Early donor chimerism levels predict relapse and survival after allogeneic stem cell transplantation with reduced-intensity conditioning

Abstract

The success of hematopoietic stem cell transplantation (HSCT) with reduced-intensity conditioning (RIC) is limited by a high rate of disease relapse. Early risk assessment could potentially improve outcomes by identifying appropriate patients for preemptive strategies that may ameliorate this high risk. Using a series of landmark analyses, we investigated the predictive value of early (day-30) donor chimerism measurements on disease relapse, graft-versus-host disease, and survival in a cohort of 121 patients allografted with a uniform RIC regimen. Chimerism levels were analyzed as continuous variables. In multivariate analysis, day-30 whole blood chimerism levels were significantly associated with relapse (hazard ratio [HR] = .90, P < .001), relapse-free survival (HR = .89, P < .001), and overall survival (HR = .94, P = .01). Day-30 T cell chimerism levels were also significantly associated with relapse (HR = .97, P = .002), relapse-free survival (HR = .97, P < .001), and overall survival (HR = .99, P = .05). Multivariate models that included T cell chimerism provided a better prediction for these outcomes compared with whole blood chimerism. Day-30 chimerism levels were not associated with acute or chronic graft-versus-host disease. We found that high donor chimerism levels were significantly associated with a low lymphocyte count in the recipient before transplant, highlighting the impact of pretransplant lymphopenia on the kinetics of engraftment after RIC HSCT. In summary, low donor chimerism levels are associated with relapse and mortality and can potentially be used as an early predictive and prognostic marker. These findings can be used to design novel approaches to prevent relapse and to improve survival after RIC HSCT.

Keywords: Chimerism; Reduced-intensity conditioning.

Copyright © 2014 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.

Figures

FIGURE 1. Pearson correlations between day-30 chimerism levels and pre-conditioning or day 0 absolute lymphocyte counts (ALC)

Donor-recipient chimerism levels were measured on day 30 post-transplant in whole blood (A,B; n=121) and in the CD3+ T-cell fraction (C,D; n=103) of peripheral blood samples. Chimerism values are plotted against each patient’s ALC prior to starting the conditioning regimen (A,C; day -6) and on the day of transplant (B,D; day 0). The x axis intervals represent natural log transformation. The Pearson correlation coefficient (r) and p-value are presented in each plot.

FIGURE 2. Univariate associations of disease relapse with day-30 donor chimerism levels

Cumulative incidence plots of disease relapse are shown, starting from the time of day-30 chimerism testing (defined here as “0” for a landmark analysis). Comparative plots for groups of patients who had higher or lower than median chimerism levels are presented for whole blood (A) and T-cell chimerism (C). Hazard ratios and p-values represent a univariate cumulative incidence analysis. All possible cutoffs for whole blood (B) and T-cell chimerism (D) were examined and plotted against the cutoffs, showing significant correlations at multiple cutoffs. The plot lines represent a moving 3-point average.

FIGURE 3. Pearson correlation between day-30 whole blood and T-cell chimerism levels

Day-30 whole blood and T-cell chimerism levels are plotted against each other (n=103), demonstrating a significant correlation by Pearson.