Background Cytomegalovirus (CMV) reactivation is one of the most common infectious complications after allogeneic hematopoietic cell transplant (HCT) and may result in significant morbidity and mortality. Primary prophylaxis with letermovir demonstrated a reduction in clinically significant CMV infections (CS-CMVi) in clinical trials of CMV-seropositive HCT recipients. This study aims at exploring the effect of primary letermovir prophylaxis in this population on the incidence and outcomes of refractory or resistant CMV infections. Methods This is a single-center, retrospective cohort study of 537 consecutive CMV-seropositive allogeneic HCT recipients cared for during March 2016 to October 2018. Baseline demographics, HCT characteristics, CMV infections, treatment and mortality data were collected from the electronic medical record. CMV outcomes were defined according to the recently standardized definitions for clinical trials. Characteristics and outcomes were assessed according to receipt of primary letermovir prophylaxis. Results Of 537 patients identified, 123 received letermovir for primary prophylaxis during the first 100 days after HCT, and 414 did not. In a multivariate analysis, primary prophylaxis with letermovir was associated with reductions in CS-CMVi (hazard ratio [HR] 0.26, 95% CI 0.16-0.41), CMV end-organ disease (HR 0.23, 95% CI 0.10-0.52), refractory or resistant CMV infection (HR 0.15, 95% CI 0.04-0.52), and non-relapse mortality at week 48 (HR 0.55, 95% CI 0.32-0.93). There was neither resistant CMV nor CMV-related mortality in the primary letermovir prophylaxis group. Conclusions Primary letermovir prophylaxis effectively prevents refractory or resistant CMV infections and decreases non-relapse mortality at week 48, as well as CS-CMVi and CMV disease after allogeneic HCT.

Cytomegalovirus (CMV) reactivation is one of the most common infections affecting allogeneic hematopoietic cell transplant recipients. Although available anti-CMV therapies have been evaluated for the prevention of CMV reactivation, their toxicity profile makes them unfavorable for use as primary prophylaxis; thus, they are routinely reserved for the treatment of CMV viremia or CMV end-organ disease. Pre-emptive CMV monitoring strategies have been widely accepted, and although they have been helpful in early detection, they have not affected the overall morbidity and mortality associated with CMV. Letermovir is a novel agent that was approved for primary prophylaxis in CMV-seropositive adult allogeneic hematopoietic cell transplant recipients. This review focuses on letermovir’s novel mechanism; clinical trials supporting its United States Food and Drug Administration (FDA) approval and subsequent follow-up analyses; clinical considerations, with an emphasis on pharmacology; and lessons learned from solid organ transplant recipients, as well as potential future directions.

Tac, CsA, or Siro and were initiated on ISV for fungal prophylaxis. The pre-ISV serum blood level of IS was compared to the serum level 48 hrs after the start of the ISV loading dose. We also examined how IS were converted from IV to oral by comparing the IS level on the day of IV to PO conversion to the IS level 48 hrs after PO was initiated while pts received ISV. Results: There were 85 instances of ISV initiation in 78 pts on IS. Of the 85 instances of ISV initiation 23 (27%) received CsA, 55 (65%) received Tac, and 7 (8%) received Siro. The median age was 56 (range 21-75) and 25 (32%) of the pts were female. Pts receiving IV CsA (n = 23) had a median percent dose change (%DC) of-10% on initiation of ISV and the median 48hr percent level change (%LC) was-5.7%, with a median net difference (%ND) of +6%. For the pts who were converted from IV CsA to PO CsA (n = 20) the empiric %DC from IV to PO was +25% with a %LC of +1.71% with a %ND of-18.51%. This corresponds to an IV:PO of 1:1.2. For pts receiving IV Tac (n = 55) the median %DC was-16.7% and the %LC was-3.4% with a %ND of +12.4 %. The pts who were converted from IV Tac to PO (n = 41) had a median empiric %DC of +200% with a corresponding %LC of-30.26, with a %ND of +228.49%. This corresponds to a IV:PO of 1:2.3. For the pts receiving Siro (n = 7) the median %DC was 0% and the median %LC of +17.8% with a %ND of +23.8%. Conclusion: Initiation of ISV did result in serum level elevations in patients receiving CsA, Tac, and Siro. For CsA the increase in level was minimal, however for Tac and Siro the level increased 12.4% and 23.8% respectively which may be clinically important and dose reductions should be considered in select patients. This study also showed how ISV affects the IV to PO conversion of Tac and CsA with IV:PO ratios of 1:2.3 and 1:1.2 respectively. This demonstrates that ISV affects first-pass metabolism of Tac and CsA and this should be taken into consideration when making IV to PO conversions.

