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Safety and efficacy of brincidofovir for Adenovirus infection in children receiving allogeneic stem cell transplantation: an AIEOP retrospective analyses

Bone Marrow Transplantation volume 56, pages 3104–3107 (2021)Cite this article

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Adenoviruses (ADV) are non-enveloped, double-stranded deoxyribonucleic acid (DNA) viruses associated with a wide range of clinical syndromes in humans. Although infection among healthy individuals is almost invariably self-limited, ADV can cause life-threatening diseases in immunocompromised patients, particularly in hematopoietic stem-cell transplant (HSCT) recipients [1]. Clinical manifestations include respiratory-tract and gastrointestinal (GI) diseases, hepatitis, interstitial nephritis, and hemorrhagic cystitis, with a 30% mortality rate [1]. There are limited treatment options in the pediatric population. Existing data suggest that cidofovir (CDV) and its lipid-ester analog, brincidofovir (BCV), may provide the highest likelihood of antiviral efficacy, but the use of CDV has been so far limited by significant toxicity [2, 3]. BCV appears to have an increased efficacy against ADV in vitro, with lower renal and bone marrow toxicity compared to CDV [4, 5]. Furthermore, BCV has excellent oral bioavailability, allowing administration once to twice weekly. In this study, we describe 30 transplanted children, who developed 44 ADV infection episodes, mostly refractory to CDV and responsive to BCV, with low mortality and toxicity.

This study retrospectively analyzed 30 HSCT patients who developed 44 ADV infection episodes at pediatric transplant centers belonging to the Italian Pediatric Hematology Oncology Association (AIEOP) between 2012 and 2019: 23 received CDV and 21 BCV. Local Ethics Committees approved the BCV compassionate use and written informed consent was signed, in accordance with the Helsinki declaration. Patient, transplant, and ADV disease characteristics are shown in Table 1. They were 22 males, with a median age of 10 years (range: 9 months–19 years), and were affected prevalently by acute leukemia (n = 20). All patients received a myeloablative conditioning regimen and donors were mostly haploidentical (n = 16) or matched unrelated (MUDs) (n = 11). Twenty-nine patients received antiviral prophylaxis, most of them with acyclovir (n = 23). Eleven patients received a second HSCT for relapse/graft failure. All engrafted patients were monitored for ADV reactivation by quantitative PCR [6] in blood, stools, and urine at least once a week from the conditioning regimen start until immune reconstitution, defined as CD4 + T cells >200/mL [7]. ADV disease was defined according to ECIL guidelines, with documentation in histopathological samples or ADV detection by culture, antigen test, or nucleic acid test from biopsies or body fluids [8,9,10].

Table 1 Demographic, transplant, and ADV disease characteristics of patients.
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Acknowledgements

We would like to acknowledge Chimerix-Inc (Durham, NC) to provide BCV in a compassionate use program, and Dr. Mariangela Brogna for editorial assistance.

AIEOP Infectious Disease and Stem Cell Transplantation Working Parties

Katia Perruccio1, Federica Galaverna3, Francesca Carraro4, Elisabetta Calore5, Valentina Baretta6, M. Speranza Massei1, Maura Faraci7, Marta Verna8, Elena Soncini9, Simone Cesaro6

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Authors and Affiliations

  1. Pediatric Oncology-Hematology, Santa Maria della Misericordia Hospital, Perugia, Italy

    Katia Perruccio, Maria Speranza Massei, Ilaria Capolsini, Maurizio Caniglia & M. Speranza Massei

  2. Pediatric Oncology-Hematology, Pisa, Italy

    Mariacristina Menconi

  3. Pediatric Oncology-Hematology Ospedale Pediatrico Bambino Gesù, Roma, Italy

    Federica Galaverna, Daria Pagliara & Franco Locatelli

  4. Pediatric Oncology-Hematology, Regina Margherita Hospital, Torino, Italy

    Francesca Carraro & Franca Fagioli

  5. Pediatric Oncology-Hematology, University of Padova, Padova, Italy

    Elisabetta Calore & Alessandra Biffi

  6. Pediatric Oncology-Hematology, University of Verona, Verona, Italy

    Valentina Baretta & Simone Cesaro

  7. HSCT Unit-Pediatric Oncology-Hematology, Istituto G. Gaslini, Genova, Italy

    Maura Faraci

  8. Pediatric Oncology-Hematology, Monza, Italy

    Marta Verna

  9. Pediatric Oncology-Hematology, Spedali Civili of Brescia, Brescia, Italy

    Elena Soncini

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  1. Katia Perruccio
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Consortia

on behalf of AIEOP Infectious Disease and Stem Cell Transplantation Working Parties

  • Katia Perruccio
  • , Federica Galaverna
  • , Francesca Carraro
  • , Elisabetta Calore
  • , Valentina Baretta
  • , M. Speranza Massei
  • , Maura Faraci
  • , Marta Verna
  • , Elena Soncini
  •  & Simone Cesaro

Contributions

K.P. designed the study, analyzed the data, and wrote the paper; S.C. M.C.M., F.G., D.P., E.C., F.F., E.C., A.B., V.B., M.S.M., I.C., M.F., M.V., and E.S. collected data and took care of patients; M.C. and F.L. gave scientific contribution in paper revising; S.C. gave major contribution to design the study and critically revised the paper. All authors approved the submitted final version of the paper.

Corresponding author

Correspondence to Katia Perruccio.

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Members of the AIEOP Infectious Disease and Stem Cell Transplantation Working Parties are listed below Acknowledgements.

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Perruccio, K., Menconi, M., Galaverna, F. et al. Safety and efficacy of brincidofovir for Adenovirus infection in children receiving allogeneic stem cell transplantation: an AIEOP retrospective analyses. Bone Marrow Transplant 56, 3104–3107 (2021). https://doi.org/10.1038/s41409-021-01285-y

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