Date Published: March 19, 2019
Publisher: Public Library of Science
Author(s): Pavankumar Reddy Varanasi, Justyna Ogonek, Susanne Luther, Elke Dammann, Michael Stadler, Arnold Ganser, Sylvia Borchers, Lothar Hambach, Eva M. Weissinger, Antonio Perez-Martinez.
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.
Relapse is the main cause for mortality after allogeneic stem cell transplantation (allo-SCT) in patients with acute leukemia and myelodysplastic syndrome (MDS) . An adverse disease status [2, 3], unfavorable cyto- and molecular-genetics [4, 5] or reduced intensity conditioning (RIC)  are major disease or transplant related risk factors for relapse after allo-SCT. The immune-mediated graft-versus-leukemia (GvL) effect after allo-SCT is often associated with the occurrence of graft-versus-host disease (GvHD) . Chronic but not acute GvHD has been shown to be protective against relapse of acute leukemia  and myelodysplastic syndrome (MDS) . The exact mechanisms driving the allo-immune responses responsible for the GvL effect and for GvHD are still unknown.
Our study is the first to show that the presence of CMV-CTLs at 3 months after allo-SCT in patients with hematological malignancies transplanted in the CMV R+/D+ setting is associated with a reduction of early relapses. The current study was prompted by our previous observations that the presence of CMV-CTLs patients in the CMV R+/D+ setting was associated with a fast T-cell reconstitution and elimination of the host hematopoiesis in patients with a broad spectrum of hematological diseases . The latter data had suggested that CMV-CTLs might be a trigger for allo-immune responses reflected by the conversion to complete donor chimerism. The present study focused on the impact of CMV-CTLs in comparison to other demographic and clinical parameters on the outcome selectively in acute leukemia and MDS patients after allo-SCT. In accordance with previous reports , patients receiving a mismatched unrelated donor graft had a (borderline) reduced OS and a reduced DFS in the multivariable regression analysis. Severe aGvHD had no impact on the CIR but was associated with a reduced OS and DFS and an increased NRM.[7, 8] In accordance with previous reports, [7, 8] cGvHD was associated with an improved OS and DFS and a reduced CIR in the multivariable regression analysis. The advanced disease status [2, 3] and high-risk cyto- and molecular-genetics [4, 5] were significantly or by trend, respectively, associated with an increased CIR in the univariate analysis. However, this effect was lost in the multivariable analyses, maybe due to the still small sample size in our cohort (S2 Table). Taken together, our cohort compares well with other publications on the impact of the major disease or transplant related factors on the outcome. The most important finding of the current study was the association of the presence of CMV-CTLs with a reduced 1- and 2-year CIR both in the uni- and multivariable analysis. These data suggest that the previously observed suppression of host chimerism at 3 months after allo-SCT in patients with CMV-CTLs  translates at a longer follow-up in an anti-leukemic effect. Of note, the presence of CMV-CTLs at 3 months after transplantation and cGvHD were the only independent parameters significantly associated with a reduced CIR. However, while cGvHD was protective against late relapses, the protective effect of CMV-CTLs was restricted to early relapses after allo-SCT.