Impact of Single or Associated CMV, EBV and BK Virus Reactivation Early after Allogeneic Hematopoietic Stem Cell Transplantation on Relapse Incidence
Authors: Michallet Mauricette , Sobh Mohamad , Leroy Sandrine , Barraco Fiorenza , Thomas Xavier , Ducastelle Sophie , Lina Bruno , Morfin Florence , Ader Florence , Frobert Emilie , Nicolini Franck E. , Michallet Anne-Sophie 
Published: October 2019

Abstract

Background:
Many recent studies have evaluated the impact of cytomegalovirus (CMV) reactivation after allogeneic hematopoietic stem cell transplantation (allo-HSCT) showing a significant association with reduced risk of relapse. On the other hand, other frequent viral infections or reactivations like Epstein-Barr virus (EBV) and BK virus (BK-V) have not been evaluated in the same context and we do not know whether their association has an impact on transplantation outcomes or not.
Objective:
The aim of this study is to evaluate the impact of CMV, EBV and BK-V reactivation up to 3 months after allo-HSCT whether alone or associated on the relapse incidence of patients with hematological malignancies.
Patients and methods:
We evaluated 359 consecutive patients with hematological malignancies who received allo-HSCT and were followed in our center between January 2008 and June 2013; there were 218 (61%) males and 141 (39%) females with a median age of 48 years (range: 18-70), 182 (51%) had acute myeloid leukemia, 44 (12%) multiple myeloma, 34 (9%) myelodysplastic syndrome, 30 (8%) Non-Hodgkin lymphoma, 7 (2%) chronic lymphocytic leukemia, 21 (6%) myeloproliferative syndrome, 14 (4%) Hodgkin disease, 13 (4%) chronic myeloid leukemia and 14 (4%) aplastic anemia. At transplantation, 227 (63%) patients were in complete response (CR) or chronic phase (CP) and 132 (37%) were in less than CR or CP. For conditioning regimen, 171 (48%) were myeloablative and 188 (52%) were reduced intensity. DNA levels of CMV, EBV and BK-V in blood were detected by quantitative real-time polymerase chain reaction (RQ-PCR) after weekly monitoring up to 3 months after allo-HSCT. CMV-DNA, EBV-DNA or BK-V-DNA was considered positive when the copies exceeded 1000 copies/ml.
Results:
Among 359 patients, there were 102 patients who had CMV reactivation after a median time of 1.4 months (1.1-1.8) after allo-HSCT with a cumulative incidence of 25 % (24-26) at 3 months; 222 patients had EBV reactivation after a median time of 1.3 months (0.7-2.5) after allo-HSCT with a cumulative incidence of 48 % (47-50) at 3 months; and 38 patients had BK-V reactivation after a median time of 1.1 months (0.7-1.5) after allo-HSCT with a cumulative incidence of 10 % (9-11) at 3 months. The cumulative incidence of relapse at one and two years for the whole population was 27% (26-28) and 34% (33-35) respectively and the cumulative incidence of transplant-related mortality (TRM) was 22% (21-23) and 25% (24-26) respectively. The multivariate analysis took into account the type of disease, the type of conditioning, the disease status at transplantation, the presence of acute GVHD and single or the association of viral reactivation; this analysis showed that the presence of a single viral reactivation was associated with a significant lower relapse rate, for CMV: sdHR=0.34 [0.12-0.92], p=0.03, for EBV: sdHR= 0.52 [0.35-1], p=0.05 and for BK-V: sdHR=0.58[0.24-0.7], p=0.002; and that patients who have an associated CMV and EBV reactivation had significantly higher risk of relapse, sdHR= 5 [1.59-16], p=0.006. There was no significant impact of these reactivations on TRM.
Conclusion:
We confirmed the positive impact of CMV reactivation on relapse incidence, in addition we demonstrated that this impact exists also for EBV and BK-V, however we showed for the first time that the association of CMV and EBV was significantly associated with a higher risk of relapse. More investigations are ongoing to evaluate the immunological status of these patients and the different administered anti-viral treatments.

Disclosures
No relevant conflicts of interest to declare.