Limited Efficacy of Prompt Therapy of Posttransplant Lymphoproliferative Disorder (PTLD) with Rituximab

Introduction:  Epstein-Barr virus (EBV)-induced posttransplant lymphoproliferative disorder (PTLD) incidence is particularly high when using graft versus host disease (GVHD) prophylaxis with rabbit antithymocyte globulin (ATG). Preemptive therapy with rituximab given when EBV DNAemia exceeds a threshold has been adopted by some centers. However, this exposes a large fraction of patients to rituximab, which is costly and toxic (neutropenia).  Wagner et al suggested a high efficacy of prompt therapy (monitoring EBV DNAemia, having a high index of suspicion for PTLD in patients with high DNAemia, and treating PTLD with rituximab at a presumed early stage)(Blood 103:3979, 2004). In Alberta, we adopted the prompt therapy in 2012. Here we report our experience.

Methods: We retrospectively studied 511 patients undergoing myeloablative allogenic hematopoietic stem cell transplant (HCT). ATG (4.5 mg/kg) was used for GVHD prophylaxis in addition to methotrexate and cyclosporine. Between 1/2007 and 1/2011, no EBV monitoring was done and PTLD (usually histologically diagnosed, including Epstein-Barr encoding RNA [EBER] in situ hybridization) was treated with rituximab (period “No EBV Monitoring”, 267 patients). Between 2/2011 and 4/2012, EBV monitoring (weekly till day 100) was done, but PTLD was treated with rituximab only when histologically diagnosed (“Transition” period, 88 patients). We noted that histologically proven PTLD occurred only with EBV DNAemia >40,000 genome copies/mL blood. Between 5/2012 and 12/2014, EBV monitoring was done, PTLD was diagnosed as clinical/radiological manifestation of PTLD with EBV DNAemia >40,000 and was treated with rituximab promptly (period “Prompt Therapy”, 156 patients).  We compared the “No EBV Monitoring” period with the “Prompt Therapy” period, using Fine-Gray analysis for cumulative incidence of PTLD, mortality due to PTLD or mortality associated with PTLD (death due to any cause after PTLD has been diagnosed) and Cox analysis for overall survival.

Results: In all 3 periods combined, a total of 48 PTLDs developed at a median day 55 after HCT. 81% PTLDs occurred before day 100. Comparison of the “No EBV Monitoring” and the “Prompt Therapy” periods showed a non-significant trend toward a higher cumulative incidence of PTLD in the latter period (possibly due to the increased index of suspicion for PTLD in patients with high DNAemia), and no difference in mortality due to PTLD, mortality associated with PTLD, or overall survival (Figure 1).  After rituximab, clinical/radiological regression of PTLD occurred in 15/21 (71%) patients in the No EBV Monitoring period and in 13/17 (76%) patients in the Prompt Therapy period (not significant). Next, we evaluated whether PTLD regression is associated with DNAemia becoming undetectable and progression with persistently detectable DNAemia. This was evaluated in patients from the “Transition” and the “Prompt Therapy” periods. As shown in Figure 2, all (7/7) patients with PTLD progression had persistently detectable DNAemia. Among patients with PTLD regression, DNAemia became undetectable in most (15/20) patients. 0/15 (0%) patients with persistently undetectable DNAemia developed PTLD progression, whereas 7/12 (58 %) patients with persistently detectable DNAemia developed PTLD progression. This suggests high negative predictive value but low positive predictive value of persistently detectable DNAemia for PTLD progression.

Conclusion: Prompt therapy of presumed early PTLD in the setting of EBV monitoring did not result in better outcomes than therapy of presumed advanced PTLD (without EBV monitoring).  Even with the prompt therapy, rituximab was only 76% efficacious. After rituximab, undetectable EBV DNAemia indicates PTLD regression, whereas persistently detectable EBV DNAemia is associated with 58% risk of PTLD progression.