Dynamical System Modeling of Immune Reconstitution after Allogeneic Stem Cell Transplantation Identifies Patients at Risk for Adverse Outcomes Amir A.

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Dynamical System Modeling of Immune Reconstitution after Allogeneic Stem Cell Transplantation Identifies Patients at Risk for Adverse Outcomes Amir A. Toor, Roy T. Sabo, Catherine H. Roberts, Bonny L. Moore, Salman R. Salman, Allison F. Scalora, May T. Aziz, Ali S. Shubar Ali, Charles E. Hall, Jeremy Meier, Radhika M. Thorn, Elaine Wang, Shiyu Song, Kristin Miller, Kathryn Rizzo, William B. Clark, John M. McCarty, Harold M. Chung, Masoud H. Manjili, Michael C. Neale Biology of Blood and Marrow Transplantation Volume 21, Issue 7, Pages 1237-1245 (July 2015) DOI: 10.1016/j.bbmt.2015.03.011 Copyright © 2015 American Society for Blood and Marrow Transplantation Terms and Conditions

Biology of Blood and Marrow Transplantation 2015 21, 1237-1245DOI: (10 Biology of Blood and Marrow Transplantation 2015 21, 1237-1245DOI: (10.1016/j.bbmt.2015.03.011) Copyright © 2015 American Society for Blood and Marrow Transplantation Terms and Conditions

Figure 1 Clinical outcomes in the ATG 5.1 and ATG 7.5 cohorts. (A) Kaplan-Meier survival curves. (B) Cumulative incidence curves for relapse (competing risk of transplant-related mortality). (C) Kaplan-Meier event-free survival (relapse and fatality). (D) Cumulative incidence curves for chronic GVHD, observations censored at DLI (competing risk of fatality without GVHD). (E) Cumulative incidence curve for DLI (competing risk of fatality). Biology of Blood and Marrow Transplantation 2015 21, 1237-1245DOI: (10.1016/j.bbmt.2015.03.011) Copyright © 2015 American Society for Blood and Marrow Transplantation Terms and Conditions

Figure 2 ALC (μL−1) recovery after ATG+TBI and SCT. (A) Two periods of growth are seen, first from days 0 to 30 when patients are on MMF (blue outline) and the second from day 20 to approximately day 120 (orange outline). Each period demonstrates an initial phase of slow growth, followed by exponential expansion and finally relatively stable counts, until tacrolimus is discontinued, when greater variability is observed. Data from a matched related donor (MRD) and an unrelated donor (URD) SCT are shown. (B) Logistic dynamics of lymphoid recovery after SCT. Three patterns are observed corresponding to high, pattern A; intermediate, pattern B; and slow growth rate, pattern C. Biology of Blood and Marrow Transplantation 2015 21, 1237-1245DOI: (10.1016/j.bbmt.2015.03.011) Copyright © 2015 American Society for Blood and Marrow Transplantation Terms and Conditions

Figure 3 Determinants of lymphoid recovery. (A) Correspondence of early monocyte recovery with lymphocyte reconstitution, association of high early monocyte recovery with late lymphoid expansion (orange circles indicate monocytes; black diamonds, lymphocytes) plotted against days post-SCT. (B) ddCD3 cell count plotted over time, and derivative for the polynomial curve determined at days 30 and 45. Derivative is the slope of the tangent to the polynomial curve (dy/dx) and gives the approximate rate of change of ddCD3 at that point in time. Accuracy of the derivative depends on the goodness of fit of the polynomial curve. Biology of Blood and Marrow Transplantation 2015 21, 1237-1245DOI: (10.1016/j.bbmt.2015.03.011) Copyright © 2015 American Society for Blood and Marrow Transplantation Terms and Conditions

Figure 4 Logistic model of lymphocyte proliferation post-transplant. Cell dose infused at the time of SCT N0 will start proliferating under the influence of the driving parameter R and expand over time t, taking on values of Nt, Nt+1,…, Nt+n. This will include a period of exponential expansion as the lymphopenic state after SCT is corrected and eventually a stable lymphocyte population K is established. Changes in antigen presentation (due to infection, tissue injury) and immunosuppression levels and the overall cytokine milieu may perturb the steady state or growing populations by altering R and result in greater variability seen at specific time points. Reconstitution of the lymphocyte subset populations by differentiation of hematopoietic cells also changes N. The curves represents an average of the lymphoid cell populations (and clones) seen in circulation, with each population repopulating with similar dynamics but at different rates. Three other hypothetical curves along the continuum of logistic expansion are also shown with different N0 (not evident due to scale) and R values (R > R1 > R2 > R3). Blue circles and top curve depict data from an actual patient. Biology of Blood and Marrow Transplantation 2015 21, 1237-1245DOI: (10.1016/j.bbmt.2015.03.011) Copyright © 2015 American Society for Blood and Marrow Transplantation Terms and Conditions