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Use of letermovir in off-label indications: Infectious Diseases Working Party of European Society of Blood and Marrow Transplantation retrospective study

Bone Marrow Transplantation volume 56, pages 1171–1179 (2021)Cite this article

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Abstract

Letermovir (LMV) is licensed for prophylaxis of CMV infection in allogeneic hematopoietic cell transplant adult CMV-seropositive patients. Due to its favorable safety profile, LMV brings potential for use in other clinical situations, outside the approved indication. The objective of the study was to analyze the efficacy and safety of the use of LMV in off-label indications in EBMT centers. A total of 49 patients were reported including 44 adults and 5 children. LMV was administered for: secondary prophylaxis (37 adults, 3 children), primary prophylaxis (2 children), pre-emptive treatment (5 adults), and therapy of CMV disease (2 adults; pneumonia, colitis). Cyclosporine was concomitantly used in 26 patients. Overall, LMV was used for a median 112 days (range: 10–473). Cumulative incidence of breakthrough infections during secondary prophylaxis was 10.1% (95% CI = 3.1–21.9). Prophylactic treatment with LMV resulted in 94.9% (95% CI = 81.0–98.7), and 81.9% (95% CI = 65.7–90.9) probability of, respectively, 60 and 120-day survival without CMV infection in patients receiving secondary prophylaxis. During therapy of CMV infection/disease, probability of 60 and 120-day overall survival was 100% and 71.4% (95% CI = 25.8–92.0), respectively. No breakthrough infection occurred in children on LMV prophylaxis. Adverse events were reported in 15/49 (30.4%) patients: the most common being nausea/vomiting (22.4%). In conclusion, the efficacy of the use of LMV as secondary prophylaxis was high, and the preliminary experience with the use of LMV for the treatment of patients with refractory CMV infection/disease was positive. Our data showed that higher dose or prolonged therapy did not result in increased rate of adverse events.

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Fig. 1: Breakthrough infections.
Fig. 2: Overall survival.

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References

  1. Green ML, Leisenring W, Xie H, Mast TC, Cui Y, Sandmaier BM, 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:e119–127. https://doi.org/10.1016/S2352-3026(15)00289-6.

    Article  PubMed  PubMed Central  Google Scholar 

  2. Schmidt-Hieber M, Labopin M, Beelen D, Volin L, Ehninger G, Finke J, 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;122:3359–64. https://doi.org/10.1182/blood-2013-05-499830.

    Article  CAS  PubMed  Google Scholar 

  3. Ljungman P, Brand R, Hoek J, de la Camara R, Cordonnier C, Einsele H, 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;59:473–81. https://doi.org/10.1093/cid/ciu364.

    Article  PubMed  Google Scholar 

  4. Garcia-Vidal C, Upton A, Kirby KA, Marr KA. Epidemiology of invasive mold infections in allogeneic stem cell transplant recipients: biological risk factors for infection according to time after transplantation. Clin Infect Dis. 2008;47:1041–50. https://doi.org/10.1086/591969.

    Article  PubMed  PubMed Central  Google Scholar 

  5. Yong MK, Slavin MA, Kontoyiannis DP. Invasive fungal disease and cytomegalovirus infection: is there an association? Curr Opin Infect Dis. 2018;31:481–9. https://doi.org/10.1097/QCO.0000000000000502.

    Article  PubMed  Google Scholar 

  6. Ljungman P, Boeckh M, Hirsch HH, Josephson F, Lundgren J, Nichols G, et al. Definitions of cytomegalovirus infection and disease in transplant patients for use in clinical trials. Clin Infect Dis. 2017;64:87–91. https://doi.org/10.1093/cid/ciw668.

    Article  PubMed  Google Scholar 

  7. Styczynski J. ABC of viral infections in hematology: focus on herpesviruses. Acta Haematol Pol. 2019;50:159–66. https://doi.org/10.2478/ahp-2019-0026.

    Article  Google Scholar 

  8. Marty FM, Ljungman P, Chemaly RF, Maertens J, Dadwal SS, Duarte RF, et al. Letermovir prophylaxis for cytomegalovirus in hematopoietic-cell transplantation. N. Engl J Med. 2017;377:2433–44. https://doi.org/10.1056/NEJMoa1706640.

    Article  CAS  PubMed  Google Scholar 

  9. Styczynski J. Prophylaxis vs preemptive therapy in prevention of CMV infection: new insight on prophylactic strategy after allogeneic hematopoietic cell transplantation. Acta Haematol Pol. 2020;51:17–23. https://doi.org/10.2478/ahp-2020-0005.

