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Dynamics of polyclonal immuno-reconstitution after allogeneic transplant with post-transplant cyclophosphamide and letermovir

Bone Marrow Transplantation volume 58, pages 1104–1111 (2023)Cite this article

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Abstract

Cytomegalovirus (CMV) reactivations are strong stimulators of immune-reconstitution (IR) in hematopoietic stem cell transplantation (HSCT) recipients. Herein, we analyzed 317 CMV-seropositive consecutive patients (n = 109 letermovir, LTV; n = 208 no-LTV), undergoing HSCT with post-transplant cyclophosphamide (PTCy) and calcineurin inhibitor- (CNI) free graft-versus-host-disease (GvHD) prophylaxis. At day+90, median CD19+/mm3 was higher in LTV-cohort: 5.5 [0;439] versus 2 [0;294], p = 0.008; median CD3+/mm3 counts were lower in LTV-cohort, with no differences in CD4+, CD8+ and NK-cells. At day+180 median CD3+, CD4+ and CD8+/mm3 values were comparable between groups. Higher CD19+/mm3 counts were observed in LTV-cohort: 62 [0; 2983] versus 42 [0; 863]. Significantly higher median NK/mm3 values were seen in LTV-cohort: 225.5 [0;763] versus 163.5 [0;1181], p = 0.0003. The impact of LTV on B-cell IR at 3 months and NK-cell levels at 6 months was retained in multivariate analysis (p < 0.01), whereas the effect on T-cells was not confirmed. Moreover, we confirmed a significant reduction of clinically-relevant CMV, and moderate-to- severe chronic GvHD in LTV-cohort. Overall, in our study the use of LTV was associated with a slight improvement of B-cell and NK-cells reconstitution, with only minor impact on T-cell subsets, giving new insights on polyclonal IR for HSCT recipients in the LTV era.

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Fig. 1: Two years cumulative incidence of Graft versus Host disease in letermovir (LTV) and no-LTV groups.
Fig. 2: CMV reactivation in letermovir (LTV) and no-LTV groups.
Fig. 3: Cellular and humoral immune reconstitution in letermovir (LTV) and no-LTV groups.
Fig. 4: Cellular and humoral immune reconstitution in letermovir (LTV) and no-LTV groups.

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Data availability

The datasets generated for this study are available on request to the corresponding author.

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Acknowledgements

We acknowledge all the patients, family members, and staff who participated in the study.

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Author notes

  1. These authors contributed equally: Giorgio Orofino, Elisabetta Xue.

  2. These authors jointly supervised this work: Maria Teresa Lupo Stanghellini, Raffaella Greco.

Authors and Affiliations

  1. Haematology and Bone Marrow Transplant Unit, IRCCS San Raffaele Hospital, Milano, Italy

    Giorgio Orofino, Elisabetta Xue, Andrea Acerbis, Daniela Clerici, Francesca Farina, Edoardo Campodonico, Alessandro Bruno, Simona Piemontese, Sara Mastaglio, Elisa Diral, Annalisa Ruggeri, Consuelo Corti, Luca Vago, Jacopo Peccatori, Fabio Ciceri, Maria Teresa Lupo Stanghellini & Raffaella Greco

  2. Università Vita-Salute San Raffaele, Milano, Italy

    Giorgio Orofino, Matteo Cristante, Andrea Acerbis, Edoardo Campodonico, Alessandro Bruno, Luca Vago, Chiara Bonini & Fabio Ciceri

  3. Experimental Hematology Unit, IRCCS San Raffaele Hospital, Milano, Italy

    Matteo Doglio, Maddalena Noviello, Elena Tassi & Chiara Bonini

  4. Cell Therapy Immunomonitoring Laboratory (MITiCi), Division of Immunology, Transplantation and Infectious Diseases, IRCCS San Raffaele Hospital, Milano, Italy

    Maddalena Noviello, Elena Tassi & Chiara Bonini

  5. Immunohematology and Transfusion Medicine Unit, IRCCS San Raffaele Hospital, Milano, Italy

    Raffaella Milani

  6. Unit of Immunogenetics, Leukemia Genomics and Immunobiology IRCCS San Raffaele Hospital, Milano, Italy

    Luca Vago

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Contributions

GO, EX, MD, MTLS and RG designed the study. RM performed flow cytometry analysis. MD, who has consolidated statistical expertise, performed statistical analysis and prepared the figures. GO, EX and MD prepared the table. GO, EX, MD, MTLS and RG interpreted the data and wrote the manuscript. RG and MTLS provided scientific advice and supervision. All authors contributed to sample and data collection, and approved the final version of the manuscript.

Corresponding authors

Correspondence to Fabio Ciceri or Raffaella Greco.

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The authors declare no competing interests.

Ethical statement

All patients were treated according to current Institutional programs upon written informed consent for transplant procedures, use of medical records and immunological studies for patients undergoing allogeneic HSCT within the non-interventional ALMON study, approved by San Raffaele Institutional Ethical Committee in date 19/10/2007.

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Orofino, G., Xue, E., Doglio, M. et al. Dynamics of polyclonal immuno-reconstitution after allogeneic transplant with post-transplant cyclophosphamide and letermovir. Bone Marrow Transplant 58, 1104–1111 (2023). https://doi.org/10.1038/s41409-023-02046-9

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