The promising efficacy of a risk-based letermovir use strategy in CMV-positive allogeneic hematopoietic cell recipients

Abstract

Letermovir is the first approved drug for cytomegalovirus (CMV) infection prophylaxis in adult CMV-positive patients undergoing allogeneic hematopoietic cell transplantation (allo-HCT). Since CMV infection risk varies from patient to patient, we evaluated whether a risk-based strategy could be effective. All consecutive CMV-positive adult patients (median age: 56.0 years, IQR: 43.5-64.0) who underwent allo-HCT between 2015 and 2021 (n=316) were included. Letermovir was not used in Period 1 (2015-2017, n=186), whereas during Period 2 (2018-2021, n=130), letermovir was used in high-risk patients but not in low-risk patients, except in those receiving corticosteroids. In high-risk patients, the incidence of clinically significant CMV infection (csCMVi) in Period 2 was lower as compared to Period 1 (p<0.001) by week 14: 10.5% (95% CI 4.6-19.2) vs 51.6% (41.0-61.3) and week 24: 16.9% (8.9-27.0) vs 52.7% (42.0-62.3), respectively. In low-risk patients, although only 28.6% of patients received letermovir in Period 2, csCMVi incidence was also significantly lower (p=0.003) by week 14: 7.9% (2.9-16.3) vs 29.0% (20.2-38.5) and week 24: 11.2% (4.9-20.5) vs 33.3% (23.9-43.0). Among low-risk patients who did not receive letermovir (n=45), 23 (51.1%) patients experienced transient positive CMV DNA without csCMVi by week 14, while it remained negative in 17 (37.8%) patients. In both risk groups, the two periods were comparable for CMV disease, overall survival, progression-free survival, relapse, and non-relapse mortality. We concluded that a risk-based strategy for letermovir use is an effective strategy which maintains the high efficacy of letermovir in high-risk patients but allows some low-risk patients not to use letermovir.

CMV prevention strategies in allogeneic hematopoietic cell transplantation; the role of prophylaxis and pre‐emptive monitoring in the era of letermovir

“…35 This study demonstrates a risk-based strategy for prophylaxis allowing sparing of some low risk patients from receiving letermovir. 35 A randomised study evaluating this strategy would be important to perform.…”

“…Better selection of the high‐risk group was addressed in a study, which developed a risk score for low, intermediate‐low, intermediate‐high, and high‐risk category using six predictors; donor CMV serostatus, type of donor, conditioning intensity, total body irradiation, ATG and mycophenolate use 34 . Applying this risk score in a prospective cohort, those in the low risk group ( n = 63) were not prescribed letermovir 35 . Although 18 of those patients (28.6%) were later commenced on letermovir (at median 28 days) with no patient developing subsequent csCMVi, few patients in the remaining 45 patients developed csCMVi (11%) and were safely treated with a single course of pre‐emptive therapy without complication 35 .…”

“…Applying this risk score in a prospective cohort, those in the low risk group ( n = 63) were not prescribed letermovir 35 . Although 18 of those patients (28.6%) were later commenced on letermovir (at median 28 days) with no patient developing subsequent csCMVi, few patients in the remaining 45 patients developed csCMVi (11%) and were safely treated with a single course of pre‐emptive therapy without complication 35 . This study demonstrates a risk‐based strategy for prophylaxis allowing sparing of some low risk patients from receiving letermovir 35 .…”

“…Although 18 of those patients (28.6%) were later commenced on letermovir (at median 28 days) with no patient developing subsequent csCMVi, few patients in the remaining 45 patients developed csCMVi (11%) and were safely treated with a single course of pre‐emptive therapy without complication 35 . This study demonstrates a risk‐based strategy for prophylaxis allowing sparing of some low risk patients from receiving letermovir 35 . A randomised study evaluating this strategy would be important to perform.…”

Immunovirology of cytomegalovirus infection in allogeneic stem cell transplant recipients undergoing prophylaxis with letermovir: A narrative review

“…There is solid evidence for the clinical efficacy of primary prophylaxis (also secondary) with LMV in preventing csCMV‐I and CMV end‐organ disease in adult CMV seropositive allo‐SCT patients and, to a much lesser extent, in pediatric patients, both in randomized trials and in a real‐life setting 13,48–81 . A comprehensive review and meta‐analysis on this subject was recently published 14 .…”