The importance of intermediate-dose Valacyclovir in primary CMV prophylaxis after Allogeneic-stem cell transplantation, and the advantages of step-wise pre-emptive treatment in CMV reactivation

Main Article Content

Osman Kara
Sinem Acar
Tayfun Elibol


Objective: Cytomegalovirus (CMV) reactivation and disease are still one of the most important causes of morbidity and mortality after allogeneic stem cell transplantation (ASCT). Letermovir prophylaxis has been clearly shown to be effective and well-tolerated. Drug interactions and cost are limitations. Alternative regimens such as Valacyclovir 3g-6g a day are of interest. In our study, we investigated the clinical results of intermediate dose (3 gr/d) valacyclovir after ASCT in primary CMV prophylaxis.

Material and Methods: The data of 70 patients who underwent ASCT between 2019-2020 were retrospectively analyzed. Valacyclovir was given at a dose of 3 g/day to all patients for primary CMV prophylaxis after ASCT. If CMV reactivation developed during Valacyclovir prophylaxis, therapeutic oral Valganciclovir or parenteral Ganciclovir was gradually switched according to CMV DNA copy numbers.

Results: The mean age of the patients included in the study was 45.5 years. The D+/R+ seropositivity was 97.2%. CMV reactivation developed in 37/70 (52.8%) patients within the first 100 days after transplantation. While CMV negativity could be achieved with oral VValganciclovir in 17 of the reactive patients (45.9%), hospitalization was required for parenteral ganciclovir use in 20 (28.1%) of them. The median PFS of patients with and without CMV reactivation was 10 months and 18 months, with a one-year PFS were 49.9% and 80.9%, respectively. One-year overall survival rates of patients with and without CMV reactivation were 52.9% and 92.9% respectively.

Conclusion: It has become more important to prevent infections that may develop after ASCT with prophylaxis rather than treating. Post-transplant intermediate-dose Valacyclovir as primary prophylaxis has been shown to reduce CMV reactivation/disease rates at desired levels and reduce hospitalizations.


Download data is not yet available.

Article Details

How to Cite
Kara, O., Acar, S., & Elibol, T. . (2022). The importance of intermediate-dose Valacyclovir in primary CMV prophylaxis after Allogeneic-stem cell transplantation, and the advantages of step-wise pre-emptive treatment in CMV reactivation. Medical Science and Discovery, 9(6), 324–333.
Research Article
Received 2022-05-30
Accepted 2022-06-08
Published 2022-06-08


Ljungman P, Brand R. Factors influencing CMV seropositivity in stem cell transplant patients and donors. haematologica. 2007 Aug 1;92(8):1139-42. DOI:

Akpınar H, Arslan H, Artuk C, et al. Consensus Report On CMV Diagnosis and Treatment in TURKEY. EKMUD. 2020;

Teira P, Battiwalla M, Ramanathan M, Barrett AJ, Ahn KW, Chen M, Green JS, Saad A, Antin JH, Savani BN, Lazarus HM. Early cytomegalovirus reactivation remains associated with increased transplant-related mortality in the current era: a CIBMTR analysis. Blood, The Journal of the American Society of Hematology. 2016 May 19;127(20):2427-38. DOI:

Green ML, Leisenring W, Xie H, Mast TC, Cui Y, Sandmaier BM, Sorror ML, Goyal S, Özkök S, Yi J, Sahoo F. Cytomegalovirus viral load and mortality after haemopoietic stem cell transplantation in the era of pre-emptive therapy: a retrospective cohort study. The Lancet Haematology. 2016 Mar 1;3(3):e119-27. DOI:

Schuster MG, Cleveland AA, Dubberke ER, Kauffman CA, Avery RK, Husain S, Paterson DL, Silveira FP, Chiller TM, Benedict K, Murphy K. Infections in hematopoietic cell transplant recipients: results from the organ transplant infection project, a multicenter, prospective, cohort study. InOpen forum infectious diseases 2017 (Vol. 4, No. 2, p. ofx050). US: Oxford University Press. DOI:

Ljungman P, Boeckh M, Hirsch HH, Josephson F, Lundgren J, Nichols G, Pikis A, Razonable RR, Miller V, Griffiths PD, Disease Definitions Working Group of the Cytomegalovirus Drug Development Forum. Definitions of cytomegalovirus infection and disease in transplant patients for use in clinical trials. Clinical Infectious Diseases. 2016 Sep 28:ciw668.

