis, and was 4.1 months (95%CI: 1.9‒8.5) from the earliest date when pts became refractory or relapsed following rituximab plus CT. Conclusions: The prognosis for pts with EBV + PTLD following SOT who fail rituximab plus CT remains poor, with an estimated median OS of about 4 months and a majority of pts dying from PTLD and related treatment. In this specific population, there remains a significant unmet medical need for effective and well-tolerated therapies. Figure 1 Figure 1. Disclosures Dharnidharka: Merck, Pfizer, Medronic, Cardinal Health: Current holder of stock options in a privately-held company; CareDx: Honoraria, Research Funding; Atara Bio, MedinCell: Consultancy. Thirumalai: Atara Biotherapeutics: Current Employment. Jaeger: Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees; Norvartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS/Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees. Zhao: Atara Biotherapeutics: Current Employment. Dierickx: Roche: Consultancy, Research Funding; Novartis: Consultancy; Sanofi: Consultancy; Sandoz: Consultancy; Takeda, Incyte, Atara: Consultancy. Xun: Atara Biotherapeutics: Current Employment. Sawas: Flat Iron Health: Current Employment; Roche: Current holder of stock options in a privately-held company; Seattle Genetics, Acrotech: Consultancy; Daiichi-Sankyo, Seattle Genetics, Gilead: Other: Travel, accommodation, expenses, Speakers Bureau; Affimed, Trillium: Research Funding. Sadetsky: Atara Biotherapeutics: Current Employment. Barlev: Atara Biotherapeutics: Current Employment. Zimmermann: Roche, Atara: Research Funding; Celgene, Roche, Atara, Jansen: Other: Travel accomodations. Trappe: Celgene: Other: Travel support; Roche: Other: Travel support; Atara Biotherapeutics: Consultancy, Other: Travel support, Research Funding; Jansen: Other: Travel support; GSK: Other: Travel support; AbbVie: Other: Travel support.

Tabelecleucel for EBV+ PTLD after allogeneic HCT or SOT in a multicenter expanded access protocol

“…These results suggest tabelecleucel imparts substantial clinical benefit after failure of standard-of-care therapies. 35 , 36 …”

“… 12 , 24 , 34 Median overall survival (OS) in patients with EBV + PTLD after HCT relapsed or refractory to rituximab with/without chemotherapy is 0.7 months, 35 whereas reported median OS in SOT recipients with EBV + PTLD relapsed or refractory to rituximab plus chemotherapy is 4.1 months. 36 Thus, there is clearly an unmet need for effective and well-tolerated therapies in this disease.…”

Expert Consensus on the Characteristics of Patients with Epstein–Barr Virus-Positive Post-Transplant Lymphoproliferative Disease (EBV+ PTLD) for Whom Standard-Dose Chemotherapy May be Inappropriate: A Modified Delphi Study

“…Treatment options are limited if patients have EBV + PTLD that relapses or is refractory to rituximab and/or chemotherapy [ 23 , 24 ]. Treatment outcomes in HCT recipients following rituximab treatment failure are usually very poor [ 25 ], with a median overall survival (OS) of 0.7 months [ 24 ].…”

“…Treatment outcomes in HCT recipients following rituximab treatment failure are usually very poor [ 25 ], with a median overall survival (OS) of 0.7 months [ 24 ]. Likewise, SOT recipients with EBV + PTLD that has relapsed or is refractory to rituximab plus chemotherapy have a reported median OS of 4.1 months [ 23 ]. Therefore, urgency is required to identify effective, well-tolerated therapies for patients with EBV + PTLD for whom rituximab and/or chemotherapy has failed.…”