Cytomegalovirus and Epstein Barr Virus Reactivation after Allogeneic Stem Cell Transplantation in Pre- and Post-Letermovir Era

Cytomegalovirus (CMV) and Epstein-Barr virus (EBV) reactivation are two of the most frequent infections affecting patients receiving allogeneic stem cell transplantation (HSCT). Up to 80% of seropositive patients might experience CMV reactivation in absence of prophylaxis, expecially when a seropositive patient receive stem cell graft from seronegative donor. The introduction of Letermovir notably reduced the risk of CMV infection also in high risk patients. EBV is a herpesvirus widely spread in common population with a prevalence of approximatively 80%. As a consequence, many recipient and donor have EBV seropositive status. We would evaluate if a difference occurred in the CMV and EBV incidence after Letermovir introduction, which casually coincided in our center with the transition to a single graft-versus host disease (GvHD) prophylaxis schedule including cyclophosphamide post (Cy-post). We enrolled patient submitted to allogeneic stem cell transplant in our centre from January 2015 to december 2020. Patients were divided into two groups. The pre-letermovir group (group A, n=230) included patients who had received prophylaxis with ciclosporine A (CSA) plus micophenolic acid (MFA) (N=17) or CSA plus short course methotrexate (MTX) (N=96) or CSA plus MFA plus Cy-post (n=117). In the post-letermovir group (group B, n=135) all patients received the same GvHD prophylaxis with CSA plus MFA plus Cy-post. Sixty-eight of them received letermovir in addition to acyclovir as CMV prophylaxis. In the group A, CMV infection rate was affected by HLA mismatch (HR 1.70, p=0.003), Cy-post use (HR1.49, p=0.02), anti-thymocyte globulin (ATG) use (HR 0.62, p=0.01), bone marrow or cord blood source (HR 1.46, p=0.03), CMV seropositive recipient (HR 10, p=0.0001) and CMV seronegative donor for a seropositive recipient (HR 2.2, p<0.0001). Multivariate analysis confirmed CMV seropositive recipient (HR 9, p=0.002), CMV seronegative donor for seropositive recipient (HR 1.67, p=0.008) and HLA mismatch (HR 3.58, p=0.006) as independent variables for CMV infection. EBV infection appeared to be affected by underlying disease remission status at transplant (HR 1.64, p=0.01), HLA mismatch (HR 0.42, p<0.0001), GvHD prophylaxis other than Cy-post (HR 2.60, p<0.0001), ATG use (HR 2.60, p<0.0001), unrelated donor (MUD) (HR 2.01, p=0.0005) and aGvHD occurrence (HR 1.62, p=0.01). Multivariate analysis confirmed aGvHD occurrence (HR 1.74, p=0.007) and underlying disease remission at transplant (HR 1.90, p=0.002) as independent variables for EBV infection. In the group B, reduced intensity conditioning (HR 5.94, p=0.007), letermovir use (HR 0.23, p=0.0009), and aGvHD occurrence (HR 3.13, p=0.007) were independent risk factors for CMV infection in multivariate analysis. The 100-day CI of CMV infection was of 3% (95% CI 1-12) in patients receiving letermovir vs. 26% (95% CI 17-39) in the others (p=0.02, figure 1A). In the same cohort of patients EBV infection appeared to be more frequent for patients receiving ATG (57% vs. 24%, p=0.05), MUD donor (32% vs. 17%, p=0.04) and who experienced CMV concomitant infection (42% vs. 28%, p=0.03). However, these data were not confirmed in multivariate analysis. According to GvHD prophylaxis, CMV infection appeared to be more frequent in patients receiving Cy-post as GvHD prophylaxis (1-yr CI 68% vs. 54.6%, p=0.02, figure 1B), contrarily to EBV infection which appeared to be less frequent in the same patients (1-yr CI 41% vs. 62%, p<0.0001, figure 1C). However, CMV infection rate was notably reduced by letermovir introduction, while EBV infection rate not appeared to be affected by that. Figure 1: A) Day 100 cumulative incidence of CMV according to letermovir prophylaxis administration; B) One year cumulative incidence of CMV according to cyclophosphamide post transplant administration; C) One year cumulative incidence of EBV according to cyclophosphamide post transplant administration. Figure 1 Figure 1. Disclosures Metafuni: Jazz: Other: Invited Clinical case presentation at meeting. Laurenti: Roche: Honoraria; Gilead: Honoraria; Abbvie: Honoraria, Speakers Bureau; Janssen: Honoraria, Speakers Bureau; AstraZeneca: Honoraria, Speakers Bureau. Sica: Alexion: Consultancy; Jazz Pharma: Consultancy.

Influence of Pre-Transplant Cytomegalovirus (CMV) Serostatus on Post-Transplant Viral Reactivation after Allogeneic Stem Cell Transplantation in Patients Receiving Post-Transplant Cyclophosphamide for Gvhd Prophylaxis

