CMV breakthrough and resistance to antiviral drug after blood stem cell transplants

From Dr. Danniel Zamora and the Boeckh Group, Vaccine and Infectious Disease Division

Organ and hematopoietic stem cell transplants (HSCTs) are life-saving treatments, but come with certain risks, like viral infection. Because some degree of immune suppression is required for the transplanted tissue to survive, patients are susceptible to opportunistic infections. Infections such as those from cytomegalovirus (CMV) can occur from receiving a donor tissue with an infection, or due to reactivation of the virus in the transplant recipient. Luckily, antiviral drugs can help prevent infection or viral reactivation. One antiviral drug treatment, “letermovir, is a fairly new addition to our armamentarium in the prevention of infection from CMV after hematopoietic stem cell transplantation (HSCT),” Dr. Danniel Zamora explained. Dr Zamora is a physician-scientist and Associate in the Vaccine and Infectious Diseases Division at Fred Hutch as well as an Acting Assistant Professor in the Division of Allergy and Infectious Diseases at the University of Washington, working with Dr. Michael Boeckh’s group. “We leveraged our clinical and virology databases to describe what our clinical experience has been with letermovir since its rollout as standard prophylaxis in CMV-seropositive HSCT recipients in 2018,” Zamora added. In their recent study published in Bone Marrow Transplantation, the researchers investigated CMV breakthrough infections and resistance in HSCT recipients treated with letermovir.

“We had the opportunity to collaborate with the UW Virology Laboratory for this study to identify the rate of de novo resistance to letermovir in patients with breakthrough CMV” that were being treated at Fred Hutch, the researchers stated. In total, the researchers analyzed 226 patients and asked how many experienced CMV reactivation within 100 days post-HSCT, which is the current treatment length of letermovir. While about 40% of patients did have detectable CMV breakthrough, very few of these cases were clinically significant. Drs.  Boeckh and Zamora noted, “fortunately, based on the results of our study the rate of resistance to letermovir at our center appears to be low (<1%).” Those few patients that did experience clinically significant CMV reactivation received other antiviral therapies that were able to manage the viral reactivation. The researchers explained that they then “explored various clinical risk factors for breakthrough CMV on letermovir and found that increased levels of immunosuppression seem to be the main driver for these breakthrough events.” One of the strongest risk factors associated with CMV reactivation was prolonged use of immunosuppressive steroids, which can lower your body’s immune defense when taken regularly. Other factors that the researchers evaluated included ethnicity, whether a patient had leukemia, as well as various graft-versus-host disease (GVHD) prophylactic drug regimens. Interestingly, GVHD prophylaxis with post-transplantation cyclophosphamide or calcineurin inhibitors plus mycophenolate were also associated with an increased risk of CMV reactivation. “Overall, our data are in alignment with the findings in the original randomized controlled trial of letermovir prophylaxis after HSCT; letermovir appears to be safe, well tolerated, and effective at preventing clinically significant CMV after HSCT. In addition, letermovir resistance appears to be rare in our patient population which is reassuring.”

graph of CMV breakthrough after HSCT with letermovir treatment
CMV breakthrough after HSCT with letermovir treatment Image provided by Dr. Danniel Zamora

“There is much that we can learn from real-world studies of letermovir prophylaxis including from an institutional standpoint,” Dr. Boeckh and Zamora explained. To this end, they can “examine whether providers are adhering to standard practice guidelines with respect to initiating and prescribing letermovir prophylaxis after HSCT. We can then identify potential barriers to implementation of our guidelines such as high drug cost, drug-drug interactions, etc. and address these factors in the future.” Moving forward, the research team “will continue to examine the rates of subclinical and clinically significant CMV infection during letermovir prophylaxis at our center. Our findings could potentially lead to downstream modifications of our standard practice guidelines, such as changes to our institutional thresholds to initiate preemptive antiviral therapy to treat CMV infection after HSCT.” Importantly, a recent phase 3 randomized clinical trial was just presented, which examined “extending letermovir prophylaxis from 100 days to 200 days post-HSCT […] and we are eager to hear whether the FDA approves extension of prophylaxis past 100 days post-HCT,” Boeckh and Zamora noted. The authors conclude by acknowledging “the UW Virology Lab and our hematology-oncology colleagues in the Clinical Research Division (CRD) for their contributions to this study. In addition, we are grateful to our Infectious Diseases Sciences (IDS) repository, clinical research data systems, and administrative staff for their contributions.”

This work was supported by the National Institutes of Health and Fred Hutchinson Cancer Center.

UW/Fred Hutch/ Seattle Children’s Cancer Consortium members Michael Boeckh, Paul Martin, Brenda Sandmaier, Keith Jerome and Masumi Ueda Oshima contributed to this study.

Perchetti GA, Biernacki MA, Xie H, Castor J, Joncas-Schronce L, Ueda Oshima M, Kim Y, Jerome KR, Sandmaier BM, Martin PJ, Boeckh M, Greninger AL, Zamora D. Cytomegalovirus breakthrough and resistance during letermovir prophylaxis. Bone Marrow Transplant. 2023 Apr;58(4):430-436. doi: 10.1038/s41409-023-01920-w. Epub 2023 Jan 24. PMID: 36693927.