Prevention and Treatment of EBV-PTLD in HSCT Recipients: A Systematic Review Based on ECIL-2 Recommendations

INTRODUCTION: The rate of death due to EBV posttransplant lymphoproliferative disorder (EBV-PTLD) in the long-term analysis of 18,014 patients from 234 transplant centers was 66/78 (84.6%) up to 1999 (Curtis RE et al, Blood, 1999).

OBJECTIVE: To evaluate the role of available treatment modalities for prevention and treatment of EBV-PTLD in HSCT recipients, based on ECIL-2 recommendations.

DATA SOURCES: A PubMed search (1999–2008) was conducted using the key words EBV, PTLD, posttransplant lymphoproliferative disorder, stem cell transplantation, rituximab, CTL, cytotoxic lymphocytes, immunosuppression withdrawal/reduction, chemotherapy. References of relevant articles and abstracts from recent hematology and stem cell transplantation scientific meetings (2003–2008) were also reviewed.

STUDY SELECTION AND DATA EXTRACTION: Prospective and retrospective studies identified from the data sources were evaluated, and all data deemed relevant were included in this analysis.

DEFINITIONS: Prophylaxis of EBV-DNA-emia (EBV reactivation) – any agents or specific cells given to seropositive, EBV-DNA-negative patient (or when donor was seropositive) to prevent EBV reactivation. Preemptive therapy – any agents or specific cells given to an asymptomatic patient with EBV detected by a screening assay. Treatment of PTLD – any agents or specific cells applied to a patient with overt EBV-PTLD.

RESULTS: High risk HSCT for PTLD development were allogeneic HSCT with following risk factors: unrelated/mismatch HSCT; T-cell depletion or ATG/OKT3 use; EBV serology mismatch; primary EBV infection; splenectomy. The risk increased with the number of risk factors. In addition to quantification of EBV DNA load, analysis of the level of (EBV-specific) T cell reconstitution during EBV reactivation might be an important second parameter to define patients at risk for EBV-PTLD who might be candidates for preemptive interventions.

1. Rituximab: A total number of 49 papers and 29 conference abstracts were available. Most reports included small number of patients. Overall response rates were: 61% (14/23 pts) for prophylactic use of rituximab; 89.7% (306/341 pts) for preemptive therapy with rituximab, and 63% (92/146 pts) for rituximab used for therapy of EBV-PTLD disease. Rituximab was safe and well tolerated.

2. Allogeneic cytotoxic T-lymphocytes (CTLs): A total numbers of 8 papers and 3 conference abstract were available. Overall response rates were: 98.5% (133/135 pts) for preemptive therapy, and 86% (12/14 pts) for CTLs used for therapy of EBV-PTLD disease. There was 6% and 12% of aGVHD and cGVHD, respectively.

3. Reduction of immunosuppressive therapy: The data is difficult to extract, since usually this method was combined with other therapeutic approach. Based on data extracted from 3 papers and 3 abstracts, overall improvement was 60% (71/118). Unlike in solid organ transplants, this approach does not appear to be effective as a primary therapy, however it can facilitate T-cell reactivation.

4. Chemotherapy: Data are largely anecdotal. 2 papers and 4 abstract were available. Overall survival was 27% (6/22 patients). Two additional case reports are available related to successful use of hydroxyurea.

5. Donor lymphocyte infusion (DLI): Data are scanty. DLI was usually used in combination with other treatment modalities. Overall survival was reported as 21/56 (37.5%) patients. There is no activity of antiviral agents (ACV, GCV, FCV, CDV) in late EBV reactivation, as reviewed in several papers.

SUMMARY AND CONCLUSIONS: Preemptive use of rituximab reduced the odds ratio (OR) of death due to EBV-PTLD 46-fold (95%CI=22- 104, p<0.0001, Mantel-Haenszel method), while therapeutic use reduced it 9.3-fold (95%CI=4.4–20, p<0.0001). Preemptive use of EBV-CTLs reduced the OR of death due to EBV-PTLD 365-fold (95%CI=73–2473, p<0.0001), while therapeutic use reduced it 33-fold (95%CI=5.7–246, p<0.0001). Reduction of immunosuppression contributed 8.3- fold (95%CI=3.8–18, p<0.0001) to reduction of OR of death. DLI contributed 3.3-fold (95%CI=1.3–8.1, p=0.035) to reduction of OR of death. Chemotherapy did not contribute to decreasing the OR of death due to PTLD after HSCT. There is no activity of antiviral agents in late EBV reactivation.