Letermovir Prophylaxis for CMV Infection in Haplo-HSCT Recipients: Single-center Data in China

Study Overview
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Brief Summary
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In the 30 years fighting against CMV infection, the mortality rate of HSCT patients was significantly reduced. Now we should turn to how to better improve the prognosis of HSCT patients and prevent CMV infection. The emergence of letermovir gave this vision a shot in the arm11-13. Letermovir is the only drug with an indication approved for the prevention of CMV infection in HSCT patients, with a novel mechanism of action characterized by inhibition of the CMV DNA terminase complex. The efficacy and safety of letermovir were well demonstrated in key phase III studies, where letermovir prophylaxis significantly reduced CMV infection and all-cause mortality after HSCT without increased myelosuppression and increased nephrotoxicity (vs. placebo)13. A real-world study of letermovir prophylaxis showed a significant reduction in CMV infection rates (47.0% vs 10.7%), and a significant reduction in antiviral use after 180 days. After more than100 days of continuous use, in addition to a significant reduction in clinically significant CMV infections and patients' overall survival increased, significant efficacy was consistently maintained in patients with grade 2 or greater GVHD14-17. A systematic review and meta-analysis of real-world studies on primary prevention in letermovir was showed in EBMT 2022. A total of 48 real-world observational studies were included, and the results showed that the use of CMV primary prevention was effective in reducing the overall risk of CMV performance (including CMV reactivation, cs-CMV infection and CMV disease), all-cause mortality and non-relapse mortality at day 200 in adult HSCT recipients. At 100 days follow-up, CMV reactivation decreased by 87%, meanwhile clinically significant CMV infection by 91%, CMV disease decreased by 69%, CMV-related hospitalization decreased by 94%, and GVHD decreased by 48%18. Letermovir has achieved excellent therapeutic benefits globally but is still in its infancy in China. Letermovir obtained an implied license for a clinical trial in June 2020, and in November 2020, Letermovir submitted and accepted four new drug marketing applications in China, including injection and tablet formulations. On December 31, 2021, the China National Medical Products Administration (NMPA) approved letermovir for cytomegalovirus (CMV) seropositive adult recipients undergoing allogeneic hematopoietic stem cell transplantation (HSCT) [R+] prevention of cytomegalovirus infection and cytomegalovirus disease. The commercial launch of letermovir is estimated to be in August 2022. Since the seropositive rate of CMV in the Chinese population is over 90%, it is not enough to judge whether CMV prevention is necessary depending on serology. In the past few years, with the increased number of only children in China, haploidentical stem cell transplantation (haplo-SCT) has been showing a steady expanding trend in China. Most hospitals' pretreatment methods use the Beijing protocol (including ATG) rather than post-transplant cyclophosphamide method to prevent GVHD, which also greatly increases the risk of CMV. To our knowledge, there is little published data focused on the efficacy of CMV prophylaxis for patients undergoing the haplo-SCT in China. A real-life evaluation of the new drug in terms of efficacy, emergence of resistance, tolerance related to CMV infection, is useful to propose recommendations on management strategies. Therefore, we would like to conduct a prospective observation study of CMV surveillance in haplo-SCT patients receiving letermovir prophylaxis in China, to evaluate the potential real-life effect of letermovir on efficacy, drug resistance emergence, tolerability, and CMV infection-related morbidity and mortality. This work contributes to recommendations regarding CMV management strategies, especially for patients at highest risk, i.e., CMV R+ haploidentical transplant recipients.

Official Title
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Letermovir Prophylaxis for Cytomegalovirus Infection in Haploidentical Allogeneic Hematopoietic Cell Transplant Recipients: Single-center Real-world Data in China

Conditions
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CMV Infection, Hematopoietic Stem Cell Transplantation

Intervention / Treatment
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* Drug: Letermovir


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Haplo-SCT candidate (adult) who has decided to primary transplant and is willing to participate in the study. The haplo-SCT candidate (adult) should be CMV seropositive recipients. Exclusion Criteria: CMV-seronegative patient receiving a negative CMV donor graft. Patients having active CMV DNAemia at the time of letermovir initiation. Patient having signed the informed consent but not grafted. Patient recruited in a clinical study on an anti-CMV trial.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| 50 haplo-HSCT recipients who are CMV seropositive<br>The study consists 50 cases CMV-R+ adult (>18 years) recipients of haplo-HCT. All patients will receive letermovir prophylaxis. Consider a simple interim analysis of the experimental group could be arranged after 30 patients are enrolled if necessary. Supportive care is provided by institutional standards of care (e.g., acyclovir for herpes simplex virus and varicella zoster virus prevention). Letermovir prophylaxis is started on day 0 or no longer than 28 days after transplantation. During the study period, letermovir 480 mg PO/IV once daily (or 240 mg per day in patients taking cyclosporine) was administered from day 0 to day +100 post-HCT. CMV monitoring and preemptive therapy were performed according to local protocol. Plasma CMV viral load (VL) is monitored by quantitative CMV PCR, starting on day +7 and continued weekly until week 6, then every 2-4 weeks for months until week 24. | Drug: Letermovir<br>* Letermovir has achieved excellent therapeutic benefits globally but is still in its infancy in China. Letermovir obtained an implied license for a clinical trial in June 2020, and in November 2020, Letermovir submitted and accepted four new drug marketing applications in China, including injection and tablet formulations. On December 31, 2021, the China National Medical Products Administration (NMPA) approved letermovir for cytomegalovirus (CMV) seropositive adult recipients undergoing allogeneic hematopoietic stem cell transplantation (HSCT) [R+] prevention of cytomegalovirus infection and cytomegalovirus disease. The commercial launch of letermovir is estimated to be in August 2022.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of clinically significant CMV infection | Defined as CMV DNAemia leading to preemptive treatment or presence of CMV disease using classificatory criteria published by the Disease Definitions Working Group of the Cytomegalovirus Drug Development Forum. CMV DNA threshold for initiation of preemptive therapy at our center is viral load >500 copies/mL or above on two consecutive tests. | at Week 14 following haplo-SCT | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of clinically significant CMV infection |  | through Week 24 following haplo-SCT | 
| Incidence of CMV DNAemia and CMV disease |  | through Week 14 and Week 24 following haplo-SCT | 
| Incidence of the resistant or refractory CMV infection |  | through Week 24 following haplo-SCT | 
| Incidence of serious adverse event leading to interruption of treatment |  | through Week 24 following haplo-SCT | 
| Incidence of CMV-related disease mortality |  | through Week 24 following haplo-SCT | 
| Incidence of all-cause mortality and non-relapse mortality |  | through Week 24 following haplo-SCT | 
| Incidence of CMV-associated morbidity | delay engraftment, acute or chronic GVHD occurrence, or other infectious diseases | through Week 24 following haplo-SCT | 
| Incidence of rehospitalization |  | through Week 14, Week 24 following haplo-HSCT | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Letermovir; Cytomegalovirus Infection; Haploidentical HSCT