Larger Numbers of Donor Naïve CD8+ T-Cells and Plasmacytoid Dendritic Cell Precursors In Allogeneic BM Grafts From Unrelated Donors Are Associated with Improved Survival: Results From BMT CTN 0201
Authors: Waller Edmund K , Harris Wayne A.C. , Devine Steven , Porter David L. , Mineishi Shin , McCarty John M. , Gonzalez Corina E , Spitzer Thomas R , Krijanovski Oleg I. , Linenberger Michael L. , Woolfrey Ann , Howard Alan , Gurgol Cathy , Logan Brent R. , Confer Dennis L , Anasetti Claudio 
Published: October 2019

Abstract 1004

Data from single institutional clinical studies have indicated that the content of CD34+ cells, T-cells, and dendritic cells in a bone marrow allograft are associated with clinical outcomes. The relationship between the cellular constituents of hematopoietic allografts and clinical outcomes was prospectively studied in BMT CTN 0201 in which patients with hematological malignancies (and their donors) were randomized to transplantation with bone marrow or G-CSF-mobilized peripheral blood stem cell (PB) allografts. A secondary objective of this study was to correlate graft characteristics with overall survival (OS).

551 patients were enrolled at 50 North American centers between January 2004 and September 2009 in a BMT CTN-sponsored randomized clinical trial supported by the NHLBI and NCI. Of the 278 subjects randomized to BM, aliquots from 173 BM allografts collected in North America were analyzed at a central laboratory for the content of CD34+ progenitors and immune cell subsets by flow cytometry, and of 151 of these BM transplants had complete clinical data and are the subject of this analysis. The subset of 151 patients were similar to the total group of patients transplanted in BMT CTN 0201, with a median age of 38, and 42% of patients with AML, 26% with ALL, 10% CML, and 21% MDS. 74% of patients had low risk disease, and 47% received 12 Gy TBI and cyclophosphamide with the remainder receiving myeloablative busulfan-based (48%) or fludarabine/melphalan conditioning (5%). GvHD prophylaxis was predominately a calcineurin inhibitor plus methotrexate (91%). 26.5% of patients received grafts from HLA mismatched donors.

Clinical outcomes, including OS, acute GVHD III–IV and chronic GVHD, were similar between the subset of patients with analysis of BM cells and the 127 BM recipients without product analysis. 46 progenitor and immune cell subsets were selected for study based upon the absence of a strong correlation with another graft subset (Pearson or Spearman correlation >0.8) and a priori interest or the number of evaluable patients. Graft characteristics were then described separately for survivors and those who died and compared using a nonparametric Mann-Whitney Wilcoxon test. P-values were not adjusted for multiple comparisons, but only covariates for which the q value is <0.2 are presented.

The median number of nucleated cells, CD34+ cells, and total T-cells in the allograft were 256, 2.7, and 23 × 10E6/kg, respectively. The numbers of these donor cells, and the numbers of B-cells, NK cells, and activated T-cells in the BM graft, were not significantly associated with OS. Two of the cell subsets in the BM graft were identified as being significantly associated with transplant outcomes with univariate p-values <0.01 and q values of <0.2: pre-plasmacytoid dendritic cells (pDC) (median number 0.3 × 10E6/kg; p=0.007), and naive CD8+ T-cells (CD8N; median number of 1.3 × 10E6/kg; p=0.009). Stratifying the entire group of transplant recipients by median values for either pre-pDC or CD8N showed better overall survival among patients receiving larger numbers of each donor cell subset (Figure 1). Estimated 3 year OS for patients receiving > 0.3 × 10E6 pre-pDC/kg was 56% versus 35% for recipients of <0.3 × 10E6 pre-pDC/kg (p=0.025, HR for high versus low of 0.58, 95% CI 0.37–0.93) and with 56% estimated 3 year OS for patients receiving > 1.3 × 10E6 CD8N/kg versus 37% for recipients of <1.3 × 10E6 CD8N/kg (p=0.012, HR for high versus low of 0.52, 95% CI 0.32–0.87). Transplantation with more than the median number of CD8N was also associated with a significantly decreased risk of grade III–IV acute GvHD 0.34 (0.12–0.96), p=0.041, but with a higher cumulative incidence of cGVHD at 2 years: 0.55 vs. 0.26, p=0.004. Relapse rates were similar among recipients of larger versus lower numbers of donor pre-pDC and CD8N.Figure 1.Overall survival for recipients of allogeneic BM grafts stratified by the median numbers of Left: donor naive CD8+ T-cells (> or ≤ 1.3 × 10E6/kg) or Right: donor pDC precursors (> or ≤ 0.3 × 10E6/kg) in the BM graft.Figure 1. Overall survival for recipients of allogeneic BM grafts stratified by the median numbers of Left: donor naive CD8+ T-cells (> or ≤ 1.3 × 10E6/kg) or Right: donor pDC precursors (> or ≤ 0.3 × 10E6/kg) in the BM graft.

Among patients receiving unrelated donor bone marrow grafts, higher numbers of donor cell that have important activity in regulating post-transplant immunity, including an unexpected role for CD8N in reducing severe acute GvHD, are associated with improved clinical outcomes.

Disclosures:

No relevant conflicts of interest to declare.