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Post‐transplant lymphoproliferative disease in children following solid organ transplant and rituximab – the final answer?

Post-transplant lymphoproliferative disease (PTLD) is a well known complication of solid organ transplantation (SOT). The majority of PTLD are associated with Epstein–Barr virus (EBV) (1). Children post-SOT are at higher risk of developing PTLD than adults, most likely due to the increased probability of acquiring primary infection following transplant (2). There have been numerous approaches to the treatment of PTLD with highly variable results, likely due to the great heterogeneity of PTLD. A common practice for patients at high-risk for PTLD following blood and marrow transplant (BMT), is to give the anti-CD20 monoclonal antibody rituximab when the EBV load becomes elevated. The rationale is to control the EBV-driven B-cell proliferation until the EBV cytotoxic T-cell (EBV-CTL) function develops sufficiently to control the process. Though this is common practice, there are no well-controlled studies proving the efficacy of this approach (3, 4). Though there are anecdotal reports using rituximab preemptively following SOT, it has not become common practice. This is because it has been demonstrated that compared to historical controls, the incidence of PTLD in children following SOT may be reduced by intervening with reduction of immunosuppression with or without antiviral therapy when patients develop elevated levels of EBV, i.e. EBV viral load, assessed by PCR (5, 6). It has also been shown that T-cell immunity, specifically EBV-CTL activity correlates better with prevention of PTLD than EBV viral load (7, 8). Therefore, to make the use of rituximab costeffective as a ‘‘preemptive’’ therapy following SOT, a practical method to measure EBV-CTL simultaneously with EBV viral load would be required. Once PTLD has developed, the most effective therapy with the least potential side effects is complete surgical resection (9). However, this is not practical in the majority of cases. Therefore, the ‘‘gold standard’’ as first-line therapy for PTLD remains reduction or withdrawal of immune suppression. It has been reported that this approach is rarely successful in cases of monomorphic PTLD (10) and risk of rejection or death as a result of allograft failure are not insignificant (1). Until recently, patients who have refractory or progressive disease despite immunosuppression reduction or withdrawal often received chemotherapy. PTLD patients tend to tolerate cytotoxic therapy less well than non-transplant patients with increased end organ toxicities and infections (11, 12). Since the vast majority of PTLD in children following SOT are B-cell disease, the use of antiB-cell monoclonal therapy is very attractive. The first use of anti-B-cell monoclonal therapy (antiCD21 and anti-CD24) was in the late 1980s and 1990s and demonstrated high response rates and 50% long-term survival (13). However, these antibodies were not made commercially available. In the late 1990s, the anti-CD20 monoclonal antibody, rituximab, became available commercially world-wide, and has been used to treat numerous complications of SOT, but PTLD has been the primary use (14). There have been numerous reports of anecdotal cases or small series of PTLD patients who have responded well to rituximab. Recently, there have been two relatively large cohorts of 17 and 46 patients with PTLD following SOT treated with rituximab (15, 16). In both studies, patients had to have failed reduction of immunosuppression before receiving rituximab. In both studies, patients were treated with the standard Pediatr Transplantation 2007: 11: 575–577 Copyright 2007 Blackwell Munksgaard