Impact of Epstein Barr virus-related complications after high-risk allo-SCT in the era of pre-emptive rituximab

Abstract

We monitored 133 high-risk allo-SCT recipients for 6 months after transplant for EBV reactivation by quantitative real-time PCR. Rituximab was given as pre-emptive therapy for viremia 41000 copies/mL. The 1-year cumulative incidence of EBV reactivation was 29.4% (95% confidence interval (CI): 18-40) in patients monitored due to initial high-risk characteristics (n = 93) and 31.8% (95% CI: 19.7-44) in those followed because of the development of refractory GVHD (n = 40). Overall response rate to Rituximab was 83%. Nine patients (9.6%) developed post-transplant lymphoproliferative disorder (PTLD) at a median of +62 days after SCT. Eight of them showed a concomitant CMV reactivation. Second SCT was the only risk factor associated with EBV infection and PTLD in multivariate analysis (hazard ratio (HR) 2.6 (95% CI: 1.1-6.4; P = 0.04) and HR 6.4 (95%CI: 1.3-32; P = 0.02)). The development of EBV reactivation was not associated with non-relapse mortality or OS (P = 0.97 and P = 0.84, respectively).Bone Marrow Transplantation (2015) 50, 579-584; doi:10.1038/bmt.2014.298; published online 12 January 2015 INTRODUCTION Epstein-Barr virus-related post-transplant lymphoproliferative disorder (PTLD) is a serious complication after SCT with a mortality as high as 85%. 1 Major risk factors for PTLD include HLA disparity, graft T-cell depletion and administration of anti-thymocyte globulin (ATG) or other anti T-cell antibodies. 2,3 PTLD is usually preceded by a preclinical phase characterized by rising EBV copies in peripheral blood which can be quantified by polymerase-chain reaction (PCR). Recent guidelines recommend monitoring EBV viral load in high-risk allo-SCT recipients, according to the mentioned predisposing factors. 4 The real incidence and prognosis of EBV disease are difficult to evaluate due to differences in the PCR methods used to test EBV DNA, the quantitative PCR thresholds for therapeutic intervention and the diversity of criteria for defining high-risk patients. 5 Efforts to improve immune responses by reducing immunosuppressive drugs remain as one of the cornerstones of management but are not applicable to patients with active GVHD; 6,7 thus, eliminating B lymphocytes with the anti-CD20 monoclonal ab Rituximab is the most feasible treatment. 7 In the current study we compare the incidence and prognosis of EBV-related complications between patients with baseline highrisk characteristics for PTLD and patients affected by refractory GVHD, prospectively monitored for EBV DNAemia with early institution of Rituximab as pre-emptive therapy.

Management of Epstein-Barr Virus infections and post-transplant lymphoproliferative disorders in patients after allogeneic hematopoietic stem cell transplantation: Sixth European Conference on Infections in Leukemia (ECIL-6) guidelines

“…B-cell depletion by prophylactic use of rituximab before or shortly after allo-HSCT might reduce the risk of EBV DNA-emia and PTLD (Table 6). 20,23,69,70 In a large retrospective analysis, prophylactic post-transplant rituximab significantly reduced the risk of EBV DNAemia; however, no statistically significant impact on PTLD incidence, treatment-related mortality, and overall survival in comparison to a pre-emptive approach was demonstrable. 69 Low risk of EBV-PTLD was observed also after the use of post-transplant high-dose cyclophosphamide, 23 or sirolimus as GvHD prophylaxis.…”

“…The reported incidence of EBV DNA-emia ranging between 0.1-63% is largely dependent on the type of transplant, assay sensitivity, defined level of DNA-emia, use of systematic screening and its timing. [18][19][20][21][22][23][24][25][26][27] In a recent EBMT study, the overall incidence of PTLD after allogeneic HSCT was 3.2%, varying from 1.2% in matched family donor (MFD) to 2.8% in mismatched family donor (haploidentical/MMFD), 4.0% in matched unrelated donor (MUD), and 11.2% in mismatched unrelated donor (MMUD) recipients. 3 In recipients of unrelated cord blood (CBT), the incidence of EBV-PTLD was 2.6-3.3% for myeloablative transplants, and 7-12.9% in nonmyeloablative transplants.…”

“…21 Pooling results from published studies in HSCT recipients suggest that administration of rituximab results in a positive outcome for approximately 90% patients treated pre-emptively, and 65% with EBV-PTLD. 2,3,11,12,19,20,24,27,[51][52][53][54][55][56][57][58][59][60][61][62] Recent data demonstrate that RI, when applied in combination with rituximab, appears to improve the outcome by over 80%. 3 RI used alone as preemptive therapy resulted in a 68% success rate.…”

“…69 Low risk of EBV-PTLD was observed also after the use of post-transplant high-dose cyclophosphamide, 23 or sirolimus as GvHD prophylaxis. 20 Since rituximab treatment after allo-HSCT has been related to an increased risk of life-threatening cytopenias 71 and bacterial infections, …”

“…Risk factors for developing EBV-PTLD can be considered as existing pre- 20,24,[33][34][35] or developing post-transplant 7,[34][35][36][37] ( Table 3). Importantly, assessing the risk of EBV-PTLD is dependent on the HSCT context with potentially complex interactions between the primary hematological malignancy, HSCT procedure, source, and other factors.…”