Clinical trial NCT05789615: Letermovir Prophylaxis for CMV Infection in Haplo-HSCT Recipients: Single-center Data in China
Official title: Letermovir Prophylaxis for Cytomegalovirus Infection in Haploidentical Allogeneic Hematopoietic Cell Transplant Recipients: Single-center Real-world Data in China
Study type: OBSERVATIONAL
Overall status: COMPLETED
Conditions: CMV Infection
Hematopoietic Stem Cell Transplantation
Keywords: Letermovir; Cytomegalovirus Infection; Haploidentical HSCT
Lead sponsor: The First Affiliated Hospital of Soochow University
Sponsor class: OTHER
Collaborators: name: Merck Sharp & Dohme LLC
First posted: 2023-03-29
Enrollment: 200
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Observational model: COHORT
Time perspective: PROSPECTIVE
Sampling method: PROBABILITY_SAMPLE
Study population: The study consists 200 cases CMV-R+ adult (\>18 years) recipients of haplo-HCT. All patients will receive letermovir prophylaxis.

Brief summary: In the 30 years of fighting CMV infection, the mortality rate among HSCT patients has significantly reduced. Now, the focus is on improving the prognosis of HSCT patients and preventing CMV infection. The emergence of letermovir has provided a new opportunity in this regard. Letermovir, the only drug approved for CMV infection prevention in HSCT patients, works by inhibiting the CMV DNA terminase complex. Phase III studies have shown that letermovir significantly reduces CMV infection and all-cause mortality after HSCT, without increasing myelosuppression or nephrotoxicity. Real-world studies have further confirmed its efficacy in reducing CMV infection rates and antiviral use. Letermovir's global success has not yet been fully realized in China, where it is still in its early stages of use.

Detailed description: Letermovir achieved excellent therapeutic outcomes globally but is still developing in China. It received an implied license for clinical trials in June 2020, followed by marketing applications in November 2020. In December 2021, it was approved by the China National Medical Products Administration (NMPA) for preventing CMV infection and disease in CMV seropositive adult recipients undergoing allogeneic hematopoietic stem cell transplantation (HSCT). Letermovir's commercial launch in China is expected in August 2022. Given that over 90% of the Chinese population is CMV seropositive, determining whether CMV prevention is necessary based solely on serology is insufficient. The growing use of haploidentical stem cell transplantation (haplo-SCT) in China, particularly using the Beijing protocol for GVHD prevention, increases CMV risk. However, limited data exists on the efficacy of CMV prophylaxis for haplo-SCT patients in China. A real-life study assessing the efficacy, resistance, and tolerability of letermovir in this patient group is essential to guide CMV management strategies, particularly for high-risk CMV R+ haploidentical transplant recipients. This prospective study aims to evaluate letermovir's real-life impact on efficacy, resistance, tolerability, and CMV-related morbidity and mortality in China.

Eligibility criteria: 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.

