Primary prophylaxis with letermovir for prevention of CMV infection in two children

Jan Styczyński 1 , Krzysztof Czyżewski 1 , and Robert Dębski 1
  • 1 Department of Pediatric Hematology and Oncology; Collegium Medicum, Nicolaus Copernicus University Toruń, Bydgoszcz, Poland
Jan Styczyński
  • Corresponding author
  • Department of Pediatric Hematology and Oncology; Collegium Medicum, Nicolaus Copernicus University Toruń, Bydgoszcz, Poland
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, Krzysztof Czyżewski
  • Department of Pediatric Hematology and Oncology; Collegium Medicum, Nicolaus Copernicus University Toruń, Bydgoszcz, Poland
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and Robert Dębski
  • Department of Pediatric Hematology and Oncology; Collegium Medicum, Nicolaus Copernicus University Toruń, Bydgoszcz, Poland
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Cytomegalovirus

Cytomegalovirus (CMV), a human herpesvirus HHV5, is present in latent form in 40%–70% children and 60%–90% of adults [1]. In patients after allogeneic hematopoietic cell transplantation (allo-HCT), it can reactivate either as recipient or donor origin. The virus can cause direct and indirect toxicity [2, 3]. Direct effects can cause organ infections (enteritis, pneumonia, hepatitis, bone marrow suppression, and retinitis) and toxicity, while indirect effects refer to associated adverse effects of antiviral therapy and increased risk of bacterial and fungal infections, and further suppression of immune system. Additionally, CMV seropositive status of recipient and/or donor, CMV reactivation, and CMV infection/disease cause decreased survival after hematopoietic cell transplantation (HCT) [4, 5, 6]. According to current knowledge, guidelines, and clinical experience, the best preventive strategy for CMV infection after allo-HCT in the year 2020 is specific antiviral prophylaxis with letermovir [7, 8, 9]. This drug is currently registered worldwide for primary prophylaxis for CMV-seropositive adults after allo-HCT. The objective of this clinical vignette is presentation of safe and efficacious use of letermovir for primary prophylaxis of CMV infection in two children after allo-HCT.

Patient 1

A 15-year-old girl, with body weight 58 kg, diagnosed for severe aplastic anemia (SAA), after failure of immunoablative therapy with anti-thymocyte globulin (ATG) + steroids + granulocyte colony stimulating factor (GCSF) + romiplostim, was qualified for HCT. Due to lack of sibling or matched unrelated donor, a haploidentical mother was selected to be the donor. Conditioning (fludarabine (FLU) + cyclophosphamide (CY) + single dose total body irradiation (sTBI) + ATG) and prophylaxis of graft-versus-host disease (GVHD) [post-transplant cyclophosphamide (PTCy) + cyclosporin A (CsA) + mycophenolate mofetil (MMF)] was performed according to Bacigalupo regimen [10]. No acute GVHD occurred. Due to CMV seropositivity of donor and recipient, the patient was administered prophylactically letermovir, orally from day 1. The dosage was 240 mg daily, and the patient was on CsA. The drug was well tolerated and no adverse effects were reported. No toxicities of ciclosporin A were observed and the CsA levels were stable. Due to pneumonia and respiratory insufficiency, the patient died without T-cell engraftment on day 60. Polymerase chain reaction (PCR) DNA-emia CMV on day 60 was negative (Fig. 1).

Fig 1
Fig 1

Use of letermovir for primary prophylaxis of CMV infection in two children

GVHD – graft-versus-host disease; SAA – severe aplastic anemia, CMV-POS - cytomegalovirus-positive; FLU+CY+sTBI+ATG – fludarabine + cyclophosphamideand +single dose total body irradiation + anti-thymocyte globulin; PTCy+MMF+CsA – post-transplant cyclophosphamide + mycophenolate mofetil + cyclosporin A; MUD – matched unrelated donor; ALL – T-cell acute lymphoblastic leukemia,

Citation: Acta Haematologica Polonica 51, 4; 10.2478/ahp-2020-0046

Patient 2

A 7-year-old boy, with body weight 27 kg, diagnosed for T-cell acute lymphoblastic leukemia (ALL), was qualified for HCT due to lack of remission by day 33 preceded by initial poor steroid response and presence of minimal residual disease. He was transplanted from female matched unrelated donor. Conditioning (total body irradiation (TBI) + etoposide) and prophylaxis of GVHD (PTCy + CsA + MMF) was performed. No acute GVHD occurred. Due to CMV seropositivity of donor and recipient, the patient was administered prophylactically letermovir, orally from day 1. The dosage was 120 mg daily, and the patient was on cyclosporine A. The drug was well tolerated and no adverse effects were reported. No toxicities of CsA were observed and the CsA levels were stable. T-cell engraftment (CD4+ >200/μl) was reached by day 60, and letermovir was discontinued by day 80, PCR DNA-emia CMV on day 90 was negative (Fig. 1).

