Vol 52, No 3 (2021)
Original research article
Published online: 2021-06-28
Real-world experience with letermovir in primary prophylaxis of cytomegalovirus in adult patients after hematopoietic cell transplantation: summary of reported data
1
, 1
, 1
Acta Haematol Pol 2021;52(3):182-189.
Abstract
Introduction: Letermovir (LMV) is a new antiviral agent approved in 2017 for prophylaxis to prevent cytomegalovirus (CMV) reactivation in CMV-seropositive allogeneic hematopoietic cell transplant recipients. Numerous reports on real-world experiences with LMV have been presented at international hematology and hematopoietic cell transplantation meetings. The objective of this study was to summarize data reported 2019–2020 on primary prophylaxis with LMV in adult patients. Methods: We analyzed 19 studies published or presented in 2019 and 2020, including two studies presented twice. Results: An overall 817 patients received primary prophylaxis with LMV. In 12 studies with a control group, the rate of breakthrough infection was 99/577 (17.2%) vs. 874/1,525 (57.3%), odds ratio (OR) =6.5 [95% confidence interval (CI) =5.1–8.2), p <0.0001]. In seven studies without a control group, the rate was 17/240 (7.1%). Overall breakthrough infection occurred in 116/817 (14.2%) patients on LMV primary prophylaxis vs. 874/1,525 (57.3%) without prophylaxis, OR =8.1 (95% CI =6.5–10.1), p <0.0001. Conclusions: LMV when used for primary prophylaxis challenges the standard of care for CMV reactivation based on preemptive therapy. Presented real-world data shows a significant improvement in reducing the risk of any CMV viremia and clinically significant CMV infection in all reported studies performed so far. LMV is a drug that breaks the paradigm of preventive therapy by moving it from pre-emptive treatment to prophylaxis.
Keywords: cytomegalovirusletermovirprophylaxispreemptive therapytransplantation
References
- Green ML, Leisenring W, Xie Hu, et al. Cytomegalovirus viral load and mortality after haemopoietic stem cell transplantation in the era of pre-emptive therapy: a retrospective cohort study. Lancet Haematol. 2016; 3(3): e119–e127.
- Schmidt-Hieber M, Labopin M, Beelen D, et al. 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. 2013; 122(19): 3359–3364.
- Ljungman P, Brand R, Hoek J, et al. Infectious Diseases Working Party of the European Group for Blood and Marrow Transplantation. 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): 473–481.
- Styczyński J. ABC of viral infections in hematology: focus on herpesviruses. Acta Haematologica Polonica. 2019; 50(3): 159–166.
- Marty FM, Ljungman P, Papanicolaou GA, et al. Maribavir 1263-300 Clinical Study Group. Maribavir prophylaxis for prevention of cytomegalovirus disease in recipients of allogeneic stem-cell transplants: a phase 3, double-blind, placebo-controlled, randomised trial. Lancet Infect Dis. 2011; 11(4): 284–292.
- Marty FM, Winston DJ, Chemaly RF, et al. SUPPRESS Trial Clinical Study Group. A randomized, double-blind, placebo-controlled phase 3 trial of oral brincidofovir for cytomegalovirus prophylaxis in allogeneic hematopoietic cell transplantation. Biol Blood Marrow Transplant. 2019; 25(2): 369–381.
- Marty FM, Ljungman PT, Chemaly RF, et al. Letermovir Prophylaxis for Cytomegalovirus in Hematopoietic-Cell Transplantation. N Engl J Med. 2017; 377(25): 2433–2444.
- Ljungman P, de la Camara R, Robin C, et al. 2017 European Conference on Infections in Leukaemia group. 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). Lancet Infect Dis. 2019; 19(8): e260–e272.
- Ljungman P, de La Camara R, Milpied N, et al. Valacyclovir International Bone Marrow Transplant Study Group. Randomized study of valacyclovir as prophylaxis against cytomegalovirus reactivation in recipients of allogeneic bone marrow transplants. Blood. 2002; 99(8): 3050–3056.
- Winston DJ, Yeager AM, Chandrasekar PH, et al. Valacyclovir Cytomegalovirus Study Group. Randomized comparison of oral valacyclovir and intravenous ganciclovir for prevention of cytomegalovirus disease after allogeneic bone marrow transplantation. Clin Infect Dis. 2003; 36(6): 749–758.
- Prentice HG, Gluckman E, Powles RL, et al. Impact of long-term acyclovir on cytomegalovirus infection and survival after allogeneic bone marrow transplantation. European Acyclovir for CMV Prophylaxis Study Group. Lancet. 1994; 343(8900): 749–753.
