Granulocyte Colony-Stimulating Factor–Mobilized Allografts Contain Activated Immune Cell Subsets Associated with Risk of Acute and Chronic Graft-versus-Host Disease

Abstract

We defined associations among immune cell subsets in granulocyte colony-stimulating factor (G-CSF)-mobilized allografts and clinical outcomes after allogeneic hematopoietic cell transplantation (alloHCT). Fresh peripheral blood stem cell (PBSC) aliquots from 238 G-CSF-mobilized allografts were extensively characterized by immunophenotype. Subset-specific transplanted cells were correlated with acute graft-versus-host disease (aGVHD), chronic GVHD (cGVHD), malignant disease relapse, nonrelapse mortality, and overall survival. Of 238 assessable alloHCT recipients, 185 patients (78%) received reduced-intensity conditioning and 152 (64%) antithymocyte globulin-based serotherapy. Incidences of aGVHD and cGVHD were 58% and 48%, respectively. Median follow-up was 21 months (range, 1.4 to 41.1). In multivariable analyses adjusted for relevant clinical factors, allograft activated natural killer (NK) cells (CD56(+)CD16(+)CD69(+)CD158b(+)) were associated with a significantly lower risk of aGVHD (P = .0016; HR, .51; 95% confidence interval, .33 to .78), whereas late-activated HLA-DR(+) CD3(+) cells were associated with significantly higher aGVHD (P < .0005; HR, 2.31; 95% confidence interval, 1.55 to 3.43). In a subgroup of patients with acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS), receipt of an allograft from an older donor (≥40 years) was associated with a higher incidence of relapse (P = .0042; HR, 2.99); allograft content of early activated CD3(+) cells (CD3(+)CD69(+); P = .0024; HR, .4) and NKT cells (CD3(+)CD56(+); P = .0006; HR, .54) were associated with a lower incidence of relapse. Presence of HLA-Bw4-80Ile(+) genotype was associated with lower relapse incidence. In conclusion, activated NK cells within PBSC allografts associate with lower aGVHD risk, whereas HLA-DR(+) T cells associate with higher aGVHD and cGVHD risk. NKT cells and early activated T cells are associated with lower relapse risk in AML and MDS patients. These findings may have implications in therapeutic targeting of select populations in the allograft to minimize incidence of GVHD.

Severe Cytokine-Release Syndrome after T Cell–Replete Peripheral Blood Haploidentical Donor Transplantation Is Associated with Poor Survival and Anti–IL-6 Therapy Is Safe and Well Tolerated

“…Additionally, peripheral blood stem cell collection through G-CSF mobilization has been shown to be associated with different T-cell subsets than bone marrow grafts. Different allograft T-cell subset contents have been associated with risk of acute and chronic GVHD as well as risk of relapse 41 . It is possible that allografts with a higher dose of allo-reactive activated T-cells favor the development of CRS syndrome, while those with a higher number of regulatory T-cells are less likely to develop CRS.…”

Graft Immune Cell Composition Associates with Clinical Outcome of Allogeneic Hematopoietic Stem Cell Transplantation in Patients with AML

“…There are only a few recent publications (11, 26, 32, 33) describing systematically variation in the levels of immune cell populations in clinical HSCT grafts. Many studies have concentrated on the effects of stem cell mobilizing regimens on immune cell levels.…”

Cobalt protoporphyrin IX increases endogenous G‐ CSF and mobilizes HSC and granulocytes to the blood

“…In contrast to G‐CSF, CoPP does not increase the number of T cells. This could be clinically relevant, as T cells may cause GVHD (Zhang et al , ; Vasu et al , ; MacDonald et al , ) and impair engraftment of HSC upon transplantation (Müller et al , ). Finally, transplantation of PBMC from CoPP‐treated donors resulted in a higher long‐term blood chimerism, even upon secondary transplantation.…”