Primary outcomes:
measure: Incidence of clinically significant CMV infection
timeFrame: at Week 14 following haplo-SCT
Secondary outcomes:
measure: Incidence of clinically significant CMV infection
timeFrame: through Week 24 following haplo-SCT
measure: Incidence of CMV DNAemia and CMV disease
timeFrame: through Week 14 and Week 24 following haplo-SCT
measure: Incidence of the resistant or refractory CMV infection
timeFrame: through Week 24 following haplo-SCT
measure: Incidence of serious adverse event leading to interruption of treatment
timeFrame: through Week 24 following haplo-SCT
measure: Incidence of CMV-related disease mortality
timeFrame: through Week 24 following haplo-SCT
measure: Incidence of all-cause mortality and non-relapse mortality
timeFrame: through Week 24 following haplo-SCT
measure: Incidence of CMV-associated morbidity
timeFrame: through Week 24 following haplo-SCT
measure: Incidence of rehospitalization
timeFrame: through Week 14, Week 24 following haplo-HSCT
Other outcomes:
Locations:
city: Suzhou
country: China
facility: The First Affiliated Hospital of Soochow university
state: Jiangsu
Study officials:
affiliation: The First Affiliated Hospital of Soochow University
name: Xiaojin Wu, Prof.
role: STUDY_CHAIR
References:
citation: Styczynski J. Who Is the Patient at Risk of CMV Recurrence: A Review of the Current Scientific Evidence with a Focus on Hematopoietic Cell Transplantation. Infect Dis Ther. 2018 Mar;7(1):1-16. doi: 10.1007/s40121-017-0180-z. Epub 2017 Dec 4.
citation: Green ML, Leisenring W, Xie H, Mast TC, Cui Y, Sandmaier BM, Sorror ML, Goyal S, Ozkok S, Yi J, Sahoo F, Kimball LE, Jerome KR, Marks MA, Boeckh M. Cytomegalovirus viral load and mortality after haemopoietic stem cell transplantation in the era of pre-emptive therapy: a retrospective cohort study. Lancet Haematol. 2016 Mar;3(3):e119-27. doi: 10.1016/S2352-3026(15)00289-6. Epub 2016 Feb 20.
citation: Tomblyn M, Chiller T, Einsele H, Gress R, Sepkowitz K, Storek J, Wingard JR, Young JA, Boeckh MJ; Center for International Blood and Marrow Research; National Marrow Donor program; European Blood and MarrowTransplant Group; American Society of Blood and Marrow Transplantation; Canadian Blood and Marrow Transplant Group; Infectious Diseases Society of America; Society for Healthcare Epidemiology of America; Association of Medical Microbiology and Infectious Disease Canada; Centers for Disease Control and Prevention. Guidelines for preventing infectious complications among hematopoietic cell transplantation recipients: a global perspective. Biol Blood Marrow Transplant. 2009 Oct;15(10):1143-238. doi: 10.1016/j.bbmt.2009.06.019. No abstract available.
citation: Akahoshi Y, Kimura SI, Inamoto Y, Seo S, Muranushi H, Shimizu H, Ozawa Y, Tanaka M, Uchida N, Kanda Y, Katayama Y, Shiratori S, Ota S, Matsuoka KI, Onizuka M, Fukuda T, Atsuta Y, Murata M, Terakura S, Nakasone H. Effect of Cytomegalovirus Reactivation With or Without Acute Graft-Versus-Host Disease on the Risk of Nonrelapse Mortality. Clin Infect Dis. 2021 Aug 2;73(3):e620-e628. doi: 10.1093/cid/ciaa1871.
citation: Hakki M, Aitken SL, Danziger-Isakov L, Michaels MG, Carpenter PA, Chemaly RF, Papanicolaou GA, Boeckh M, Marty FM. American Society for Transplantation and Cellular Therapy Series: #3-Prevention of Cytomegalovirus Infection and Disease After Hematopoietic Cell Transplantation. Transplant Cell Ther. 2021 Sep;27(9):707-719. doi: 10.1016/j.jtct.2021.05.001.
citation: Razonable R. Direct and indirect effects of cytomegalovirus: can we prevent them? Enferm Infecc Microbiol Clin. 2010 Jan;28(1):1-5. doi: 10.1016/j.eimc.2009.07.008. Epub 2009 Dec 21. No abstract available.
citation: Goodrich JM, Mori M, Gleaves CA, Du Mond C, Cays M, Ebeling DF, Buhles WC, DeArmond B, Meyers JD. Early treatment with ganciclovir to prevent cytomegalovirus disease after allogeneic bone marrow transplantation. N Engl J Med. 1991 Dec 5;325(23):1601-7. doi: 10.1056/NEJM199112053252303.
citation: Boeckh M, Nichols WG. The impact of cytomegalovirus serostatus of donor and recipient before hematopoietic stem cell transplantation in the era of antiviral prophylaxis and preemptive therapy. Blood. 2004 Mar 15;103(6):2003-8. doi: 10.1182/blood-2003-10-3616. Epub 2003 Nov 26.
citation: Marty FM, Ljungman P, Chemaly RF, Maertens J, Dadwal SS, Duarte RF, Haider S, Ullmann AJ, Katayama Y, Brown J, Mullane KM, Boeckh M, Blumberg EA, Einsele H, Snydman DR, Kanda Y, DiNubile MJ, Teal VL, Wan H, Murata Y, Kartsonis NA, Leavitt RY, Badshah C. Letermovir Prophylaxis for Cytomegalovirus in Hematopoietic-Cell Transplantation. N Engl J Med. 2017 Dec 21;377(25):2433-2444. doi: 10.1056/NEJMoa1706640. Epub 2017 Dec 6.
citation: Su Y, Stern A, Karantoni E, Nawar T, Han G, Zavras P, Dumke H, Cho C, Tamari R, Shaffer B, Giralt S, Jakubowski A, Perales MA, Papanicolaou G. Impact of Letermovir Primary Cytomegalovirus Prophylaxis on 1-Year Mortality After Allogeneic Hematopoietic Cell Transplantation: A Retrospective Cohort Study. Clin Infect Dis. 2022 Sep 14;75(5):795-804. doi: 10.1093/cid/ciab1064.
citation: Derigs P, Radujkovic A, Schubert ML, Schnitzler P, Schoning T, Muller-Tidow C, Hegenbart U, Schonland SO, Luft T, Dreger P, Schmitt M. Letermovir prophylaxis is effective in preventing cytomegalovirus reactivation after allogeneic hematopoietic cell transplantation: single-center real-world data. Ann Hematol. 2021 Aug;100(8):2087-2093. doi: 10.1007/s00277-020-04362-2. Epub 2020 Dec 3.
citation: Sassine J, Khawaja F, Shigle TL, Handy V, Foolad F, Aitken SL, Jiang Y, Champlin R, Shpall E, Rezvani K, Ariza-Heredia EJ, Chemaly RF. Refractory and Resistant Cytomegalovirus After Hematopoietic Cell Transplant in the Letermovir Primary Prophylaxis Era. Clin Infect Dis. 2021 Oct 20;73(8):1346-1354. doi: 10.1093/cid/ciab298.