922. The Impact of Clinically Significant CMV Infections on Other Viral Infections in the Era of Letermovir Primary Prophylaxis

Abstract Background Cytomegalovirus (CMV) is a frequent complication after hematopoietic cell transplant (HCT) and may increase the risk of other viral infections through its immunomodulatory effects. Letermovir, a novel antiviral targeting the viral terminase complex, was approved for primary prophylaxis in CMV-seropositive adult recipients after allogeneic HCT (allo-HCT). Because of its efficacy and safety, letermovir has become the standard of care for primary prophylaxis against CMV during the first 100 days post-transplant. However, its impact on the frequency of other viral infections and non-relapse mortality (NRM), through its reduction in clinically significant CMV infections (CS-CMVi), is not known. Methods This is a single-center, retrospective cohort study of 150 allo-HCT recipients, including controls that were matched by the transplant type (match-unrelated, matched-related, cord, and haploidentical), cared for at our institution between March 2016 and December 2018. Baseline demographics, transplant characteristics, prophylaxis, CMV and other viral infections, and outcomes were collected (Table 1) and analyzed on IBM® SPSS version 26 using a binary logistic regression model for multivariate analysis. For univariate analysis, we used Chi-square and Fischer’s Exact Test. Results In our 2:1 matched cohort analysis, 50 patients received letermovir for primary prophylaxis during the first 100 days post-HCT, and 100 did not. In a univariate analysis with CS-CMVi as the outcome, there was a statistically significant difference in NRM at 24 and 48 weeks. Our data indicated a trend towards a decrease in other viral infections for those without CS-CMVi (Table 2). However, in a multivariate analysis accounting for primary prophylaxis with letermovir as an effect modulator, CS-CMVi did not demonstrate a significant impact on the frequency of other viral infections but was associated with NRM at week 24 and 48 (Table 3). Interestingly, having ALL and donor CMV seropositivity were protective factors against other viral infections (Herpesviridae). Conclusion Our study showed that CS-CMVi is associated with higher 24- and 48-week non-relapse mortality but with no increase in the incidence of other non-respiratory viral infections in this matched cohort of allo-HCT recipients. Disclosures Fareed Khawaja, MBBS, Eurofins Viracor (Research Grant or Support) Ella Ariza Heredia, MD, Merck (Grant/Research Support) Roy F. Chemaly, MD, MPH, FACP, FIDSA, AiCuris (Grant/Research Support)Ansun Biopharma (Consultant, Grant/Research Support)Chimerix (Consultant, Grant/Research Support)Clinigen (Consultant)Genentech (Consultant, Grant/Research Support)Janssen (Consultant, Grant/Research Support)Karius (Grant/Research Support)Merck (Consultant, Grant/Research Support)Molecular Partners (Consultant, Advisor or Review Panel member)Novartis (Grant/Research Support)Oxford Immunotec (Consultant, Grant/Research Support)Partner Therapeutics (Consultant)Pulmotec (Consultant, Grant/Research Support)Shire/Takeda (Consultant, Grant/Research Support)Viracor (Grant/Research Support)Xenex (Grant/Research Support)


The Impact of Clinically Significant CMV Infections on Other Viral Infections in the Era of Letermovir Primary Prophylaxis
Background. Cytomegalovirus (CMV) is a frequent complication after hematopoietic cell transplant (HCT) and may increase the risk of other viral infections through its immunomodulatory effects. Letermovir, a novel antiviral targeting the viral terminase complex, was approved for primary prophylaxis in CMV-seropositive adult recipients after allogeneic HCT (allo-HCT). Because of its efficacy and safety, letermovir has become the standard of care for primary prophylaxis against CMV during the first 100 days post-transplant. However, its impact on the frequency of other viral infections and non-relapse mortality (NRM), through its reduction in clinically significant CMV infections (CS-CMVi), is not known.
Methods. This is a single-center, retrospective cohort study of 150 allo-HCT recipients, including controls that were matched by the transplant type (match-unrelated, matched-related, cord, and haploidentical), cared for at our institution between March 2016 and December 2018. Baseline demographics, transplant characteristics, prophylaxis, CMV and other viral infections, and outcomes were collected (Table 1) and analyzed on IBM® SPSS version 26 using a binary logistic regression model for multivariate analysis. For univariate analysis, we used Chi-square and Fischer's Exact Test.
Results. In our 2:1 matched cohort analysis, 50 patients received letermovir for primary prophylaxis during the first 100 days post-HCT, and 100 did not. In a univariate analysis with CS-CMVi as the outcome, there was a statistically significant difference in NRM at 24 and 48 weeks. Our data indicated a trend towards a decrease in other viral infections for those without CS-CMVi (Table 2). However, in a multivariate analysis accounting for primary prophylaxis with letermovir as an effect modulator, CS-CMVi did not demonstrate a significant impact on the frequency of other viral infections but was associated with NRM at week 24 and 48 (Table 3). Interestingly, having ALL and donor CMV seropositivity were protective factors against other viral infections (Herpesviridae).

Conclusion.
Our study showed that CS-CMVi is associated with higher 24-and 48-week non-relapse mortality but with no increase in the incidence of other non-respiratory viral infections in this matched cohort of allo-HCT recipients.
Disclosures  Background. Respiratory virus infections are associated with significant and specific local and systemic inflammatory response patterns, which may lead to reactivation of latent viruses. We examined whether viral upper (URTI) or lower respiratory tract infection (LRTI) with common respiratory viruses increased the risk of CMV viremia after allogeneic hematopoietic cell transplantation (HCT).

Respiratory Syncytial and Parainfluenza Virus Infection Increase the Risk of Cytomegalovirus Reactivation in Allogeneic Hematopoietic Cell Transplant Recipients
Methods. We retrospectively analyzed patients undergoing allogeneic HCT between 4/2008 and 9/2018. CMV surveillance was performed weekly and the presence of upper and lower respiratory symptoms were evaluated by multiplex respiratory viral PCR. We used Cox proportional hazards models to evaluate risk factors for development of any CMV viremia or high level CMV viremia in the first 100 days post-HCT. Each respiratory virus infection episode was considered positive for 30 days beginning the day of diagnosis.
Results. Among 2,545 patients (404 children, 2141 adults), 1,221 and 247 developed CMV viremia and high level CMV viremia, respectively, in the first 100 days post-HCT. Infections due to human rhinoviruses (HRV, N=476) were most frequent, followed by parainfluenza viruses 1-4 (PIV, N=139), seasonal human coronaviruses (COV, N=134), respiratory syncytial virus (RSV, N=77), influenza A/B (FLU, N=35), human metapneumovirus (MPV, N=37), and adenovirus (ADV, N=61). In adjusted models, RSV LRTI was associated with increased risk of developing CMV viremia at all levels (Figures 1 and 2), and PIV or RSV URTI increased the risk of high level CMV viremia; all other viruses showed no association in univariable models. Conclusion. We demonstrated that RSV and PIV infections are associated with an increased risk for development of CMV viremia after allogeneic HCT. This novel association provides the rationale to explore virus-specific inflammatory pathways that may trigger CMV reactivation. CMV viremia may also serve as an endpoint in clinical trials that assess new preventative or therapeutic interventions of RSV or PIV infection.