Hybrid Ganciclovir/Valacyclovir Prophylaxis Reduces CMV Reactivation in High-Risk Allogeneic Stem Cell Transplant Recipients
-
Maryam Barkhordar
,
Amirabbas Rashidi
,
Mohammad Vaezi
,
Neda Alijani
,
Seied Asadollah Mousavi
,
Sahar Tavakoli Shiraji
,
Mojtaba Azari Alanjeq
,
Morteza Azari Alanjeq
,
Mehrdad Abbaszadeh
,
Hossein Kamranzadeh Fumani
,
Tanaz Bahri
Abstract
Background: Cytomegalovirus (CMV) reactivation remains a critical concern following allogeneic hematopoietic stem cell transplantation (allo-HSCT), particularly in CMV-seropositive patients undergoing allo-HSCT from alternative donors. This study explored whether a hybrid CMV prophylaxis regimen would be more effective than the standard preemptive regimen in resource-limited settings where Letermovir is unavailable or cost-prohibitive.
Materials and Methods: This prospective single-center cohort study included adult patients with acute leukemia who received allo-HSCT from alternative donors between November 2018 and May 2022. The primary outcome was the evaluation of the CMV reactivation incidence in allo-HSCT patients receiving the hybrid CMV prophylaxis regimen comprising pretransplant ganciclovir followed by high-dose valacyclovir compared with the control patients who received the preemptive regimen. Secondary outcomes included overall survival (OS), disease-free survival (DFS), GVHD-free relapse-free survival (GRFS), and non-relapse mortality (NRM) between the two groups.
Results: A total of 80 patients, 34 received hybrid CMV prophylaxis, and 46 received the preemptive protocol. The hybrid prophylaxis group exhibited a significantly lower incidence of CMV reactivation at 90 days post-transplantation (34% vs. 82%, P = 0.000). However, no statistically significant differences were observed in overall survival, disease-free survival, or non-relapse mortality rates.
Conclusion: The hybrid regimen reduced CMV reactivation in high-risk HSCT recipients but did not improve survival outcomes, offering a practical alternative in settings with limited access to Letermovir.
1. Dziedzic M, Sadowska-Krawczenko I, Styczynski J. Risk factors for cytomegalovirus infection after allogeneic hematopoietic cell transplantation in malignancies: proposal for classification. Anticancer Res. 2017;37(12):6551-6.
2. Styczyński J. ABC of viral infections in hematology: focus on herpesviruses. Acta Haematol Pol. 2019;50(3):159-66.
3. Vallejo M, Muñiz P, Kwon M, et al. Risk prediction of CMV reactivation after allogeneic stem cell transplantation using five non-HLA immunogenetic polymorphisms. Ann Hematol. 2022;101(7):1567-76.
4. Barkhordar M, Kasaeian A, Janbabai G, et al. Modified combination of anti-thymocyte globulin (ATG) and post-transplant cyclophosphamide (PTCy) as compared with standard ATG protocol in haploidentical peripheral blood stem cell transplantation for acute leukemia. Front Immunol. 2022;13:921293.
5. Teira P, Battiwalla M, Ramanathan M, et al. Early cytomegalovirus reactivation remains associated with increased transplant-related mortality in the current era: a CIBMTR analysis. Blood. 2016;127(20):2427-38.
6. Kollman C, Howe CW, Anasetti C, et al. Donor characteristics as risk factors in recipients after transplantation of bone marrow from unrelated donors: the effect of donor age. Blood. 2001;98(7):2043-51.
7. Ljungman P, Brand R, Einsele H, et al. Donor CMV serologic status and outcome of CMV-seropositive recipients after unrelated donor stem cell transplantation: an EBMT megafile analysis. Blood. 2003;102(13):4255-60.
8. Ljungman P, Brand R, Hoek J, et al. Donor cytomegalovirus status influences the outcome of allogeneic stem cell transplant: a study by the European group for blood and marrow transplantation. Clin Infect Dis. 2014;59(4):473-81.
9. Broers AE, van der Holt R, van Esser JW, et al. Increased transplant-related morbidity and mortality in CMV-seropositive patients despite highly effective prevention of CMV disease after allogeneic T-cell–depleted stem cell transplantation. Blood. 2000;95(7):2240-5.
10. Einsele H, Hebart H, Kauffmann-Schneider C, et al. Risk factors for treatment failures in patients receiving PCR-based preemptive therapy for CMV infection. Bone Marrow Transplant. 2000;25(7):757-63.
11. Goldsmith SR, Abid MB, Auletta JJ, et al. Posttransplant cyclophosphamide is associated with increased cytomegalovirus infection: a CIBMTR analysis. Blood. 2021;137(23):3291-305.
