Epstein–Barr virus reactivation in allogeneic stem cell transplantation is highly related to cytomegalovirus reactivation

Abstract

Monitoring of Epstein-Barr virus (EBV) load and pre-emptive rituximab is an appropriate approach to prevent post-transplant lymphoproliferative disease (PTLD) occurring after hematopoietic stem cell transplantation (HSCT). This pre-emptive approach, based on EBV-DNA monitoring through a quantitative polymerase chain reaction, was applied to 101 consecutive patients who underwent allo HSCT at our Institute (median age 50). A single infusion of rituximab was administered to 11 of 16 patients who were at high risk for progression to PTLD, defined as a DNA value >10 000 copies/mL. All patients cleared EBV DNAemia, without any recurrences. Main factors significantly associated with high risk for PTLD were as follows: (i) unrelated vs. sibling (26% vs. 7%; p = 0.011); (ii) T-cell depletion (29% vs. 6%; p = 0.001); (iii) graft versus host disease (GVHD; 30% vs. 7%; p = 0.002); and (iv) cytomegalovirus (CMV) reactivation (29% vs. 4%; p = 0.001). Multivariate analysis showed that CMV reactivation was the only independent variable associated with EBV reactivation. We conclude that: (i) a single infusion of rituximab is able to prevent the risk of progression into EBV-related PTLD; and (ii) CMV reactivation is strongly associated with EBV reactivation; therefore, an intensive EBV monitoring strategy could be advisable only in case of CMV reactivation.

Posttransplantation lymphoproliferative disorder after pediatric solid organ transplantation: experiences of 20 years in a single center

“…We achieved complete remission in every case with a low rate of graft loss (5.6%), which is much higher than reported in the early 2000's1415) but similar to those of a recent report16). In order to assess risk factors of PTLD among pediatric SOT recipients, comparison between patients with PTLD and without PTLD should be done, which is beyond the scope of this report and it is the limitation of this report; Among the known risk factors14), frequency of CMV infection in our cases was 22%, not different from known frequency of CMV in pediatric SOT recipients of one forth17). HLA types of recipients A2, A11, A26, B5, B8, B18, B21, B38 and B40 had been reported to be of risk of PTLD18192021), and in our cases HLA-A2 was common; however in Korean population HLA A2 is common15), therefore significance thereof is yet elusive.…”

The Epstein-Barr Virus (EBV) in T Cell and NK Cell Lymphomas: Time for a Reassessment

“…In addition to age, genetic background, and ethnicity [174, 175], other factors may modify EBV-induced cancer risk, including co-infection with other pathogens [176, 177], EBV strain type [178], development of serious illnesses, and chronic exposure to therapeutic drugs [179]. In this context, the emergence of EBV-associated MTNKL may represent one of many possible neoplastic end results of the prolonged and dynamic interplay between the virus and its aging host.…”

Epstein‐Barr virus post‐transplant lymphoproliferative disease (PTLD) after hematopoietic stem cell transplantation

“…The incidence of EBV-PTLD with haplo-identical donor was significantly higher [19] 2+ HLA antigen-mismatched related or unrelated donor had significant higher risks [15] UCBT UCBT could increase the risk of EBV events and EBV-PTLD probably due to the condition and immunosuppression [20,21] EBV-DNA Load Both high and very low level of EBV-DNA load had a higher OS than patients with moderate intermediate EBV-DNA load [23] The very low level of EBV load was indicated as a predictive biomaker of a poor survival [24] GVHD Acute GVHD grades II-IV had a significantly higher risk for EBV viremia [25] Acute GVHD grades III-IV was a risk factor of EBV viremia [26] Both acute and chronic GVHD increased the risk of PTLD [15] Acute GVHD impairs specific immune reconstruction due to pro-inflammatory cytokine storm [3] Constant antigen stimulation occurred in GVHD and profound immunosuppressive treatment could probably contribute the risk for PTLD [14] CMV CMV reactivation reflected recovery speed of immune system in pediatric recipients after HSCT [29] CMV has been confirmed as a risk factor after both solid organ transplantation and HSCT [30][31][32]34] CMV reactivation is strongly connected with EBV reactivation [33] Splenectomy Splenectomy was a risk factor [14,35] CD5+ B cell rely on spleen, its immune regulatory function would be impaired after splenectomy, leading to EBV load explosive growth [14,37] TCD There is a dichotomy of PTLD incidence between patients with or without TCD (≥10% vs <1%) [24,[38][39][40][41][42] Recipients with grafts T-cell depletion highly predicted EBV-PTLD [43,44] The selective T-cell depletion had a strong association with risks higher than other TCD methods [15] Alemtuzu mab Alemtuzumab increased virus infections [17] Alemtuzumab was a risk factor for the arising of PTLD…”

“…58 Rituximab is the most recommended agent for patients to prevent the occurrence of PTLD. 33 However, pre-emptive rituximab therapy threshold remained to be defined, and the benefit of long-term survival was certified only in patients with very high load as 50 000 cp/mL. Apart from it, other groups of researchers suggested the threshold to receive rituximab is when the EBV viral load ≥ 1000 cp/mL on two consecutive occasions or one over 10 000 cp/mL in plasma in high-risk recipients (with unrelated or mismatched related donor or underwent RIC) or exceeding 40 000 cp/mL in WB.…”