Cytomegalovirus-specific CD8+ T-cells are associated with a reduced incidence of early relapse after allogeneic stem cell transplantation

PLoS One. 2019 Mar 19;14(3):e0213739. doi: 10.1371/journal.pone.0213739. eCollection 2019.

Abstract

Leukemia relapse is the main cause for mortality after allogeneic stem cell transplantation (allo-SCT). Donor-derived allo-immune responses eliminate the residual host hematopoiesis and protect against relapse. Cytomegalovirus (CMV) reactivation (CMV-R) after allo-SCT may trigger anti-leukemic effects. The impact of CMV-specific CD8+ T-cells (CMV-CTLs) on the outcome after allo-SCT is currently unknown. Here, we studied the relationship between CMV-CTLs, overall T-cell reconstitution and relapse incidence in 103 patients with acute leukemia (n = 91) or myelodysplastic syndrome (n = 12) following CMV-seropositive recipient/donor (R+/D+) allo-SCT. Patients were subdivided based on the presence or absence of CMV-CTLs at 3 months after allo-SCT. Presence of CMV-CTLs was associated with preceding CMV-R and a fast T-cell reconstitution. Univariate analysis showed a significantly lower 1-, 2- and 5-year cumulative incidence of relapse (CIR) in patients with CMV-CTLs compared to those without CMV-CTLs. Multivariable regression analysis of the outcome performed with other relevant parameters chosen from univariate analysis revealed that presence of CMV-CTLs and chronic graft-versus-host disease (cGvHD) were the only independent factors associated with a low CIR. Onset of relapse was significantly later in patients with CMV-CTLs (median 489 days) than in in those without (median 152 days, p = 0.041) during a five-year follow-up. Presence of CMV-CTLs was associated with a lower incidence of early relapses (1 and 2-years), while cGvHD lead to a lower incidence of late relapses (2 to 5-years). In conclusion, our data show that CMV-CTLs indicate a functional immune-reconstitution protective against early relapse.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • CD8-Positive T-Lymphocytes / cytology
  • CD8-Positive T-Lymphocytes / virology*
  • Cytomegalovirus / isolation & purification
  • Cytomegalovirus / physiology*
  • Female
  • Graft vs Host Disease / diagnosis
  • Graft vs Host Disease / etiology
  • Humans
  • Leukemia / mortality
  • Leukemia / pathology
  • Leukemia / therapy*
  • Male
  • Middle Aged
  • Myelodysplastic Syndromes / mortality
  • Myelodysplastic Syndromes / pathology
  • Myelodysplastic Syndromes / therapy*
  • Recurrence
  • Regression Analysis
  • Stem Cell Transplantation* / adverse effects
  • Survival Rate
  • Transplantation, Homologous
  • Treatment Outcome
  • Virus Activation / physiology
  • Young Adult

Grants and funding

The project was supported in part by grants from the BMBF the German Center of Infectious Research (DZIF), TTU 07.804 and 07.801 to EMW and from the European Union Marie Curie Initial Training Networks Project Number 315963 “Improving HSCT By Validation of Biomarkers & Development Of Novel Cellular Therapies” awarded to J. Ogonek. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. RHEACELL GmbH & Co. KG, Heidelberg, Germany is now the employer of SB, thus provided support in the form of salary for author SB, but did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. The specific roles of the author are articulated in the ‘author contributions’.