12. Jamy O, Hebert C, Dunn-Valadez S, et al. Risk of cytomegalovirus infection with post-transplantation cyclophosphamide in haploidentical and HLA-matched unrelated donor transplantation. Transplant Cell Ther. 2022;28(4):213. e1-. e6.
13. Meijer E, Boland Greet J, Verdonck Leo F. Prevention of Cytomegalovirus Disease in Recipients of Allogeneic Stem Cell Transplants. Clin Microbiol Rev. 2003;16(4):647-57.
14. Chen K, Cheng MP, Hammond SP, et al. Antiviral prophylaxis for cytomegalovirus infection in allogeneic hematopoietic cell transplantation. Blood Adv. 2018;2(16):2159-75.
15. Reed DR, Petroni GR, West M, et al. Prophylactic pretransplant ganciclovir to reduce cytomegalovirus infection after hematopoietic stem cell transplantation. Hematol Oncol Stem Cell Ther. 2023;16(1):61-69.
16. Bacigalupo A, Tedone E, Van Lint M, et al. CMV prophylaxis with foscarnet in allogeneic bone marrow transplant recipients at high risk of developing CMV infections. Bone Marrow Transplant. 1994;13(6):783-8.
17. Bregante S, Bertilson S, Tedone E, et al. Foscarnet prophylaxis of cytomegalovirus infections in patients undergoing allogeneic bone marrow transplantation (BMT): a dose-finding study. Bone Marrow Transplant. 2000;26(1):23-9.
18. Burns L, Miller W, Kandaswamy C, et al. Randomized clinical trial of ganciclovir vs acyclovir for prevention of cytomegalovirus antigenemia after allogeneic transplantation. Bone Marrow Transplant. 2002;30(12):945-51.
19. Freyer CW, Carulli A, Gier S, et al. Letermovir vs. high-dose valacyclovir for cytomegalovirus prophylaxis following haploidentical or mismatched unrelated donor allogeneic hematopoietic cell transplantation receiving post-transplant cyclophosphamide. Leuk Lymphoma. 2022;63(8):1925-33.
20. Imlay HN, Kaul DR. Letermovir and maribavir for the treatment and prevention of cytomegalovirus infection in solid organ and stem cell transplant recipients. Clin Infect Dis. 2021;73(1):156-60.
21. Frange P, Leruez-Ville M. Maribavir, brincidofovir and letermovir: Efficacy and safety of new antiviral drugs for treating cytomegalovirus infections. Med Mal Infect. 2018;48(8):495-502.
22. Piret J, Boivin G. Clinical development of letermovir and maribavir: Overview of human cytomegalovirus drug resistance. Antiviral Res. 2019;163:91-105.
23. Barkhordar M, Kasaeian A, Tavakoli S, et al. Selection of suitable alternative donor in the absence of matched sibling donor: A retrospective single-center study to compare between haploidentical, 10/10 and 9/10 unrelated donor transplantation. Int J Hematol Oncol Stem Cell Res. 2021;15(1):51-60.
24. Glucksberg H, Storb R, Fefer A, et al. Clinical manifestations of graft-versus-host disease in human recipients of marrow from hl-a-matched sibling donors. Transplantation. 1974;18(4):295-304.
25. Filipovich AH, Weisdorf D, Pavletic S, et al. National Institutes of Health consensus development project on criteria for clinical trials in chronic graft-versus-host disease: I. Diagnosis and staging working group report. Biol Blood Marrow Transplant. 2005;11(12):945-56.
26. Milano F, Pergam SA, Xie H, et al. Intensive strategy to prevent CMV disease in seropositive umbilical cord blood transplant recipients. Blood. 2011;118(20):5689-96.
27. Winston DJ, Ho WG, Bartoni K, et al. Ganciclovir prophylaxis of cytomegalovirus infection and disease in allogeneic bone marrow transplant recipients: results of a placebo-controlled, double-blind trial. Ann Intern Med. 1993;118(3):179-84.
28. Kline J, Pollyea D, Stock W, et al. Pre-transplant ganciclovir and post-transplant high-dose valacyclovir reduce CMV infections after alemtuzumab-based conditioning. Bone marrow Transplant. 2006;37(3):307-10.
29. Atkinson K, Downs K, Golenia M, et al. Prophylactic use of ganciclovir in allogeneic bone marrow transplantation: absence of clinical cytomegalovirus infection. Br J Haematol. 1991;79(1):57-62.
30. Verma A, Devine S, Morrow M, et al. Low incidence of CMV viremia and disease after allogeneic peripheral blood stem cell transplantation. Role of pretransplant ganciclovir and post-transplant acyclovir. Bone Marrow Transplant. 2003;31(9):813-6.
31. Hill JA, Pergam SA, Cox E, et al. A modified intensive strategy to prevent cytomegalovirus disease in seropositive umbilical cord blood transplantation recipients. Biol Blood Marrow Transplant. 2018;24(10):2094-100.
