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Longer Letermovir Prophylaxis Reduced Risk of Cytomegalovirus Infection After HSCT

— Randomized study showed extending prophylaxis from 100 to 200 days was effective and safe

MedpageToday
A computer rendering of cytomegaloviruses

Extending the duration of letermovir (Prevymis) prophylaxis following hematopoietic stem cell transplantation (HSCT) was effective in reducing the risk of late clinically significant cytomegalovirus infection, a phase III randomized study showed.

Just 3% of patients with hematologic cancers who received 200 days of letermovir after HSCT developed clinically significant cytomegalovirus infection compared with 19% of patients who received 100 days of placebo following 100 days of letermovir, resulting in a treatment difference of -16.1% (95% CI -25.8 to -6.5, P=0.0005), reported Sanjeet S. Dadwal, MD, of the City of Hope National Medical Center in Duarte, California, and colleagues.

"Extending the duration of letermovir prophylaxis to 200 days is a patient-centric, risk-adapted approach to letermovir prophylaxis warranted in patients who remain at risk of late clinically significant cytomegalovirus infection," they wrote in .

Based on data from this study, the for letermovir allowing for an extension of the dosing regimen from 100 to 200 days for HSCT patients at risk for late cytomegalovirus infection.

The study "has important implications for clinical practice and provides important information for guideline and policy decision makers," wrote Abby P. Douglas, MBBS, and Monica A. Slavin, MBBS, MD, both of the Peter MacCallum Cancer Centre in Melbourne, Australia, in a

For example, they observed that reducing the rate of clinically significant cytomegalovirus infection also reduces patient exposures to currently available anti-cytomegalovirus agents such as valaciclovir, ganciclovir, foscarnet, and cidofovir, which are associated with clinically significant myelotoxicity and/or nephrotoxicity.

"This reduction could also translate to a downstream reduced risk of resistant or refractory cytomegalovirus," they added. "Furthermore, reduced rates of clinically significant cytomegalovirus infection could reduce the risk of secondary infections, such as invasive fungal diseases."

Cytomegalovirus is a common viral infection in recipients of allogeneic HSCT. Results from a showed that in the first 100 days after transplant, cytomegalovirus-seropositive patients who received letermovir had a greatly reduced incidence of clinically significant cytomegalovirus infection compared with patients who received placebo.

However, in that study, there was an increased incidence of clinically significant cytomegalovirus infection observed between 100 days and 200 days after letermovir was discontinued at 100 days.

Thus, the objective of this study was to evaluate the effectiveness and safety of extending letermovir prophylaxis by another 100 days in the subpopulation of HSCT recipients at risk of clinically significant cytomegalovirus infection.

took place at 32 sites in six countries and included cytomegalovirus-seropositive adults who had underwent allogeneic HSCT within the 100 days before randomization, received letermovir for up to 100 days following HSCT before randomization, and were at high risk of clinically significant cytomegalovirus infection.

Of the 255 patients screened for eligibility from June 2019 to March 2022, 145 were randomly assigned to the letermovir group and 75 to the placebo group. Mean age was 55, and a majority were men and white.

A little over 40% of each group had acute myeloid leukemia, 12-16% had acute lymphocytic leukemia, 8-12% had myelodysplastic syndrome, 6-12% had lymphoma, 6-7% had myelofibrosis, and 19-20% had another disease.

Dadwal and colleagues also observed that after letermovir was discontinued at 200 days, there was an increase in the incidence of clinically significant cytomegalovirus infection until week 38 in the letermovir group (19 vs 14 patients in the placebo group), but the difference was not significant.

The time to onset of clinically significant cytomegalovirus infection from baseline to week 48 was similar between both treatment groups.

"The rebound in the incidence of clinically significant cytomegalovirus infection after letermovir discontinuation was not entirely unexpected, given that letermovir use results in virological suppression, not cure," they wrote. "There were no additional cases of clinically significant cytomegalovirus infection among participants in either treatment group at week 48, which could reflect a degree of cytomegalovirus-specific immunity adequate to prevent further viral reactivation beyond week 38 following HSCT."

Regarding the benefit of prophylaxis beyond 200 days, Douglas and Slavin said that considering the probable diminishing efficacy at some point, "the question remains: how long is long enough?"

Dadwal and colleagues also observed that all-cause mortality was similar between both treatment groups from baseline to week 28 and from baseline to week 48, and suggested that the failure to establish a mortality benefit with extended letermovir prophylaxis was likely due to the study design and sample size.

The most common adverse events among participants in the letermovir group versus the placebo group were graft-versus-host disease (30% vs 31%), diarrhea (12% vs 12%), nausea (11% vs 18%), pyrexia (9% vs 12%), and decreased appetite (4% vs 12%).

The most frequently reported serious adverse events were recurrent acute myeloid leukemia (4% vs 0%) and pneumonia (2% vs 3%).

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    Mike Bassett is a staff writer focusing on oncology and hematology. He is based in Massachusetts.

Disclosures

The study was funded by Merck Sharp & Dohme.

Dadwal reported receiving research grants (to his institution) from AlloVir, Ansun Biopharma, Karius, and Merck; serving as an advisory board member or consultant for AlloVir, AseptiScope, Merck, and Takeda; and serving on speakers' bureaus for Astellas Pharma, Merck, and Takeda.

Co-authors reported relationships with industry, and several are current employees of Merck Sharp & Dohme.

Douglas reported receiving honoraria paid to her institution from Gilead Sciences. Slavin reported receiving grants to her institution from F2G and Merck, honoraria paid to her institution by Shionogi, and participating on the data safety monitoring board of trials by Roche and Pfizer.

Primary Source

Lancet Haematology

Russo D, et al "Efficacy and safety of extended duration letermovir prophylaxis in recipients of haematopoietic stem-cell transplantation at risk of cytomegalovirus infection: a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial" Lancet Haematol 2023; DOI: 10.1016/S2352-3026(23)00344-7.

Secondary Source

Lancet Haematology

Douglas AP, Slavin MA "Extended duration of letermovir prophylaxis: how long is enough?" Lancet Haematol 2023; DOI: 10.1016/S2352-3026(23)00368-X.