Discussion

Due to its extremely favorable safety profile, letermovir brings potential for the use in clinical situations, other than approved indication. We decided to administer letermovir to our two patients being at very high risk of CMV reactivation. In Patient 1, we applied typical dosing as for adults when concomitantly treated with cyclosporine A. As the patient body weight was 58 kg, it was comparable to adults. With pediatric approach, the drug was administered at dosage of 4.1 mg/kg bw. In Patient 2, with body weight 27 kg, we decided to use letermovir at the daily dose of 120 mg, which corresponded to pediatric dosing 4.4 mg/kg bw. In summary, in both cases the administration of letermovir was safe and protected the patients from CMV reactivation, as confirmed in several PCR assays.

Acknowledgments

The authors thank the nurses team of the HCT unit chaired by Ewa Dembna for excellent care of the patients.

Authors’ contributions

JS – was responsible for the study design and provided administrative support. KC, JS – carried out data analysis and interpretation and manuscript writing. All the authors – carried out data check-up and provided final approval.

Conflict of interest

JS has received scientific grants or served at the speakers’ bureau of MSD. All other authors declared no conflict of interest related to this study.

Financial support

None.

Ethics

The work described in this article has been carried out in accordance with The Code of Ethics of the World Medical Association (Declaration of Helsinki) for experiments involving humans; EU Directive 2010/63/EU for animal experiments; uniform requirements for manuscripts submitted to biomedical journals.

References

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    Ljungman P, Boeckh M, Hirsch HH, et al. Definitions of cytomegalovirus infection and disease in transplant patients for use in clinical trials. Clin Infect Dis 2017;64:87–91.

    • Crossref
    • PubMed
    • Export Citation
  • [2]

    Styczynski J. ABC of viral infections in hematology: focus on herpesviruses. Acta Haematol Pol 2019;50:159–66.

    • Crossref
    • Export Citation
  • [3]

    Styczynski J. Infectious complications in children and adults with hematological malignancies. Acta Haematol Pol 2019;50:167–73.

    • Crossref
    • Export Citation
  • [4]

    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;59:473–81.

    • Crossref
    • Export Citation
  • [5]

    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;122:3359–64.

    • PubMed
    • Export Citation
  • [6]

    Green ML, Leisenring W, Xie H, 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:e119–27.

    • Crossref
    • PubMed
    • Export Citation
  • [7]

    Ljungman P, de la Camara R, Robin C, et al. 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:e260–72.

    • Crossref
    • PubMed
    • Export Citation
  • [8]

    Marty FM, Ljungman P, Chemaly RF, et al. Letermovir prophylaxis for cytomegalovirus in hematopoietic-cell transplantation. N Engl J Med 2017;377:2433–44.

    • Crossref
    • PubMed
    • Export Citation
  • [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.

    • Crossref
    • Export Citation
  • [10]

    Bacigalupo A, Giammarco S. Haploidentical donor transplants for severe aplastic anemia. Semin Hematol 2019;56:190–3.

    • Crossref
    • PubMed
    • Export Citation

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  • [1]

    Ljungman P, Boeckh M, Hirsch HH, et al. Definitions of cytomegalovirus infection and disease in transplant patients for use in clinical trials. Clin Infect Dis 2017;64:87–91.

    • Crossref
    • PubMed
    • Export Citation
  • [2]

    Styczynski J. ABC of viral infections in hematology: focus on herpesviruses. Acta Haematol Pol 2019;50:159–66.

    • Crossref
    • Export Citation
  • [3]

    Styczynski J. Infectious complications in children and adults with hematological malignancies. Acta Haematol Pol 2019;50:167–73.

    • Crossref
    • Export Citation
  • [4]

    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;59:473–81.

    • Crossref
    • Export Citation
  • [5]

    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;122:3359–64.

    • PubMed
    • Export Citation
  • [6]

    Green ML, Leisenring W, Xie H, 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:e119–27.

    • Crossref
    • PubMed
    • Export Citation
  • [7]

    Ljungman P, de la Camara R, Robin C, et al. 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:e260–72.

    • Crossref
    • PubMed
    • Export Citation
  • [8]

    Marty FM, Ljungman P, Chemaly RF, et al. Letermovir prophylaxis for cytomegalovirus in hematopoietic-cell transplantation. N Engl J Med 2017;377:2433–44.

    • Crossref
    • PubMed
    • Export Citation
  • [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.

    • Crossref
    • Export Citation
  • [10]

    Bacigalupo A, Giammarco S. Haploidentical donor transplants for severe aplastic anemia. Semin Hematol 2019;56:190–3.

    • Crossref
    • PubMed
    • Export Citation
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    Use of letermovir for primary prophylaxis of CMV infection in two children

    GVHD – graft-versus-host disease; SAA – severe aplastic anemia, CMV-POS - cytomegalovirus-positive; FLU+CY+sTBI+ATG – fludarabine + cyclophosphamideand +single dose total body irradiation + anti-thymocyte globulin; PTCy+MMF+CsA – post-transplant cyclophosphamide + mycophenolate mofetil + cyclosporin A; MUD – matched unrelated donor; ALL – T-cell acute lymphoblastic leukemia,