Ljungman P, De La Camara R, Cordonnier C, Einsele H, Engelhard D, Reusser P, Styczynski J, Ward K. Management of CMV, HHV-6, HHV-7 and Kaposi-sarcoma herpesvirus (HHV-8) infections in patients with hematological malignancies and after SCT. Bone marrow transplantation. 2008 Aug;42(4):227-40. DOI:

Ljungman P, de la Camara R, Robin C, Crocchiolo R, Einsele H, Hill JA, Hubacek P, Navarro D, Cordonnier C, Ward KN. Guidelines for the management of cytomegalovirus infection in patients with haematological malignancies and after stem cell transplantation from the 2017 European Conference on Infections in Leukaemia (ECIL 7). The Lancet Infectious Diseases. 2019 Aug 1;19(8):e260-72. DOI:

Tissot F, Agrawal S, Pagano L, Petrikkos G, Groll AH, Skiada A, Lass-Flörl C, Calandra T, Viscoli C, Herbrecht R. ECIL-6 guidelines for the treatment of invasive candidiasis, aspergillosis and mucormycosis in leukemia and hematopoietic stem cell transplant patients. haematologica. 2017 Mar;102(3):433. DOI:

Boeckh M, Gooley TA, Myerson D, Cunningham T, Schoch G, Bowden RA. Cytomegalovirus pp65 antigenemia-guided early treatment with ganciclovir versus ganciclovir at engraftment after allogeneic marrow transplantation: a randomized double-blind study.

Meyers JD, Reed EC, Shepp DH, Thornquist M, Dandliker PS, Vicary CA, Flournoy N, Kirk LE, Kersey JH, Thomas ED, Balfour Jr HH. Acyclovir for prevention of cytomegalovirus infection and disease after allogeneic marrow transplantation. New England Journal of Medicine. 1988 Jan 14;318(2):70-5. DOI:

Prentice HG, Gluckman E, Powles R, Ljungman P, Milpied NJ, Fernandez-Ranada JM, Mandelli F, Kho P, Bell AR, Kennedy L. Impact of long-term acyclovir on cytomegalovirus infection and survival after allogeneic bone marrow transplantation. The Lancet. 1994 Mar 26;343(8900):749-53. DOI:

Reshef R, Saber W, Bolaños-Meade J, Chen G, Chen YB, Ho VT, Ponce DM, Nakamura R, Martens MJ, Hansen JA, Levine JE. Acute GVHD diagnosis and adjudication in a multicenter trial: a report from the BMT CTN 1202 Biorepository Study. Journal of Clinical Oncology. 2021 Jun 10;39(17):1878-87. DOI:

Jagasia MH, Greinix HT, Arora M, Williams KM, Wolff D, Cowen EW, Palmer J, Weisdorf D, Treister NS, Cheng GS, Kerr H. National Institutes of Health consensus development project on criteria for clinical trials in chronic graft-versus-host disease: I. The 2014 diagnosis and staging working group report. Biology of Blood and Marrow Transplantation. 2015 Mar 1;21(3):389-401. DOI:

Schmidt-Hieber M, Labopin M, Beelen D, Volin L, Ehninger G, Finke J, Socié G, Schwerdtfeger R, Kröger N, Ganser A, Niederwieser D. CMV serostatus still has an important prognostic impact in de novo acute leukemia patients after allogeneic stem cell transplantation: a report from the Acute Leukemia Working Party of EBMT. Blood, The Journal of the American Society of Hematology. 2013 Nov 7;122(19):3359-64. DOI:

Marty FM, Ljungman P, Chemaly RF, Maertens J, Dadwal SS, Duarte RF, Haider S, Ullmann AJ, Katayama Y, Brown J, Mullane KM. Letermovir prophylaxis for cytomegalovirus in hematopoietic-cell transplantation. New England Journal of Medicine. 2017 Dec 21;377(25):2433-44. DOI:

Diaz L, Rosales J, Rosso F, Rosales M, Estacio M, Manzi E, Jaramillo FJ. Cytomegalovirus disease in patients with hematopoietic stem cell transplantation, experience over 8 years. Hematology, Transfusion and Cell Therapy. 2020 Mar 30;42:18-24. DOI:

Ljungman P, De la Camara R, Milpied N, Volin L, Russell CA, Crisp A, Webster A, Valacyclovir International Bone Marrow Transplant Study Group. Randomized study of valacyclovir as prophylaxis against cytomegalovirus reactivation in recipients of allogeneic bone marrow transplants. Blood, The Journal of the American Society of Hematology. 2002 Apr 15;99(8):3050-6. DOI:

Winston DJ, Yeager AM, Chandrasekar PH, Snydman DR, Petersen FB, Territo MC, Valacyclovir Cytomegalovirus Study Group. Randomized comparison of oral valacyclovir and intravenous ganciclovir for prevention of cytomegalovirus disease after allogeneic bone marrow transplantation. Clinical infectious diseases. 2003 Mar 15;36(6):749-58. DOI:

