Department of Medicine
Weill Medical College
Director, Clinical Trials
Infectious Disease Service
Memorial Sloan Kettering
New York, New York
Genovefa A. Papanicolaou, MD, has disclosed that she has received consulting fees from Astellas, Chimerix, and Shire and funds for research support from Astellas, Chimerix, and Merck.
Letermovir was recently approved as cytomegalovirus (CMV) prophylaxis for patients receiving hematopoietic cell transplantation (HCT). What are the implications of this approval for clinicians, patients, and caregivers?
Historical Barriers to Optimal Post-HCT CMV Management
During the last decade, nonrelapse mortality following HCT has decreased by approximately 50%, primarily due to advances in the management of graft-vs-host disease (GVHD) and infections. CMV infection (manifested as CMV viremia or DNAemia) is the most common post-HCT viral infection, occurring in 30% to 80% of CMV-seropositive recipients. Progression to CMV disease (ie, organ involvement by CMV) is now uncommon with current CMV management approaches.
In general, preemptive therapy—in which patients are monitored and treated with antivirals upon detection of asymptomatic CMV infection—is the standard approach to managing CMV infection in patients undergoing HCT. Some centers also utilize prophylaxis for patients at high risk of CMV reactivation with available antivirals, typically valganciclovir, ganciclovir, valacyclovir, acyclovir, or foscarnet. While these antivirals are effective in reducing the risk of CMV reactivation, they are also associated with significant toxicity for many patients (eg, bone marrow suppression with valganciclovir/ganciclovir and nephrotoxicity with foscarnet).
Letermovir for CMV Prophylaxis: The Evidence
Letermovir is a first-in-class small molecule that targets the CMV terminase complex, which is responsible for packaging CMV DNA into preformed viral capsids. The pivotal phase III trial of letermovir randomized 570 CMV-seropositive HCT recipients to receive either 14 weeks of letermovir or placebo. Approximately one third of the patients were considered to be at high risk for CMV infection (eg, had haploidentical or mismatched unrelated donors). Letermovir, given through post-HCT Week 14, was highly effective in preventing CMV viremia through post-HCT Week 24; rates of clinically significant infection were 18% with letermovir prophylaxis vs 42% with placebo at this time point. Although the net benefit of prevention was greater in the high-risk patients, significant benefit was shown across all patient groups.
Letermovir was safe, without any signs of hematologic, liver, or renal toxicity even when administered pre-engraftment. This lack of toxicity was predicted, as the target of letermovir (CMV terminase) does not have any human analogue. Of importance, letermovir use was associated with a reduction in overall mortality at post-HCT Week 24 vs placebo (10.2% vs 15.9%, respectively; P = .03), which has persisted through post-HCT Week 48.
Letermovir for CMV Prophylaxis: Practical Considerations
Letermovir was approved by the FDA in November 2017 as CMV prophylaxis for CMV-seropositive HCT recipients. It is available in oral and injectable forms and may be initiated between Days 0 and 28 post HCT and continued through Day 100 post transplantation. Based on the survival benefit, I anticipate that letermovir will be widely adopted for CMV prevention in CMV-seropositive HCT recipients in the first 14 weeks (100 days) after transplantation. It is important to note that because letermovir has a unique mechanism of action, there is no expected cross resistance with currently available CMV antivirals, all of which target the CMV DNA polymerase. As such, any letermovir breakthrough CMV infections can be treated with ganciclovir or foscarnet. It should also be noted that because the target of letermovir is unique to CMV, letermovir is not active against other herpes viruses. As such, additional acyclovir prophylaxis is required for prevention herpes simplex and varicella virus infections.
Several questions still remain. For instance, the optimal duration of letermovir prophylaxis has not been clearly established. Late CMV events were observed in the phase III trial after discontinuation of letermovir at post-HCT Week 14. We know that conditions such as GVHD and T-cell depletion prolong the period of CMV risk; should the duration of letermovir prophylaxis be extended in these patients? By contrast, might some lower-risk patients be eligible to receive fewer than the full 14 weeks of recommended prophylaxis? Refined assays of immune function may be able to provide an individualized approach to CMV prevention. If letermovir prophylaxis is extended beyond 14 weeks, it will be important to establish the long-term safety and efficacy of this agent. The impact of highly effective CMV prevention on immune reconstitution to CMV is another topic that merits investigation. In the future, I expect to see additional trials with this agent as prophylaxis or treatment for other patient groups, including solid organ transplantation recipients or patients with congenital CMV.
Do you plan to integrate letermovir prophylaxis into your CMV management strategies for HCT recipients? If so, for which patients will you recommend this agent and for what duration? Will you continue to monitor your letermovir recipients for CMV viremia as with a conventional preemptive treatment approach? Please share your experiences and insights by joining the conversation in the comments box below and responding to the question at the right of your screen.