Abstract
Cytomegalovirus (CMV) DNAemia and CMV disease have been reported as more frequent in patients undergoing haploidentical allogeneic hematopoietic stem cell transplantation (Haplo-HSCT) than in those receiving HLA-matched allografts. This could be due to impaired CMV-specific T-cell reconstitution. Here, we conducted a multicenter observational study to assess CMV pp65 and IE-1-specific T cells kinetics in patients undergoing unmanipulated Haplo-HSCT with posttransplant cyclophosphamide (PT/Cy-haplo) and compared it with patients allografted with HLA-matched donors. Plasma CMV DNA load was monitored by real-time PCR and enumeration of CMV-specific IFN-γ-producing CD8+ and CD4+ T cells was performed by flow cytometry for intracellular cytokine staining at days +30, +60, +90, and +180 after transplantation. CMV DNAemia developed in 62 patients, occurring with comparable frequency in PT/Cy-haplo and MRD/MUD recipients (P = 0.14). There were no significant differences across groups in the number of patients either displaying detectable CMV-specific CD8+ and CD4+ T-cell responses or acquiring CMV-specific T-cell levels conferring protection against subsequent infection. CMV-specific T-cell counts were comparable between groups at most time points examined, irrespective of whether CMV DNAemia occurred or not prior to monitoring. Collectively the data suggest that PT/Cy-haplo recipients may reconstitute CMV-specific T-cell immunity to the same extent as patients undergoing HLA-matched allo-HSCT.
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References
McCurdy SR, Luznik L. Immune reconstitution after T-cell replete HLA-haploidentical transplantation. Semin Hematol. 2019;56:221–26.
Gagelmann N, Bacigalupo A, Rambaldi A, Hoelzer D, Halter J, Sanz J, et al. Haploidentical stem cell transplantation with posttransplant cyclophosphamide therapy vs other donor transplantations in adults with hematologic cancers: a systematic review and meta-analysis. JAMA Oncol. 2019;5:1739–48.
Luznik L, O’Donnell PV, Symons HJ, Chen AR, Leffell MS, Zahurak M, et al. HLA-haploidentical bone marrow transplantation for hematologic malignancies using nonmyeloablative conditioning and high-dose, posttransplantation cyclophosphamide. Biol Blood Marrow Transpl. 2008;14:641–50.
Pérez-Romero P, Blanco P, Giménez E, Solano C, Navarro D. An update on the management and prevention of cytomegalovirus infection following allogeneic hematopoietic stem cell transplantation. Future Virol. 2015;10:113–34.
Slade M, Goldsmith S, Romee R, DiPersio JF, Dubberke ER, Westervelt P, et al. Epidemiology of infections following haploidentical peripheral blood hematopoietic cell transplantation. Transpl Infect Dis. 2017;19. https://doi.org/10.1111/tid.12629.
Goldsmith SR, Slade M, DiPersio JF, Westervelt P, Lawrence SJ, Uy GL, et al. Cytomegalovirus viremia, disease, and impact on relapse in T-cell replete peripheral blood haploidentical hematopoietic cell transplantation with post-transplant cyclophosphamide. Haematologica. 2016;101:e465–8.
Shmueli E, Or R, Shapira MY, Resnick IB, Caplan O, Bdolah-Abram T, et al. High rate of cytomegalovirus drug resistance among patients receiving preemptive antiviral treatment after haploidentical stem cell transplantation. J Infect Dis. 2014;209:557–61.
Lin CH, Su YJ, Hsu CY, Wang PN, Teng CJ. Haploidentical allogeneic hematopoietic stem cell transplantation increases the risk of cytomegalovirus infection in adult patients with acute leukemia. Transpl Infect Dis. 2019;20:e13096.
Chen Y, Xu LP, Liu KY, Chen H, Chen YH, Zhang XH, et al. Risk factors for cytomegalovirus DNAemia following haploidentical stem cell transplantation and its association with host hepatitis B virus serostatus. J Clin Virol. 2016;75:10–15.
Hammerstrom AE, Lombardi LR, **ali SR, Rondon G, Chen J, Milton DR, et al. Prevention of cytomegalovirus reactivation in haploidentical stem cell transplantation. Biol Blood Marrow Transpl. 2018;24:353–8.
Baker M, Wang H, Rowley SD, Cai L, Pecora AL, Skarbnik A, et al. Comparative outcomes after haploidentical or unrelated donor bone marrow or blood stem cell transplantation in adult patients with hematological malignancies. Biol Blood Marrow Transpl. 2016;22:2047–55.
