Improved Survival After Transplantation of More Donor Plasmacytoid Dendritic or Naïve T Cells From Unrelated-Donor Marrow Grafts: Results From BMTCTN 0201

Abstract

A B S T R A C T PurposeTo characterize relationships between specific immune cell subsets in bone marrow (BM) or granulocyte colony-stimulating factor-mobilized peripheral blood (PB) stem cells collected from unrelated donors and clinical outcomes of patients undergoing transplantation in BMTCTN 0201. Patients and MethodsFresh aliquots of 161 BM and 147 PB stem-cell allografts from North American donors randomly assigned to donate BM or PB stem cells and numbers of transplanted cells were correlated with overall survival (OS), relapse, and graft-versus-host disease (GvHD). ResultsPatients with evaluable grafts were similar to all BMTCTN 0201 patients. The numbers of plasmacytoid dendritic cells (pDCs) and naïve T cells (Tns) in BM allografts were independently associated with OS in multivariable analyses including recipient and donor characteristics, such as human leukocyte antigen mismatch, age, and use of antithymocyte globulin. BM recipients of Ͼ median number of pDCs, naïve CD8 ϩ T cells (CD8Tns), or naïve CD4 ϩ T cells (CD4Tns) had better 3-year OS (pDCs, 56% v 35%; P ϭ .025; CD8Tns, 56% v 37%; P ϭ .012; CD4Tns, 55% v 37%; P ϭ .009). Transplantation of more BM Tns was associated with less grade 3 to 4 acute GvHD but similar rates of relapse. Transplantation of more BM pDCs was associated with fewer deaths resulting from GvHD or from graft rejection. Analysis of PB grafts did not identify a donor cell subset significantly associated with OS, relapse, or GvHD. ConclusionDonor immune cells in BM but not PB stem-cell grafts were associated with survival after unrelated-donor allogeneic hematopoietic stem-cell transplantation. The biologic activity of donor immune cells in allogeneic transplantation varied between graft sources. Donor grafts with more BM-derived Tns and pDCs favorably regulated post-transplantation immunity in allogeneic hematopoietic stem-cell transplantation. J Clin Oncol 32:2365-2372. © 2014 by American Society of Clinical Oncology INTRODUCTIONMuch of the clinical utility of allogeneic hematopoietic stem-cell transplantation (alloHSCT) in treating patients with hematologic malignancies depends on the graft-versus-leukemia (GvL) activity of donor T cells.1-3 Improving outcomes after alloHSCT requires understanding how the GvL or graft-versushost disease (GvHD) functions of donor T cells are regulated, including interactions with donor or host dendritic cells (DCs) and homing to hematolymphoid or GvHD-target organs. 1,4 Previous reports have suggested the content of donor DCs is associated with incidence of chronic GvHD and relapse, 5 and the content of CD34 ϩ cells is associated with survival 6 and GvHD among peripheral blood (PB) stem-cell allograft recipients. 7 To explore associations between cell subsets in the allograft with clinical outcomes in a prospective clinical trial, fresh aliquots of bone marrow (BM) and PB stem-cell grafts collected from unrelated volunteer donors recruited in BMTCTN (Blood and Marrow Transplant Clinical Trials Network) 0201 were analyzed for their cont...

Larger number of invariant natural killer T cells in PBSC allografts correlates with improved GVHD-free and progression-free survival

“…5 The absence of impact of CD8 1 T cells in our study is probably explained by the use of ATG for in vivo T-cell depletion in the majority of patients, whereas no T-cell depletion was performed in the study of Reshef et al Of note, Waller et al did not identify a PBSC graft cell subset significantly associated with patient outcome 10 ; however, the impact on the GPFS composite end point was not evaluated in that study. Of note, one could speculate that iNKT frequencies might represent a surrogate for some favorable combination of other subset.…”

“…9 The only report on a large collection of immune subsets failed to demonstrate an association between donor immune cells in the PBSC graft and the SCT outcome, 10 whereas bone marrow grafts with more naïve T cells and plasmacytoid dendritic cells were associated with an improved survival. 10 Furthermore, in these studies, improved outcome associated with graft cell subsets was linked to either a decreased incidence of relapse 5 or a decreased incidence of GVHD. 6 However, although 1 graft cell subset can contribute to reduce GVHD, it may also reduce GVT and therefore increase the relapse risk.…”

High Graft CD8 Cell Dose Predicts Improved Survival and Enables Better Donor Selection in Allogeneic Stem-Cell Transplantation With Reduced-Intensity Conditioning

“…[10][11][12][13][14] The majority of RIC transplantations use mobilized PBSC grafts that contain 10 10 to 10 11 T cells, the primary mediators of the immunologic graft-versus-host and graft-versus-tumor (GVT) responses. Because the curative potential of RIC transplantation relies entirely on a potent GVT effect, T-cell doses and their subsets may be critical.…”

Mobilized peripheral blood grafts include more than hematopoietic stem cells: the immunological perspective

“…49 Further, Waller et al 50 recently found an association between the number of pDCs within BM graft and OS, but failed to show any correlation between pDCs in PBSC and outcome or GVHD.…”