- Goodrich JM, Bowden RA, Fisher L, et al. Ganciclovir prophylaxis to prevent cytomegalovirus disease after allogeneic marrow transplant. Ann Intern Med. 1993; 118(3): 173–178.
- 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): 179–184.
- Ordemann R, Naumann R, Geissler G, et al. Foscarnet--an alternative for cytomegalovirus prophylaxis after allogeneic stem cell transplantation? Ann Hematol. 2000; 79(8): 432–436.
- 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): 23–29.
- Chemaly RF, Ullmann AJ, Stoelben S, et al. AIC246 Study Team. Letermovir for cytomegalovirus prophylaxis in hematopoietic-cell transplantation. N Engl J Med. 2014; 370(19): 1781–1789.
- Marty FM, Winston DJ, Rowley SD, et al. CMX001-201 Clinical Study Group. CMX001 to prevent cytomegalovirus disease in hematopoietic-cell transplantation. N Engl J Med. 2013; 369(13): 1227–1236.
- Winston DJ, Young JAH, Pullarkat V, et al. Maribavir prophylaxis for prevention of cytomegalovirus infection in allogeneic stem cell transplant recipients: a multicenter, randomized, double-blind, placebo-controlled, dose-ranging study. Blood. 2008; 111(11): 5403–5410.
- Maertens J, Cordonnier C, Jaksch P, et al. Maribavir for Preemptive Treatment of Cytomegalovirus Reactivation. N Engl J Med. 2019; 381(12): 1136–1147.
- Papanicolaou GA, Silveira FP, Langston AA, et al. Maribavir for Refractory or Resistant Cytomegalovirus Infections in Hematopoietic-cell or Solid-organ Transplant Recipients: A Randomized, Dose-ranging, Double-blind, Phase 2 Study. Clin Infect Dis. 2019; 68(8): 1255–1264.
- Chemaly RF, Hill JA, Voigt S, et al. In vitro comparison of currently available and investigational antiviral agents against pathogenic human double-stranded DNA viruses: A systematic literature review. Antiviral Res. 2019; 163: 50–58.
- Shigle TL, Handy VW, Chemaly RF. Letermovir and its role in the prevention of cytomegalovirus infection in seropositive patients receiving an allogeneic hematopoietic cell transplant. Ther Adv Hematol. 2020; 11: 2040620720937150.
- Sharma P, Gakhar N, MacDonald J, et al. 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 Transplant. 2020; 55(4): 780–786.
- Lin A, Maloy M, Su Y, et al. Letermovir for primary and secondary cytomegalovirus prevention in allogeneic hematopoietic cell transplant recipients: Real-world experience. Transpl Infect Dis. 2019; 21(6): e13187.
- Derigs P, Radujkovic A, Schubert ML, et al. Letermovir prophylaxis is effective in preventing cytomegalovirus reactivation after allogeneic hematopoietic cell transplantation: single-center real-world data. Ann Hematol. 2020 [Epub ahead of print].
- Anderson A, Raja M, Vazquez N, et al. Clinical "real-world" experience with letermovir for prevention of cytomegalovirus infection in allogeneic hematopoietic cell transplant recipients. Clin Transplant. 2020; 34(7): e13866.
- Milano F, Pergam SA, Xie Hu, et al. Intensive strategy to prevent CMV disease in seropositive umbilical cord blood transplant recipients. Blood. 2011; 118(20): 5689–5696.
- Ljungman P, Schmitt M, Marty FM, et al. A Mortality Analysis of Letermovir Prophylaxis for Cytomegalovirus (CMV) in CMV-seropositive Recipients of Allogeneic Hematopoietic Cell Transplantation. Clin Infect Dis. 2020; 70(8): 1525–1533.
- Marty FM, Ljungman PT, Chemaly RF, et al. Outcomes of patients with detectable CMV DNA at randomization in the phase III trial of letermovir for the prevention of CMV infection in allogeneic hematopoietic cell transplantation. Am J Transplant. 2020; 20(6): 1703–1711.
- Styczyński J, Czyżewski K, Dębski R. Primary prophylaxis with letermovir for prevention of CMV infection in two children. Acta Haematologica Polonica. 2020; 51(4): 263–264.
- Styczyński J, Tridello G, Xhaard A, et al. Use of letermovir in off-label indications: Infectious Diseases Working Party of European Society of Blood and Marrow Transplantation retrospective study. Bone Marrow Transplant. 2020 [Epub ahead of print].