Vusirikala M, Wolff SN, Stein RS, Brandt SJ, Morgan DS, Greer JP, Schuening FG, Dummer JS, Goodman SA. Valacyclovir for the prevention of cytomegalovirus infection after allogeneic stem cell transplantation: a single institution retrospective cohort analysis. Bone marrow transplantation. 2001 Aug;28(3):265-70. DOI:

Junghanss C, Storb R, Maris MB, Carter RA, Sandmaier BM, Maloney DG, McSweeney PA, Corey L, Boeckh M. Impact of unrelated donor status on the incidence and outcome of cytomegalovirus infections after non‐myeloablative allogeneic stem cell transplantation. British journal of haematology. 2003 Nov;123(4):662-70. DOI:

Yoon JH, Lee S, Kim HJ, Jeon YW, Lee SE, Cho BS, Lee DG, Eom KS, Kim YJ, Min CK, Cho SG. Impact of cytomegalovirus reactivation on relapse and survival in patients with acute leukemia who received allogeneic hematopoietic stem cell transplantation in first remission. Oncotarget. 2016 Mar 29;7(13):17230. DOI:

Schelfhout J, Bonafede M, Cappell K, Cole AL, Manjelievskaia J, Raval AD. Impact of cytomegalovirus complications on resource utilization and costs following hematopoietic stem cell transplant. Current Medical Research and Opinion. 2020 Jan 2;36(1):33-41. DOI:

Cordonnier C, Maury S, Esperou H, Pautas C, Beaune J, Rodet M, Lagrange JL, Rouard H, Beaumont JL, Bassompierre F, Glückman E. Do minitransplants have minicosts? A cost comparison between myeloablative and nonmyeloablative allogeneic stem cell transplant in patients with acute myeloid leukemia. Bone marrow transplantation. 2005 Oct;36(7):649-54. DOI:

Sharma P, Gakhar N, MacDonald J, Abidi MZ, Benamu E, Bajrovic V, Purev E, Haverkos BM, Tobin J, Kaiser J, Chase S. Letermovir prophylaxis through day 100 post transplant is safe and effective compared with alternative CMV prophylaxis strategies following adult cord blood and haploidentical cord blood transplantation. Bone Marrow Transplantation. 2020 Apr;55(4):780-6. DOI:

Lin A, Maloy M, Su Y, Bhatt V, DeRespiris L, Griffin M, Lau C, Proli A, Barker J, Shaffer B, Giralt SA. Letermovir for primary and secondary cytomegalovirus prevention in allogeneic hematopoietic cell transplant recipients: Real‐world experience. Transplant Infectious Disease. 2019 Dec;21(6):e13187. DOI:

Karam E, LaPorte J, Sizemore C, Zhang X, Holland HK, Solh M, Morris LE, Bashey A, Solomon SR. Real world outcomes of letermovir prophylaxis in unselected high risk CMV seropositive hematopoietic stem cell transplant recipients. Blood. 2019 Nov 13;134:3269. DOI:

Dwabe S, Hsiao M, Yaghmour G. Real-World Experience Using Letermovir for CMV Prophylaxis in High-Risk Allogeneic Hematopoietic Stem Cell Patients in the Setting of Using T-Cell Depletion As Gvhd Prophylaxis and the Impact on CMV Reactivation, 1-Year Overall Survival, and 1-Year Gvhd-Free-Relapse-Free Survival. Blood. 2020 Nov 5;136:29. DOI:

Löunnqvist B, Ringdegn O, Ljungman P, Wahren B, Gahrton G. Reduced risk of recurrent leukaemia in bone marrow transplant recipients after cytomegalovirus infection. British journal of haematology. 1986 Aug;63(4):671-9. DOI:

Béziat V, Liu LL, Malmberg JA, Ivarsson MA, Sohlberg E, Björklund AT, Retière C, Sverremark-Ekström E, Traherne J, Ljungman P, Schaffer M. NK cell responses to cytomegalovirus infection lead to stable imprints in the human KIR repertoire and involve activating KIRs. Blood, The Journal of the American Society of Hematology. 2013 Apr 4;121(14):2678-88. DOI:

Ljungman P, Perez-Bercoff L, Jonsson J, Avetisyan G, Sparrelid E, Aschan J, Barkholt L, Larsson K, Winiarski J, Yun Z, Ringdén O. Risk factors for the development of cytomegalovirus disease after allogeneic stem cell transplantation. haematologica. 2006 Jan 1;91(1):78-83.

Boeckh M. Current antiviral strategies for controlling cytomegalovirus in hematopoietic stem cell transplant recipients: prevention and therapy. Transplant infectious disease. 1999 Sep;1(3):165-78. DOI: