Professor of Medicine
Department of Infectious Diseases, Infection Control, and Employee Health
The University of Texas MD Anderson Cancer Center
Roy F. Chemaly, MD, has disclosed that he has received consulting fees from Astellas, Chimerix, Merck, and Oxford Immunotec and funds for research support from Chimerix, Merck, and Novartis.
Despite the availability of FDA-approved antivirals and screening methods, cytomegalovirus (CMV) infection and disease remain a major complication in patients undergoing hematopoietic cell transplantation (HCT). Up to 80% of adults in the United States are infected with CMV, which usually causes no symptoms. However, among immunocompromised transplantation recipients, latent CMV can reactivate. Up to 20% of allogeneic HCT recipients may develop CMV disease.
Our current strategies for preventing and managing CMV reactivation have serious limitations, most notably drug-related toxicities. In this commentary, I discuss emerging investigational agents and strategies that may allow for improved prevention and management of CMV infection in the vulnerable HCT patient population.
Letermovir for CMV Prophylaxis
The investigational agent most advanced in clinical development is letermovir, which targets a component of the viral terminase complex associated with viral DNA cleavage and packaging. Results of a phase III study assessing letermovir for CMV prophylaxis were recently reported. In this double-blind trial, CMV-seropositive, adult allogeneic HCT recipients were randomized 2:1 to receive either daily letermovir or placebo for up to 14 weeks (N = 570). Through post-HCT Week 24, letermovir prophylaxis was associated with significantly lower rates of clinically significant CMV infection vs placebo (18% vs 42%; P < .0001), as well as an improved rate of all-cause mortality (10% vs 16%; P = .0317). Unlike currently approved antivirals, no major drug-related adverse events were reported with letermovir.
Letermovir is currently under FDA review, with an approval decision expected before the end of 2017. If letermovir is approved, I anticipate that our treatment paradigm may shift away from preemptive therapy and toward prophylaxis because we would have an effective oral drug that can be used up to 3 months from transplantation with no notable adverse events profile. I would think that because this drug is associated with improved survival at Week 24, it would then be used for all patients to prevent CMV reactivation and not just be reserved for high-risk patients. If letermovir is approved, it might eventually be possible to monitor low-risk patients less frequently for CMV after transplantation.
Brincidofovir for CMV Prophylaxis
Another drug currently under investigation is brincidofovir, an oral agent converted intracellularly to cidofovir diphosphate. Reports from a phase II trial of this agent in the prophylactic setting showed reduced CMV events vs placebo; however, brincidofovir was associated with gastrointestinal toxicities (eg, diarrhea, nausea). These same toxicities were observed in the phase III SUPPRESS trial, in which CMV-seropositive, allogeneic HCT recipients were randomized to receive either twice-weekly brincidofovir prophylaxis or placebo for 14 weeks (N = 458). At post-HCT Week 24, brincidofovir failed to prevent CMV infection vs placebo and was associated with a numerical increase in mortality. For many patients, gastrointestinal manifestations were interpreted as graft-vs-host-disease, thereby leading to increased steroid use and subsequently more immunosuppression in the brincidofovir arm vs the placebo arm; this may explain the increased mortality in the brincidofovir arm. This increase in immunosuppression may have accounted for the phase III trial’s negative outcomes.
Maribavir for Preemptive Therapy
Maribavir is an oral agent that binds CMV kinase UL97, inhibiting viral encapsidation and cell exit. A phase III trial showed that maribavir prophylaxis failed to prevent CMV disease. Maribavir was hence assessed as a preemptive management strategy, both in first-line and resistant/refractory settings. In a dose-finding randomized phase II trial in which stem cell or solid organ transplantation patients (N = 159) were managed preemptively with twice-daily oral maribavir 400-1200 mg or oral valganciclovir, comparable rates of patients in the maribavir and valganciclovir groups achieved undetectable CMV DNA within 6 weeks (65% to 83%). Another phase II trial randomized 120 stem cell or solid organ transplantation patients with refractory or resistant CMV infection to 1 of 3 doses of maribavir; within 6 weeks, 67% of patients had undetectable plasma CMV DNA. Dysgeusia and gastrointestinal toxicities are the most frequently observed adverse events with this agent.
Several additional CMV management strategies are also under investigation. CMV vaccines represent a different, yet promising, preventive strategy. ASP0113 is an investigational CMV vaccine containing plasmids encoding pp65 and surface glycoprotein B. A double-blind, placebo-controlled phase II trial showed that the vaccine significantly decreased CMV viremia occurrence and recurrence in CMV-seropositive patients undergoing allogeneic HCT. A phase III trial assessing the impact of this vaccine on mortality and CMV end organ disease is ongoing.
Post-HCT infusion of donor-derived cytotoxic T lymphocytes (CTLs) attempts to overcome CMV resistance with an immunotherapeutic approach: T-cells from the blood of a CMV-seropositive stem cell donor are purified and made specific for CMV viral antigens, such as pp65. They are then reinfused back into the HCT patient. This approach has met with success in several pilot studies in treating CMV viremia or disease in patients with resistant virus.
How do you currently manage CMV reactivation in HCT patients? What do you see as the greatest needs in this area? Share your experiences and insights by joining the conversation in the comments box below, and check out this expert analysis of current and emerging strategies for managing post-HCT CMV infection with Kathleen Mullane, DO, PharmD.