    Article  Google Scholar 

  10. Ljungman P, Schmitt M, Marty FM, Maertens J, Chemaly RF, Kartsonis NA, et al. A mortality analysis of letermovir prophylaxis for cytomegalovirus (cmv) in cmv-seropositive recipients of allogeneic hematopoietic-cell transplantation. Clin Infect Dis. 2020;70:1525–33. https://doi.org/10.1093/cid/ciz490.

    Article  CAS  PubMed  Google Scholar 

  11. Marty FM, Ljungman PT, Chemaly RF, Wan H, Teal VL, Butterton JR, 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 Transpl. 2020;20:1703–11. https://doi.org/10.1111/ajt.15764.

    Article  CAS  Google Scholar 

  12. Chong PP, Teiber D, Prokesch BC, Arasaratnam RJ, Peltz M, Drazner MH, et al. Letermovir successfully used for secondary prophylaxis in a heart transplant recipient with ganciclovir-resistant cytomegalovirus syndrome (UL97 mutation). Transpl Infect Dis. 2018;20:e12965. https://doi.org/10.1111/tid.12965.

    Article  CAS  PubMed  Google Scholar 

  13. Jung S, Michel M, Stamminger T, Michel D. Fast breakthrough of resistant cytomegalovirus during secondary letermovir prophylaxis in a hematopoietic stem cell transplant recipient. BMC Infect Dis. 2019;19:388. https://doi.org/10.1186/s12879-019-4016-1.

    Article  PubMed  PubMed Central  Google Scholar 

  14. Lin A, Maloy M, Su Y, Bhatt V, DeRespiris L, Griffin M, et al. Letermovir for primary and secondary cytomegalovirus prevention in allogeneic hematopoietic cell transplant recipients: real-world experience. Transpl Infect Dis. 2019;21:e13187. https://doi.org/10.1111/tid.13187.

    Article  CAS  PubMed  Google Scholar 

  15. Kilgore JT, Becken B, Varga MG, Parikh S, Prasad V, Lugo D, et al. Use of letermovir for salvage therapy for resistant cytomegalovirus in a pediatric hematopoietic stem cell transplant recipient. J Pediatr Infect Dis Soc. 2019. https://doi.org/10.1093/jpids/piz050.

    Article  Google Scholar 

  16. Perez Marin M, Decosterd LA, Andre P, Buclin T, Mercier T, Murray K, et al. Compassionate use of letermovir in a 2-year-old immunocompromised child with resistant cytomegalovirus disease. J Pediatr Infect Dis Soc. 2020;9:96–99. https://doi.org/10.1093/jpids/piz033.

    Article  CAS  Google Scholar 

  17. Chemaly RF, Chou S, Einsele H, Griffiths P, Avery R, Razonable RR, et al. Definitions of resistant and refractory cytomegalovirus infection and disease in transplant recipients for use in clinical trials. Clin Infect Dis. 2019;68:1420–6. https://doi.org/10.1093/cid/ciy696.

    Article  CAS  PubMed  Google Scholar 

  18. Nagler A, Shimoni A. Conditioning. In: Carreras E, Dufour C, Mohty M, Kroger N, editors. The EBMT handbook: hematopoietic stem cell transplantation and cellular therapies. Springer Open. Cham (CH); 2019. pp. 99–107.

  19. Robin C, Thiebaut A, Alain S, Sicre de Fontbrune F, Berceanu A, D’Aveni M, et al. Letermovir for secondary prophylaxis of cytomegalovirus infection and disease after allogeneic hematopoietic cell transplantation: results from the french compassionate program. Biol Blood Marrow Transpl. 2020;26:978–84. https://doi.org/10.1016/j.bbmt.2020.01.027.

    Article  CAS  Google Scholar 

  20. 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;7:1–16. https://doi.org/10.1007/s40121-017-0180-z.

    Article  PubMed  Google Scholar 

Download references

Acknowledgements

Patients were reported from the following centers: Department of Pediatric Hematology and Oncology, Collegium Medicum, Bydgoszcz, Poland (n = 1); Hospital St. Louis, Paris, France (n = 18); Klinik für Innere Medizin/Hämatologie, Universitätsspital Basel, Switzerland (n = 5); Department for Cellular Therapy and Allogeneic Stem Cell Transplantation, Stockholm, Karolinska University Hospital Huddinge, Sweden (n = 2); Division of Pediatric Hematology, Oncology and Stem Cell Transplantation, Helsinki University Hospital, Helsinki, Finland (n = 1); Department of Hematology, Radboud University Center Nijmegen, The Netherlands (n = 1); Hospital U. Marqués de Valdecilla, Santander, Spain (n = 4); Hospital Clínico Universitario-INCLIVA. University of Valencia, Spain (n = 2); Birmingham Heartlands Hospital, Birmingham, UK (n = 1); Division of Pediatric Hematology, Oncology and Stem Cell Transplantation, University of Padova, Padova, Italy (n = 2); Infectious Disease Research Program, Center for Bone Marrow Transplantation and Department of Pediatric Hematology and Oncology, University Children’s Hospital Muenster, Germany (n = 2); Universitaet Rostock, Rostock, Germany (n = 1); Attikon University General Hospital, Athens, Greece (n = 2); Techniciens d’Etude Clinique suivi de patients greffes, Strasbourg, France (n = 1); Charles University Hospital, Pilsen, Czech Republic (n = 1); University Regensburg, Regensburg, Germany (n = 4); IRRCS Ospedale Pediatrico Bambino Gesù, Sapienza, University of Rome, Rome, Italy (n = 1); Onco-Ematologia Pediatrica, Torino, Italy (n = 1).

