Refractory and Resistant Cytomegalovirus After Hematopoietic Cell Transplant in the Letermovir Primary Prophylaxis Era.

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 between March 2016 and 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; 414 did not. In a multivariate analysis, primary prophylaxis with letermovir was associated with reductions in CS-CMVi (hazard ratio [HR] 0.26; 95% confidence interval [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 nonrelapse 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 nonrelapse mortality at week 48, as well as CS-CMVi and CMV disease after allogeneic HCT.

Letermovir and its role in the prevention of cytomegalovirus infection in seropositive patients receiving an allogeneic hematopoietic cell transplant.

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.

Incidence of viral and fungal complications after utilization of alternative donor sources in hematopoietic cell transplantation.

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.