Efficacy and Safety of Rituximab in Post Transplant Lymphoproliferative Disorders (PTLD): Pooled Analysis and Review of Literature.

PTLD are heterogeneous monoclonal or polyclonal neoplasm usually of B-cell origin with a variable incidence in allogenic bone marrow and solid organ transplant recipients. Due to immunosuppresion in transplant patients, PTLD follows an aggressive course with enhanced treatment-associated toxicity, leading to a overall poor clinical outcome and mortality. Rituximab is a chimeric monoclonal anti-CD20 antibody with known activity in B-cell PTLD and minimal toxicity. A few anecdotal uncontrolled studies and case reports have evaluated the use of rituximab-based therapy for PTLD. In order to define the efficacy and safety of rituximab single agent in the treatment of patients with PTLD we conducted a review of the current available literature and performed a pooled-analysis. We conducted a MEDLINE literature search using Pub med, Ovid software for the key words rituximab, anti-CD20 antibody, PTLD, hematopoetic stem cell transplant (HSCT), solid organ transplant (SOT) and lymphoproliferative disorders on all available published literature analyzed to date (January 1998 to June 30, 2007). Studies involving children (<18 years), individual case reports with less than 5 patients, patients who were treated with chemo-immunotherapy combination were excluded and our search was limited to those PTLD patients treated with rituximab single agent after failure to respond to withdrawal of immunosuppressants. References of each article were also reviewed for additional literature. Studies were also analyzed for duration of PTLD from time of transplantation, rituximab toxicity, and characteristics of responders. A total of 164 peer-reviewed publications were identified after the electronic search using the above keywords. After excluding patients based on above criteria, the pooled-analysis consisted of 308 patients described in 17 reports. Diagnosis of PTLD cases was based on histological examination and World Health Organization classification. Among the 17 reports, 3 studies included HSCT patients with n=24; the rest consisted of SOT patients. The mean age of the patients was 57; PTLD classified as late onset (>1 year) in most patients (∼70%). Rituximab was used as first line therapy after failure of immunosuppression withdrawal, and patients were initially treated with four weekly doses of rituximab at 375mg/m². Rituximab was continued as maintenance therapy in responding patients in few studies. The complete response rate (International Workshop Criteria) was 58% (29%–78%), among SOT patients and 70% (66%–83%) among HSCT patients. Side effects were minimal and no treatment related deaths were attributed to rituximab. Long term follow up from 2 prospective studies demonstrate a durable remission in 30%–37% SOT patients at 5 years. Limited evidence exists for optimal treatment approach in PTLD. Clinical heterogeneity among small number of patients diagnosed makes it difficult to conduct randomized prospective studies in this disorder. Our study is the first pooled analysis evaluating the role of rituximab in PTLD. Minimal toxicity with good efficacy favors rituximab’s use among patients with less aggressive PTLD who fail or unable to tolerate withdrawal of immunosuppression.