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Authors and Affiliations

  1. Department of Pediatric Hematology and Oncology, Collegium Medicum, Nicolaus Copernicus University Torun, Bydgoszcz, Poland

    Jan Styczyński

  2. Pediatric Hematology Oncology, Verona, Italy

    Gloria Tridello

  3. Service d’hématologie-greffe, Hôpital Saint-Louis, Université Paris-Diderot, 75010, Paris, France

    Alienor Xhaard

  4. Divisions of Hematology and Internal Medicine, Department of Medicine, University Hospital Basel, Basel, Switzerland

    Michael Medinger

  5. Department for Cellular Therapy and Allogeneic Stem Cell Transplantation, Karolinska University Hospital Huddinge, Stockholm, Sweden

    Stephan Mielke & Per Ljungman

  6. Division of Pediatric Hematology, Oncology and Stem Cell Transplantation, Helsinki University Hospital, Helsinki, Finland

    Mervi Taskinen

  7. Department of Hematology, Radboud University Center Nijmegen, Nijmegen, The Netherlands

    Nicole Blijlevens

  8. Hospital U. Marqués de Valdecilla, Santander, Spain

    M. Aranzazu Bermudez Rodriguez

  9. Hospital Clínico Universitario-INCLIVA. University of Valencia, Valencia, Spain

    Carlos Solano

  10. Birmingham Heartlands Hospital, Birmingham, UK

    Emmanouil Nikolousis

  11. Division of Pediatric Hematology, Oncology and Stem Cell Transplantation, University of Padova, Padova, Italy

    Alessandra Biffi

  12. Infectious Disease Research Program, Center for Bone Marrow Transplantation and Department of Pediatric Hematology and Oncology, University Children’s Hospital Muenster, Muenster, Germany

    Andreas H. Groll

  13. Universitaet Rostock, Rostock, Germany

    Christian Junghanss

  14. Attikon University General Hospital, Athens, Greece

    Panagiotis Tsirigotis

  15. Hematology, ICANS, Strasbourg, France

    Bruno Lioure

  16. Department of Hematology and Oncology, University Hospital Pilsen, Pilsen, Czech Republic

    Jiří Šrámek

  17. Department of Histology and Embryology, Faculty of Medicine, Pilsen, Czech Republic

    Jiří Šrámek

  18. University Regensburg, Regensburg, Germany

    Ernst Holler

  19. Department of Pediatric Oncology, Hematology, Cell and Gene therapy, IRCCS Bambino Gesu’ Pediatric Hospital, Rome, Italy

    Federica Galaverna

  20. Onco-Ematologia Pediatrica, Torino, Italy

    Franca Fagioli

  21. EBMT Data Office, Dept. of Medical Statistics & Bioinformatics, Leiden, Netherlands

    Nina Knelange & Lotus Wendel

  22. Department of Hematology and Hematopoietic Cell Transplantation, Medical University, Poznan, Poland

    Lidia Gil

  23. Hospital de la Princesa, Madrid, Spain

    Rafael de la Camara

  24. Division of Infectious Diseases, University of Genoa (DISSAL) and IRCCS Ospedale Policlinico San Martino, Genova, Italy

    Malgorzata Mikulska

  25. Division of Hematology, Department of Medicine Huddinge, Karolinska Institutet, Stockholm, Sweden

    Per Ljungman

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Contributions

Concept of the study: PL. Design of the study: PL, JS, MM, and RdlC. Analysis of data: all authors. Data check-up and coordination: NK and LW. Statistical analysis and figures: GT. Manuscript writing: JS, LG, and PL. Critical revision: all authors. Final approval: all authors.

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Correspondence to Jan Styczyński.

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JS, LG, PL—Lecture fees from MSD. PL—advisory board participation MSD. Other authors have nothing to disclose.

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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 56, 1171–1179 (2021). https://doi.org/10.1038/s41409-020-01166-w

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