Viral Reactivation after Allogeneic Hematopoietic Stem Cell Transplantation: Benefits and Risks for Disease Relapse
Authors: Loron Sandrine , Sobh Mohamad , Barraco Fiorenza , Thomas Xavier , Ducastelle Sophie , Renault Myriam , Ader Florence , Frobert Emilie , Nicolini Franck-Emmanuel , Labussière Hélène , Michallet Mauricette 
Published: October 2019

Abstract
Background:
In the setting of allogeneic hematopoietic stem cell transplantation (allo-HSCT), donor and/or recipient cytomegalovirus (CMV) seropositivity is still associated with a lower overall survival (OS) despite current strategies to decrease CMV disease incidence. However, recent studies have suggested that early CMV reactivation decreases the risk of disease relapse after allo-HSCT. Other reactivations like Epstein-Barr virus (EBV) and BK virus (BKV) with an adverse impact on OS have not been evaluated in the same context. The aim of our study was to evaluate the impact of early CMV, EBV and BK-V reactivation after allo-HSCT on the relapse incidence.
Patients and methods:
We evaluated 292 allo-HSCT in adults recipients with acute myeloid leukemia (n=114), acute lymphoid leukemia (n=60), multiple myeloma (n=41), non-Hodgkin lymphoma (n=27), myelodysplastic syndrome (n=18), Hodgkin's disease (n=14), myeloproliferative neoplasms (n=13), and chronic lymphoid leukemia (n=7) treated at the University Hospital Centre of Lyon between years 2008 and 2013. At transplantation, 77% of patients were in complete response (CR) or chronic phase and 23% in less than CR. One hundred and thirty-two (45%) patients received bone marrow, 119 peripheral blood stem cells, 41 cord blood, conditioning regimen was myeloablative (MAC) in 163 (56%) cases. Antithymocyte globulin was used in conditioning regimen for GVHD prophylaxis in 70% of patients. After allo-HSCT, patients underwent twice weekly screening for CMV and EBV reactivation using a RQ-PCR until day 90 whereas BKV was screened in case of urinary symptoms and/or hematuria. CMV and EBV reactivation was defined as any level of DNAemia ≥ 1000 copies/mL, the diagnosis of BKV reactivation was relied on the presence of hemorrhagic cystitis with positive BKV viruria and/or viremia.
Results:
In the global population, the cumulative incidence of CMV, EBV, BKV reactivations by day 90 was 29.1% (95%CI: 24-34), 33.9% (95%CI: 29-39), and 16.8% (95% CI: 13-21) with a median occurrence time after allo-HSCT of 40 days, 41 days, and 36 days respectively. The cumulative incidence of relapse at 2 and 4 years was 26% (21-31%) and 29% (24-34%) respectively with a cumulative incidence of NRM of 16% (12-21) and 24% (19-29) respectively. Among the 99 patients with EBV reactivation, 32 (32.3%) needed treatment with rituximab. In univariate analysis, disease status at transplantation and type of conditioning were significantly impacting relapse incidence. In multivariate analysis, when adjusting on type of conditioning regimen and disease status at transplantation, patients with CMV reactivation had significantly lower rate of relapse, HR=0.81, 95% CI: 0.67-0.98, p=0.03, this was the same for those with EBV reactivation, HR=0.86, 95%CI: 0.72-1), p=0.05, as well as for BKV, HR=0.79, 95%CI: 0.66-0.95, p=0.012. In addition, we found that patients who had a simultaneous reactivation of CMV and EBV were at higher risk of relapse, HR=4.2, 95%CI: 1.9-8.1, p=0.002.
Conclusion:
We confirmed the positive impact viral reactivation after allo-HSCT on relapse incidence, which could be explained as a stimulation of both function and amplification of NK compartment. Our finding about viral co-reactivation that includes EBV with a higher risk of relapse should be further explored and carefully interpreted as this might come from EBV treatment by rituximab that impairs the immunological system by impacting the GVL effect and therefore leads to more relapse.

Disclosures
Michallet: Octapharma: Membership on an entity's Board of Directors or advisory committees; Chugai: Consultancy; Novartis: Research Funding.