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

Hematopoietic Stem Cell Transplantation Clinical Trial

Official title:

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05789615
• Other study ID #: SOOCHOW-WXJ-2022-366
• Status: Recruiting
• Start date: April 15, 2023
• Est. completion date: December 31, 2024

Study information

• Verified date: March 2024
• Source: The First Affiliated Hospital of Soochow University
• Contact: Xiaojin Wu
• Phone: +8613057493105
• Email: wuxiaojin[@]suda.edu.cn
• Is FDA regulated: No
• Study type: Observational

Clinical Trial Summary

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 200
• Est. completion date: December 31, 2024
• Est. primary completion date: December 1, 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• CMV Infection
• Communicable Diseases
• Cytomegalovirus Infections
• Hematopoietic Stem Cell Transplantation
• Infections

Intervention

Drug:
• Letermovir
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.

Locations

Country	Name	City	State
China	The First Affiliated Hospital of Soochow university	Suzhou	Jiangsu

Sponsors (1)

Lead Sponsor	Collaborator
The First Affiliated Hospital of Soochow University

Country where clinical trial is conducted

China, 

References & Publications (12)

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. — View 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. — View 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. — View 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. — View 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. — View 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. — View 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. — View 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. — View 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. — View 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. — View 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. — View 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. Erratum In: Biol Blood Marrow Transplant. 2010 Feb;16(2):294. Boeckh, Michael A [corrected to Boeckh, Michael J]. — View Citation

* Note: There are 12 references in all — Click here to view all references

Outcome

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