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High CD8 Cell Doses Correlate with Reduced Relapse Risk and Improved Survival after Allogeneic Peripheral Blood Stem-Cell Transplantation with Reduced-Intensity Conditioning

Track: Poster Abstracts
Saturday, March 1, 2014, 6:45 PM-7:45 PM
Longhorn Hall E (Exhibit Level 1) (Gaylord Texan)
Ran Reshef, MD , Blood and Marrow Transplantation Program, Abramson Cancer Center, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA
Selina Luger, MD , Blood and Marrow Transplantation Program, Abramson Cancer Center, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA
Alison Loren, MD, MS , Blood and Marrow Transplantation Program, Abramson Cancer Center, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA
Elizabeth O. Hexner, MD , Blood and Marrow Transplantation Program, Abramson Cancer Center, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA
Sunita D. Nasta, MD , Blood and Marrow Transplantation Program, Abramson Cancer Center, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA
Noelle V. Frey , Blood and Marrow Transplantation Program, Abramson Cancer Center, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA
Edward A. Stadtmauer, MD , Blood and Marrow Transplantation Program, Abramson Cancer Center, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA
Jacqueline Smith, CRNP , Blood and Marrow Transplantation Program, Abramson Cancer Center, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA
David L. Porter, MD , Abramson Cancer Center, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA

Background: Disease relapse remains the most common cause of death after allogeneic hematopoietic stem-cell transplantation (SCT). Specifically, prevention of relapse in transplants performed after reduced intensity conditioning (RIC) relies on a donor derived graft-versus-tumor (GVT) effect, which is primarily mediated by T-cells. We hypothesized that a high graft T-cell dose enhances GVT and improves outcomes. We therefore analyzed the impact of graft composition on transplant outcomes in patients undergoing allogeneic peripheral blood SCT with a uniform RIC regimen.

Methods: We studied 183 consecutive patients who underwent a first allogeneic SCT with peripheral blood stem-cells and fludarabine (120mg/m2) + busulfan (6.4mg/kg) conditioning. Patients were allografted at the University of Pennsylvania between August 2006 and March 2013. Doses of CD3, CD8, CD4 and CD34 cells in the graft were determined by standard methods. Univariate analyses of outcomes were performed using cumulative incidence and Cox regression analyses. Multivariable models were constructed using the backward elimination method, including variables with p<0.1.

Results: The median follow-up was 20.2 mo. (range 0.4 – 78). Patients had a median age of 62 (range 21-76) and diseases included AML (71), MDS (45), NHL (38), CLL (9), ALL (5) and others (15). Mean cell doses were CD3: 2.2x108/kg (range 0.17-5.5), CD8: 0.38x108/kg (range 0.03 – 1.49), CD4: 0.96x108/kg (range 0.1 – 3.05) and CD34: 5.8x106/kg (range 1.2-21.4).

A univariate analysis of overall survival showed a trend for improved survival in patients with high CD8 cell doses (HR=0.51, 95%CI [0.24, 1.09], p=0.08). The total nucleated cell dose significantly correlated with overall survival (HR=0.95, [0.90, 0.99], p=0.04). In a multivariate model CD8 cell doses significantly correlated with improved survival (HR=0.41, [0.19, 0.91], p=0.03).

Similar analyses of the relapse risk and relapse free survival revealed a significant protective effect of high CD8 cell doses (HR=0.36, [0.15, 0.90], p=0.03 and HR=0.46, [0.23, 0.93], p=0.03, respectively). Figure 1 illustrates the impact of high (>0.7) and low CD8 cell doses on relapse-free survival.

Acute graft-versus-host disease (GVHD) did not correlate with T-cell doses, but the risk for moderate-severe chronic GVHD was higher in patients who received high CD8 cell doses without reaching statistical significance (HR=3.35, [0.93, 12.05], p=0.06).

Conclusion: CD8 dose predicts clinical outcome in patients undergoing peripheral blood RIC SCT. A higher CD8 cell dose is a primary predictor of a lower relapse rate and improved relapse-free and overall survival, while there is a possible increase in chronic GVHD. Targeting high CD8 cell doses should be considered in prospective trials of reduced intensity conditioned SCT.

Figure 1: The impact of CD8 cell dose on RFS

Disclosures:
R. Reshef, Tobira Therapeutics, Advisor: Consultancy and Research Funding

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