Letermovir prophylaxis in T-cell–depleted transplants: breakthrough and rebound infections in the postmarketing setting

Abstract

Conflict of interest: COI declared -see note COI notes: V.M. received research grants from MSD/ Gilead and speakership from MSD, Gilead, Pfizer, Novartis, Jazz, Incyte. E.T. declares advisory boards for Celgene, Gilead/Kite, Jazz, Novartis, Pfizer and MSD, speaker fees for Gilead/Kite, Janssen, Jazz, Novartis and Pfizer and consultancy for educational materials for Gilead/Kite. A.P. declares advisory board for MSD. R.L. received educational grants and speaker fees for MSD, Chugai Pharma, Astellas, Gilead, Sanofi. E.N. declares advisory boards for Kite/Gilead, Novartis, BMS/Celgene, Pfizer and conference support for Kite/Gilead, Novartis and speaker fees for Kite/Gilead. J.A.S. declares honoraria for educational events supported by Jazz, Mallinckrodt, Gilead, Janssen, and Actelion, advisory board participation for Medac and IDMC membership for a Kiadis Pharma supported clinical trial, none of which are directly related to this study. E.H.

Extended-duration letermovir prophylaxis for cytomegalovirus infection after cord blood transplantation in adults

“…This finding is consistent with prior studies reporting that the risk of late csCMVi occurs within a few weeks after prophylaxis discontinuation. 11 , 18 , 21 , 22 , 29 , 30 Accordingly, as suggested by others, 30 and regardless of prophylaxis duration, viremia monitoring is warranted for approximately the first 8 weeks after discontinuing letermovir; intensive monitoring for an extended period after cessation is likely not necessary.…”

“…The efficacy of letermovir prophylaxis in reducing the risk of csCMVi after HSCT is well established. 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 27 However, high rates of late csCMVi have been observed when letermovir prophylaxis is limited to the first 100 days’ posttransplant, especially in high-risk patient groups such as HLA-disparate donor recipients. 11 , 22 A single-center analysis has shown that extending prophylaxis duration beyond 100 days is highly effective in preventing csCMVi in patients with GVHD, another high-risk patient group.…”

“… 15 , 22 It is also in contrast to the findings of most analyses of letermovir prophylaxis in adult donor HSCT recipients that have reported higher incidence of breakthrough infections by day 100 posttransplant. 11 , 12 , 13 , 14 , 15 , 18 , 19 Differences in patient characteristics, timing of prophylaxis initiation, type of assay used for viral load monitoring, and threshold to initiate antiviral agents for csCMVi may account for the differences between these studies. It should be acknowledged that the practice of extended letermovir prophylaxis at our center coincided with the addition of tocilizumab to standard CSA/MMF for GVHD prevention in adult CBT recipients ( clinicaltrials.gov # NCT03434730 ).…”

“… 10 In the pivotal phase 3 trial, letermovir prophylaxis for 14 weeks posttransplant reduced the risk of clinically significant CMV infection (csCMVi), defined as viremia leading to preemptive treatment or CMV end-organ disease, in CMV-seropositive hematopoietic stem cell transplant (HSCT) recipients. 11 Several studies have since corroborated that letermovir continued through day 100 posttransplant is safe and effective CMV prophylaxis in adult donor HSCT 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 or CBT 15 , 21 , 22 recipients. However, a high incidence of delayed-onset csCMVi after letermovir discontinuation has been observed when prophylaxis is limited to the first 14 weeks posttransplant.…”

Hematopoietic stem cell donor vaccination with cytomegalovirus triplex augments frequencies of functional and durable cytomegalovirus‐specific T cells in the recipient: A novel strategy to limit antiviral prophylaxis

“…In summary, this novel approach has the potential to reduce the use of letermovir prophylaxis, overcoming breakthrough resistant viremia, 8,74 delays and deficits in T cell reconstitution, 12 and limit morbidity associated with high rates of CMV viremia rebound, requiring toxic antiviral treatment. 9,75…”