Treatment Patterns for Patients with Post-Transplant Lymphoproliferative Disorder Who Fail Rituximab after Allogeneic Hematopoietic Stem Cell Transplantation: Findings from a Systematic Literature Review
Authors: Xu Hairong , Watson Crystal , Garib Shan Ashton , Forsythe Anna , Barlev Arie 
Published: October 2019

Abstract
Introduction: Post-transplant lymphoproliferative disorder (PTLD) is a well-recognized disease after allogeneic hematopoietic stem cell transplantation (HCT) and is one of the most common post-transplant malignancies. In most cases, PTLD is associated with Epstein-Barr Virus (EBV) infection. The management of PTLD remains a challenge, with no approved treatments for patients. Clinical practice treatment guidelines recommend rituximab as first-line therapy for PTLD post-allogeneic HCT; however, treatment options for PTLD patients who fail rituximab are not clearly defined. We conducted a systematic literature review of the published literature to better understand treatment patterns for patients with PTLD who fail rituximab post-allogeneic HCT in a real-world setting.
Methods: The systematic literature review was performed following Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines with the scope defined in terms of Population, Intervention Comparators, Outcomes, and Study design (PICOS) criteria. Using extensive search terms for the indication and study designs, studies were identified using key biomedical literature databases: EMBASE, MEDLINE, and Cochrane. The literature search was conducted on July 19, 2018 and included studies published between database inception in January 1, 1959 and July 19, 2018. Relevant congress abstracts published between January 2015 and June 2018 were also identified. The PICOS-based inclusion and exclusion criteria were used to review identified citations. No treatment limitations were imposed to ensure inclusion of all relevant evidence; the study designs were limited to prospective and retrospective observational studies. Case reports were included regardless of sample size. Two independent reviewers screened all citations and full-text articles; any discrepancies were resolved by a third independent reviewer. Data from included studies were extracted into a pre-defined template, and results were summarized using the PRISMA flow diagram.
Results: A total of 69 studies were identified that described patients with PTLD post-allogeneic HCT. The majority (61 studies) were retrospective chart reviews, of which 54 studies were single-center studies. Forty-eight studies reported data on treatment of patients with PTLD. Among these, 5 studies included data prior to 2000, 33 studies included data from 2000-2010, and 26 studies included data from 2010-2016. The sample size for PTLD patients was between 1 and 144 patients, with only one study of > 100 patients. First-line therapy in PTLD included rituximab (41 studies), various chemotherapy regimens (15 studies), and lymphocyte infusion (10 studies). Nine studies reported treatment for patients who failed first-line rituximab (13-67% of PTLD patients); the number of patients with second-line treatments ranged from 2-10 across studies. Second-line treatments varied greatly across studies and included cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP, n=1); rituximab plus CHOP (R-CHOP, n=1-2); cyclophosphamide, etoposide/cytarabine (VP16/ARA-C, n=1); rituximab plus cyclophosphamide (n=1); rituximab plus high-dose cytarabine (n=1); chemotherapy unspecified (n=2-4), and lymphocyte infusion (n=3-5). Only 2 studies reported treatment outcomes in rituximab-refractory patients. One study (N=62, second-line n=10, median age 49 years) reported no complete or partial remission in the chemotherapy group; 60% had complete remission in the lymphocyte infusion group. The second study (N=12, second-line n=3, mean age 5 years) reported complete remission in 1 patient with lymphocyte infusion as second-line treatment.
Conclusions: This systematic literature review demonstrates that data on treatment patterns for PTLD patients who failed rituximab post-allogeneic HCT are limited (9 studies with a sample size ≤ 10). Published data suggest that the percentage of patients who fail rituximab vary greatly (13-67%), there is no consistent standard of care for PTLD patients who fail rituximab, and outcomes are poor. There continues to be a significant unmet need among PTLD patients who fail rituximab, and further studies are needed to better understand rituximab response rates in the real-world setting.

Disclosures
Xu: Atara Biotherapeutics, Inc: Employment, Equity Ownership. Watson:Atara Biotherapeutics, Inc: Employment, Equity Ownership. Forsythe:Novartis: Consultancy. Barlev:Atara Biotherapeutics, Inc: Employment, Equity Ownership.