32. Hammerstrom AE, Lombardi LR, Pingali SR, et al. Prevention of cytomegalovirus reactivation in haploidentical stem cell transplantation. Biol Blood Marrow Transplant. 2018;24(2):353-8.
33. Ljungman P, de la Camara R, Milpied N, et al. Randomized study of valacyclovir as prophylaxis against cytomegalovirus reactivation in recipients of allogeneic bone marrow transplants. Blood. 2002;99(8):3050-6.
34. Taherian MR, Azarbar P, Barkhordar M, et al. Efficacy and safety of adoptive T-cell therapy in treating cytomegalovirus infections post-haematopoietic stem cell transplantation: A systematic review and meta-analysis. Rev Med Virol. 2024;34(4):e2558.
2. Styczyński J. ABC of viral infections in hematology: focus on herpesviruses. Acta Haematol Pol. 2019;50(3):159-66.
3. Vallejo M, Muñiz P, Kwon M, et al. Risk prediction of CMV reactivation after allogeneic stem cell transplantation using five non-HLA immunogenetic polymorphisms. Ann Hematol. 2022;101(7):1567-76.
4. Barkhordar M, Kasaeian A, Janbabai G, et al. Modified combination of anti-thymocyte globulin (ATG) and post-transplant cyclophosphamide (PTCy) as compared with standard ATG protocol in haploidentical peripheral blood stem cell transplantation for acute leukemia. Front Immunol. 2022;13:921293.
5. Teira P, Battiwalla M, Ramanathan M, et al. Early cytomegalovirus reactivation remains associated with increased transplant-related mortality in the current era: a CIBMTR analysis. Blood. 2016;127(20):2427-38.
6. Kollman C, Howe CW, Anasetti C, et al. Donor characteristics as risk factors in recipients after transplantation of bone marrow from unrelated donors: the effect of donor age. Blood. 2001;98(7):2043-51.
7. Ljungman P, Brand R, Einsele H, et al. Donor CMV serologic status and outcome of CMV-seropositive recipients after unrelated donor stem cell transplantation: an EBMT megafile analysis. Blood. 2003;102(13):4255-60.
8. Ljungman P, Brand R, Hoek J, et al. Donor cytomegalovirus status influences the outcome of allogeneic stem cell transplant: a study by the European group for blood and marrow transplantation. Clin Infect Dis. 2014;59(4):473-81.
9. Broers AE, van der Holt R, van Esser JW, et al. Increased transplant-related morbidity and mortality in CMV-seropositive patients despite highly effective prevention of CMV disease after allogeneic T-cell–depleted stem cell transplantation. Blood. 2000;95(7):2240-5.
10. Einsele H, Hebart H, Kauffmann-Schneider C, et al. Risk factors for treatment failures in patients receiving PCR-based preemptive therapy for CMV infection. Bone Marrow Transplant. 2000;25(7):757-63.
11. Goldsmith SR, Abid MB, Auletta JJ, et al. Posttransplant cyclophosphamide is associated with increased cytomegalovirus infection: a CIBMTR analysis. Blood. 2021;137(23):3291-305.
12. Jamy O, Hebert C, Dunn-Valadez S, et al. Risk of cytomegalovirus infection with post-transplantation cyclophosphamide in haploidentical and HLA-matched unrelated donor transplantation. Transplant Cell Ther. 2022;28(4):213. e1-. e6.
13. Meijer E, Boland Greet J, Verdonck Leo F. Prevention of Cytomegalovirus Disease in Recipients of Allogeneic Stem Cell Transplants. Clin Microbiol Rev. 2003;16(4):647-57.
14. Chen K, Cheng MP, Hammond SP, et al. Antiviral prophylaxis for cytomegalovirus infection in allogeneic hematopoietic cell transplantation. Blood Adv. 2018;2(16):2159-75.
15. Reed DR, Petroni GR, West M, et al. Prophylactic pretransplant ganciclovir to reduce cytomegalovirus infection after hematopoietic stem cell transplantation. Hematol Oncol Stem Cell Ther. 2023;16(1):61-69.
16. Bacigalupo A, Tedone E, Van Lint M, et al. CMV prophylaxis with foscarnet in allogeneic bone marrow transplant recipients at high risk of developing CMV infections. Bone Marrow Transplant. 1994;13(6):783-8.
17. Bregante S, Bertilson S, Tedone E, et al. Foscarnet prophylaxis of cytomegalovirus infections in patients undergoing allogeneic bone marrow transplantation (BMT): a dose-finding study. Bone Marrow Transplant. 2000;26(1):23-9.
18. Burns L, Miller W, Kandaswamy C, et al. Randomized clinical trial of ganciclovir vs acyclovir for prevention of cytomegalovirus antigenemia after allogeneic transplantation. Bone Marrow Transplant. 2002;30(12):945-51.
