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The use of anti-thymocyte globulin (ATG) in reduced intensity conditioning (RIC) regimens is controversial because of impairment in post-transplant immune reconstitution. In this abstract the dynamics of immune recovery following RIC regimen for either MRD or URD SCT in a randomized phase II clinical trial are reported. Conditioning was with Thymoglobulin (ATG 5.1 (n=19) or ATG 7.5 (n=22) mg/kg) and 450 cGy TBI; GVHD prophylaxis was with tacrolimus and mycophenolate mofetil. The patients were heavily pretreated, and had relapsed or high-risk hematological malignancies. Two-year survival was 71 and 61% respectively in the ATG 5.1 and ATG 7.5 arms, with corresponding relapse rates of 21 and 46% (P= NS), day 100 mortality was zero. Lineage specific chimerism and lymphocyte subsets were measured at 4, 8, and 12 weeks and as clinically indicated. There was a trend towards superior T cell engraftment in the ATG 5.1 arm, with respect to both CD3+ cell chimerism during each of the first 3 months (0, 1, 2* vs. 7, 9, 19%* recipient chimerism; *P=0.024), and donor derived (dd) CD3+ cells (93, 106, 92* vs. 214, 577, 405 無-1 *; *P=0.031). The ddCD3+ cell counts for each individual over time was plotted and the polynomial equation describing the curve determined in 27 patients. The derivative of this curve at day 45 yielded the instantaneous rate of change of ddCD3+ cells at that time. In the ten patients where this value was <1.5, relapse and donor lymphocyte infusions (DLI) were more frequent (P=0.01 and 0.0033 respectively). Because ddCD3 data was available for limited time points, absolute lymphocyte counts (ALC, 無-1) for each individual were plotted over time to accurately model immune reconstitution kinetics. Similar to population growth models, lymphocyte recovery following SCT occurred as a logistic function of time. Three patterns of lymphoid recovery over time were observed (Figure); sigmoid growth with early rapid lymphoid expansion and a high steady state level (A; ALC >1000 無-1, inflection point <60 days post SCT; n=17); a lower steady state level arrived at slowly (B; ALC ≥500-1000 無-1, inflection point >60 days; n=14) and poor ALC recovery (C; ALC <500 無-1; n=10). Patients displaying the pattern C had the highest rate of relapse (P=0.015 and 0.011 compared with patterns A and B respectively); and DLI (P=0.009 and 0.03). These findings indicate that immune reconstitution can be modeled as a mathematically defined logistic dynamical system, and that lymphoid expansion in the early days following SCT influences eventual clinical outcomes when ATG is used. If this model is generalizable then it may represent a paradigm shift away from current practice of post-transplant interventions derived from population based studies.
Figure: Logistic dynamics of lymphoid recovery following SCT. Three patterns are observed, corresponding to high, pattern A, intermediate, pattern B and slow growth rate, pattern C.