Raj RV, Hari P, Pasquini M, Epperla N, D’Souza A, Fenske T, et al. Impact of haploidentical hematopoietic cell transplantation conditioning intensity on the incidence and severity of post-transplantation viral infections. Bone Marrow Transpl. 2016;51:1602–4.
Tischer J, Engel N, Fritsch S, Prevalsek D, Hubmann M, Schulz C, et al. Virus infection in HLA-haploidentical hematopoietic stem cell transplantation: incidence in the context of immune recovery in two different transplantation settings. Ann Hematol. 2015;94:1677–88.
Chang YJ, Zhao XY, Huo MR, Xu LP, Liu DH, Liu KY, et al. Immune reconstitution following unmanipulated HLA-mismatched/haploidentical transplantation compared with HLA-identical sibling transplantation. J Clin Immunol. 2012;32:268–80.
Crocchiolo R, Bramanti S, Vai A, Sarina B, Mineri R, Casari E, et al. Infections after T-replete haploidentical transplantation and high-dose cyclophosphamide as graft-versus-host disease prophylaxis. Transpl Infect Dis. 2015;17:242–9.
Huntley D, Giménez E, Pascual MJ, Hernández-Boluda JC, Gago B, Vázquez L, et al. Incidence, features, and outcomes of cytomegalovirus DNAemia in unmanipulated haploidentical allogeneic hematopoietic stem cell transplantation with post-transplantation cyclophosphamide. Transpl Infect Dis. 2019;22:e13206.
Luo XH, Huang XJ, Li D, Liu KY, Xu LP, Liu DH. Immune reconstitution to cytomegalovirus following partially matched-related donor transplantation: impact of in vivo T-cell depletion and granulocyte colony-stimulating factor-primed peripheral blood/bone marrow mixed grafts. Transpl Infect Dis. 2013;15:22–33.
Luo XH, Chang YJ, Huang XJ. Improving cytomegalovirus-specific T cell reconstitution after haploidentical stem cell transplantation. J Immunol Res. 2014;63:1951.
Kato R, Tamaki H, Ikegame K, Yoshihara S, Kaida K, Taniguchi K, et al. Early detection of cytomegalovirus-specific cytotoxic T lymphocytes against cytomegalovirus antigenemia in human leukocyte antigen haploidentical hematopoietic stem cell transplantation. Ann Hematol. 2015;94:1707–15.
Noviello M, Forcina A, Veronica V, Crocchiolo R, Stanghellini MT, Carrabba M, et al. Early recovery of CMV immunity after HLA-haploidentical hematopoietic stem cell transplantation as a surrogate biomarker for a reduced risk of severe infections overall. Bone Marrow Transpl. 2015;50:1262–4.
Kanda Y, Oshima K, Asano-Mori Y, Kandabashi K, Nakagawa M, Sakata-Yanagimoto M, et al. In vivo alemtuzumab enables haploidentical human leukocyte antigen-mismatched hematopoietic stem-cell transplantation without ex vivo graft manipulation. Transplantation. 2005;79:1351–7.
Lilleri D, Gerna G, Fornara C, Chiesa A, Comolli G, Zecca M, et al. Human cytomegalovirus-specific T cell reconstitution in young patients receiving T cell-depleted, allogeneic hematopoietic stem cell transplantation. J Infect Dis. 2009;15:829–36.
Solano C, Benet I, Clari MA, Nieto J, de la Cámara R, López J, et al. Enumeration of cytomegalovirus-specific interferongamma CD8+ and CD4+ T cells early after allogeneic stem cell transplantation may identify patients at risk of active cytomegalovirus infection. Haematologica. 2008;93:1434–6.
Tormo N, Solano C, Benet I, Clari MA, Nieto J, de la Cámara R, et al. Lack of prompt expansion of cytomegalovirus pp65 and IE-1-specific IFNgamma CD8+ and CD4+ T cells is associated with rising levels of pp65 antigenemia and DNAemia during pre-emptive therapy in allogeneic hematopoietic stem cell transplant recipients. Bone Marrow Transpl. 2010;45:543–9.
Tormo N, Solano C, Benet I, Nieto J, de la Cámara R, López J, et al. Reconstitution of CMV pp65 and IE-1-specific IFN-γ CD8(+) and CD4(+) T-cell responses affording protection from CMV DNAemia following allogeneic hematopoietic SCT. Bone Marrow Transpl. 2011;46:1437–43.