19. Freyer CW, Carulli A, Gier S, et al. Letermovir vs. high-dose valacyclovir for cytomegalovirus prophylaxis following haploidentical or mismatched unrelated donor allogeneic hematopoietic cell transplantation receiving post-transplant cyclophosphamide. Leuk Lymphoma. 2022;63(8):1925-33.
20. Imlay HN, Kaul DR. Letermovir and maribavir for the treatment and prevention of cytomegalovirus infection in solid organ and stem cell transplant recipients. Clin Infect Dis. 2021;73(1):156-60.
21. Frange P, Leruez-Ville M. Maribavir, brincidofovir and letermovir: Efficacy and safety of new antiviral drugs for treating cytomegalovirus infections. Med Mal Infect. 2018;48(8):495-502.
22. Piret J, Boivin G. Clinical development of letermovir and maribavir: Overview of human cytomegalovirus drug resistance. Antiviral Res. 2019;163:91-105.
23. Barkhordar M, Kasaeian A, Tavakoli S, et al. Selection of suitable alternative donor in the absence of matched sibling donor: A retrospective single-center study to compare between haploidentical, 10/10 and 9/10 unrelated donor transplantation. Int J Hematol Oncol Stem Cell Res. 2021;15(1):51-60.
24. Glucksberg H, Storb R, Fefer A, et al. Clinical manifestations of graft-versus-host disease in human recipients of marrow from hl-a-matched sibling donors. Transplantation. 1974;18(4):295-304.
25. Filipovich AH, Weisdorf D, Pavletic S, et al. National Institutes of Health consensus development project on criteria for clinical trials in chronic graft-versus-host disease: I. Diagnosis and staging working group report. Biol Blood Marrow Transplant. 2005;11(12):945-56.
26. Milano F, Pergam SA, Xie H, et al. Intensive strategy to prevent CMV disease in seropositive umbilical cord blood transplant recipients. Blood. 2011;118(20):5689-96.
27. Winston DJ, Ho WG, Bartoni K, et al. Ganciclovir prophylaxis of cytomegalovirus infection and disease in allogeneic bone marrow transplant recipients: results of a placebo-controlled, double-blind trial. Ann Intern Med. 1993;118(3):179-84.
28. Kline J, Pollyea D, Stock W, et al. Pre-transplant ganciclovir and post-transplant high-dose valacyclovir reduce CMV infections after alemtuzumab-based conditioning. Bone marrow Transplant. 2006;37(3):307-10.
29. Atkinson K, Downs K, Golenia M, et al. Prophylactic use of ganciclovir in allogeneic bone marrow transplantation: absence of clinical cytomegalovirus infection. Br J Haematol. 1991;79(1):57-62.
30. Verma A, Devine S, Morrow M, et al. Low incidence of CMV viremia and disease after allogeneic peripheral blood stem cell transplantation. Role of pretransplant ganciclovir and post-transplant acyclovir. Bone Marrow Transplant. 2003;31(9):813-6.
31. Hill JA, Pergam SA, Cox E, et al. A modified intensive strategy to prevent cytomegalovirus disease in seropositive umbilical cord blood transplantation recipients. Biol Blood Marrow Transplant. 2018;24(10):2094-100.
32. Hammerstrom AE, Lombardi LR, Pingali SR, et al. Prevention of cytomegalovirus reactivation in haploidentical stem cell transplantation. Biol Blood Marrow Transplant. 2018;24(2):353-8.
33. Ljungman P, de la Camara R, Milpied N, et al. Randomized study of valacyclovir as prophylaxis against cytomegalovirus reactivation in recipients of allogeneic bone marrow transplants. Blood. 2002;99(8):3050-6.
34. Taherian MR, Azarbar P, Barkhordar M, et al. Efficacy and safety of adoptive T-cell therapy in treating cytomegalovirus infections post-haematopoietic stem cell transplantation: A systematic review and meta-analysis. Rev Med Virol. 2024;34(4):e2558.
| Files | ||
| Issue | Vol 19 No 4 (2025) | |
| Section | Original Article(s) | |
| Keywords | ||
| Cytomegalovirus prophylaxis; Allogeneic stem cell transplantation; Ganciclovir; Valacyclovir; Hybrid regimen; Preemptive therapy; CMV reactivation; Haploidentical transplant | ||
| Rights and permissions | |
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How to Cite
1.
Barkhordar M, Rashidi A, Vaezi M, Alijani N, Mousavi SA, Tavakoli Shiraji S, Azari Alanjeq M, Azari Alanjeq M, Abbaszadeh M, Kamranzadeh Fumani H, Bahri T. Hybrid Ganciclovir/Valacyclovir Prophylaxis Reduces CMV Reactivation in High-Risk Allogeneic Stem Cell Transplant Recipients. Int J Hematol Oncol Stem Cell Res. 2025;19(4):310-319.