Background CMV reactivation is one of the most common infections after allogeneic hematopoietic cell transplantation (allo-HCT) and carries considerable morbidity and mortality. Primary prophylaxis with letermovir demonstrated in clinical trials reduction of the incidence of clinically significant CMV infection (CS-CMVi). This study aims at exploring the effect of letermovir primary prophylaxis on the occurrence of refractory or resistant CMV infections. Methods This is a single-center, retrospective cohort study of 537 consecutive allo-HCT CMV-seropositive recipients cared for between March 2016 and December 2018. Baseline demographics, transplant characteristics, CMV infections, treatment and mortality data were collected from the electronic medical record (Table 1). CMV outcomes were defined according to the standardized definitions for clinical trials. Data was analyzed on IBM® SPSS version 24 using a logistic regression model for multivariate analysis. Results Out of 537 patients identified, 123 received letermovir for primary prophylaxis during the first 100 days post-HCT and 414 did not. In a multivariate analysis, primary prophylaxis with letermovir was associated with a reduction in CS-CMVi (OR 0.11, 95% CI 0.06–0.20), CMV disease (OR 0.20, 95% CI 0.08–0.46) and refractory or resistant CMV infection (OR 0.11, 95% CI 0.02–0.49) (Table 2). Notably, there was no resistant CMV and no CMV-related mortality in the letermovir group. There was a trend towards lower all-cause mortality at day 100 in the letermovir group (OR 0.48, 95% CI 0.18–1.2). Table 1 - Baseline Characteristics. Table 2 - Multivariate Analysis of Clinical Outcomes. Conclusion Our study showed a strong association between primary prophylaxis with letermovir and reduction in refractory or resistant CMV infections and CMV disease in allo-HCT recipients. Disclosures Ella Ariza Heredia, MD, Merck Sharp & Dohme (Grant/Research Support)Oxford Immunotec (Grant/Research Support) Roy F. Chemaly, MD, MPH, FACP, FIDSA, Chimerix (Consultant, Research Grant or Support)Clinigen (Consultant)Merck (Consultant, Research Grant or Support)Novartis (Research Grant or Support)Oxford Immunotec (Consultant, Research Grant or Support)Shire/Takeda (Research Grant or Support)Viracor (Research Grant or Support)

Allogeneic hematopoietic cell transplantation (HCT) remains the only curable option for adult patients with hematologic malignancies. According to guidelines published by the American Society for Transplantation and Cellular Therapy, allogeneic HCT should be offered to all intermediate‐ and high‐risk patients with acute leukemia. While matched‐related donor (MRD) grafts continue to be the preferred stem cell source for allogeneic HCT, studies comparing MRD grafts to matched‐unrelated donor (MUD) grafts showed comparable outcomes in patients with acute leukemia. Unfortunately, for those without a suitable matched‐related graft, the probability of finding a suitable matched‐unrelated donor varies significantly depending on racial and ethnic background. With allogeneic HCT procedures increasing year after year due to the increased availability of suitable donors, each of these alternative donor sources merits special clinical considerations, specifically with regard to infections. Infections remain a significant cause of morbidity and mortality after allogeneic transplant, especially in those receiving alternative donor grafts. Due to the high‐risk nature associated with these donor grafts, it is important to understand the true risk of developing infectious complications. While there are a multitude of infections that have been described in patients post‐allogeneic HCT, this review seeks to focus on the incidence of cytomegalovirus (CMV) and invasive fungal infections (IFI) in adult patients receiving alternative donor source transplantation for hematologic malignancies.