Clari MÁ, Bravo D, Costa E, Muñoz-Cobo B, Solano C, Remigia MJ, et al. Comparison of the new Abbott Real Time CMV assay and the Abbott CMV PCR Kit for the quantitation of plasma cytomegalovirus DNAemia. Diagn Microbiol Infect Dis. 2013;75:207–9.
Solano C, Giménez E, Piñana JL, Vinuesa V, Poujois S, Zaragoza S, et al. Preemptive antiviral therapy for CMV infection in allogeneic stem cell transplant recipients guided by the viral doubling time in the blood. Bone Marrow Transpl. 2016;51:718–21.
Muñoz-Cobo B, Solano C, Costa E, Bravo D, Clari MÁ, Benet I, et al. Dynamics of cytomegalovirus (CMV) plasma DNAemia in initial and recurrent episodes of active CMV infection in the allogeneic stem cell transplantation setting: implications for designing preemptive antiviral therapy strategies. Biol Blood Marrow Transpl. 2011;17:1602–11.
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;64:87–89.
Glucksberg H, Storb R, Fefer A, Buckner CD, Neiman PE, Clift RA, et al. Clinical manifestations of graft-versus-host disease in human recipients of marrow from HL-A-matched sibling donors. Transplantation. 1974;18:295–304.
McCurdy SR, Vulic A, Symons HJ. Comparable and robust immune reconstitution after HLA-haploidentical or HLA-matched allogeneic transplantation (BMT) utilizing post-transplantation cyclophosphamide. Biol Blood Marrow Transpl. 2015;21:S71–71.
Tormo N, Solano C, Benet I, Nieto J, de la Cámara R, Garcia-Noblejas A, et al. Kinetics of cytomegalovirus (CMV) pp65 and IE-1-specific IFNgamma CD8+ and CD4+ T cells during episodes of viral DNAemia in allogeneic stem cell transplant recipients: potential implications for the management of active CMV infection. J Med Virol. 2010;82:1208–15.
Bak S, Tischer S, Dragon A, Ravens S, Pape L, Koenecke C, et al. Selective effects of mTOR inhibitor sirolimus on naïve and CMV-specific T cells extending its applicable range beyond immunosuppression. Front Immunol. 2018;9:2953.
Hakki M, Riddell SR, Storek J, Carter RA, Stevens-Ayers T, Sudour P, et al. Immune reconstitution to cytomegalovirus after allogeneic hematopoietic stem cell transplantation: impact of host factors, drug therapy, and subclinical reactivation. Blood. 2003;102:3060–7.
Navarro D, Amat P, de la Cámara R, López J, Vázquez L, Serrano D, et al. Efficacy and safety of a preemptive antiviral therapy strategy based on combined virological and immunological monitoring for active cytomegalovirus infection in allogeneic stem cell transplant recipients. Open Forum Infect Dis. 2016;3:ofw107.
Lacey S, La Rosa C, Zhou W, Sharma MC, Martinez J, Krishnan A, et al. Functional comparison of T cells recognizing cytomegalovirus pp65 and immediate-early antigen polypeptides in hematopoietic stem-cell transplant and solid organ transplant recipients. J Infect Dis. 2006;194:1410–21.
Zhou W, Longmate J, Lacey SF, Palmer JM, Gallez-Hawkins G, Thao L, et al. Impact of donor CMV status on viral infection and reconstitution of multifunction CMV specific T cells in CMV-positive transplant recipients. Blood. 2009;113:6465–76.
Giménez E, Muñoz-Cobo B, Solano C, Amat P, de la Cámara R, Nieto J, et al. Functional patterns of cytomegalovirus (CMV) pp65 and immediate early-1-specific CD8(+) T cells that are associated with protection from and control of CMV DNAemia after allogeneic stem cell transplantation. Transpl Infect Dis. 2015;17:361–70.
Acknowledgements
EG holds a Juan Rodés research contract from the Carlos III Health Institute (Ref. JR18/00053). Eliseo Albert holds a Río Hortega research contract from the Carlos III Health Institute (Ref. CM18/00221).
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This research was supported by grant 15/0090 from FIS (Fondo de Investigaciones Sanitarias), Ministerio de Sanidad y Consumo, Spain.
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Huntley, D., Giménez, E., Pascual, M.J. et al. Reconstitution of cytomegalovirus-specific T-cell immunity following unmanipulated haploidentical allogeneic hematopoietic stem cell transplantation with posttransplant cyclophosphamide. Bone Marrow Transplant 55, 1347–1356 (2020). https://doi.org/10.1038/s41409-020-0865-x
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DOI: https://doi.org/10.1038/s41409-020-0865-x
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