Introduction/Background Human cytomegalovirus (CMV) infection remains one of the major complications affecting the transplant outcomes as it is associated with considerable morbidity and mortality. Pre-transplant CMV serostatus is considered as an important determinant of CMV reactivation after allogeneic HSCT. In 2012 we started using post-transplant cyclophosphamide (post-CY) as GVHD prophylaxis for matched and mismatched unrelated transplant (CY 1 dose) and haploidentical transplant (CY 2 doses). In this study we compared the incidence of CMV reactivation based on donor and recipient pre-transplant serostatus in patients who received post-CY and who did not. Methods and Results Post-transplant CMV reactivation was analyzed in relation to donor/recipient CMV serostatus in 117 patients who underwent alternative donor transplant at UAB between 2009 and 2014. Donors were matched unrelated (94), mismatched unrelated (11) and haploidentical (12) (Table 1). The study patients had at least two months of follow up after the transplant. Graft source was peripheral blood and bone marrow stem cells in 95 (81%) and 22 (19%) patients respectively. Two doses of CY at 50 mg/kg/day was administered on days 3 and 4 following haploidentical and a single dose on day 3 following unrelated donor transplant as a part of GVHD prophylaxis in addition to mycophenolate mofetil (MMF) and tacrolimus. Serial weekly monitoring for CMV viremia was performed using a PP65 antigenemia testing or quantitiative polymerase chain reaction (PCR). Sixty-four (55%) patients received post-CY (group C), 37 (32%) patients received anti-thymocyte globulin (ATG, group A) and 16 (13%) patients received neither ATG nor post-CY (group N). Forty-seven (40%) patients were found to have reactivation of CMV. The majority (99%) in this group had CMV reactivation by day 60 and only 8 of them received more than 7 days of systemic steroid by the time of CMV reactivation. Analyses were performed including these cases. Conclusions have been the same with or without these cases. There have been no CMV diseases in this group. The risk of CMV reactivation appears to be higher in group C (48%) when compared to group A (27%) or group N (37%) but it was not significant (p=0.104). Once CMV reactivated, the peak values of CMV PCR were the same regardless of the group (11,173 copies/ml and 12,173 in group C and group A+N, respectively, p=0.949). If the recipient (R) is seronegative (-), transplant from a seronegative donor (D-) is associated with lower CMV reactivation (0/26 and 2/8 in R-D- and R-D+, respectively, p=0.009). However, if the recipient is seropositive (R+), CMV reactivation incidence tends to be the same whether transplanted from D- or D+ (10/19 and 35/64 in R+D- and R+D+, respectively, p=0.874). In the group C, R+D+ tends to have higher incidence of CMV reactivation than R+D- (24/36 vs 6/12 in R+D+ vs R+D-, respectively, p=0.302). (Table 2) Conclusion: Post-CY has higher risk of CMV reactivation when compared to other GVHD prophylaxis, but once CMV is reactivated the peak values of CMV-PCR have been the similar. In CMV seropositive post-CY patients, transplant from a seropositive donor tends to higher incidence of CMV reactivation rather than from a seronegative donor. This result contradicts to previous publication (Luznik et al, Blood. 2010 Apr 22; 115(16):3224-30.). Our GVHD prophylaxis used only one dose of CY for unrelated donor transplant as opposed to previous publication (2 doses), and also we used tacrolimus and MMF after day 5, which may have caused this difference. Our results warrant further investigation in the mechanism of CMV reactivation in post-CY patients. Table 1 Group CMV Reactivation Post Transplant N Y Count Count A B C 27 33 10 10 31 6 P=0.104 Table 2 Table 2. Disclosures Off Label Use: Cytoxan for GVHD prophylaxis.

Donor CMV Status Influence On the Outcome of Allogeneic Stem Cell Transplantation (HSCT); A Study by the Infectious Diseases Working Party (IDWP) of the EBMT

Abstract 465 A previous study from the IDWP of the EBMT showed that CMV seropositive patients undergoing unrelated donor HSCT had increased NRM and decreased survival if they were grafted from a CMV seronegative donor. This finding has been controversial and we therefore decided to revisit the question with a larger number of patients and including new factors such as conditioning intensity. Patients were selected from the EBMT database who had received an allogeneic HSCT from 1992 – 2008 and for whom both the donor and recipient CMV status were known. Patients receiving cord blood grafts were excluded. 54660 patients were identified and included in the study; 32320 seropositive and 22340 seronegative patients. The different donor categories (sibling, mis-matched family, unrelated) were analyzed separately. Cox multivariate models were fitted to estimate the effect of donor serological status (positive versus negative) on outcome both in CMV seropositive and CMV seronegative patients adjusted for year of HSCT, donor and patient gender, recipient age, stem cell source, diagnosis, use of alemtuzumab or ATG, country, and conditioning intensity (RIC vs. MAC). Seronegative patients receiving grafts from seropositive unrelated donors had an decreased overall survival (OS; HR 1.13; p<.01); relapse free survival (RFS; HR 1.10; <p<.01) and increased non-relapse mortality (NRM; HR 1.13; p<;.01) while no significant effect was seen on relapse incidence (RI; HR 1.06). There were no significant effects in patients receiving HLA-identical or mis-matched family donors. Seropositive patients receiving grafts from seropositive unrelated donors had improved OS (HR 0.91; p<.01), RFS (HR 0.94; p<.05), and decreased NRM (HR 0.87; p<.01) if they had received MAC. No effect of donor serostatus was seen in patients receiving unrelated donor grafts after RIC. No effect of donor status was seen on RI. There were no significant effects in patients receiving HLA-identical or mis-matched family donors. Based on the recent study of Elmaagacli et al showing a decreased relapse risk in patients transplanted for AML of early CMV replication, a separate analysis regarding RI was performed only in AML patients in first CR. However, no effect of donor serostatus on RI was found in either seropositive or seronegative patients. In this analysis we confirm the negative effect on OS, RFS, and NRM if a CMV seropositive unrelated donor is selected for a CMV seronegative patient. It therefore remains important to select a seronegative donor when the patient is seronegative. For a CMV seropositive patient our data support the choice of a CMV seropositive donor if the patient is planned to receive a myeloablative conditioning regimen. Disclosures: No relevant conflicts of interest to declare.