Pharmacodynamic Monitoring Predicts Outcomes of CCR5 Blockade as Graft-versus- Host Disease Prophylaxis Austin P. Huffman, Lee P. Richman, Lisa Crisalli,

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Pharmacodynamic Monitoring Predicts Outcomes of CCR5 Blockade as Graft-versus- Host Disease Prophylaxis Austin P. Huffman, Lee P. Richman, Lisa Crisalli, Alex Ganetsky, David L. Porter, Robert H. Vonderheide, Ran Reshef Biology of Blood and Marrow Transplantation Volume 24, Issue 3, Pages 594-599 (March 2018) DOI: 10.1016/j.bbmt.2017.10.028 Copyright © 2017 The American Society for Blood and Marrow Transplantation Terms and Conditions

Figure 1 CCR5 blockade sufficiency can be determined by phosphoflow. (A) Representative flow plot from patient 04712-015 on day –6 pretransplant, before initiation of MVC. CD8 T cell pCCR5 MFI increases in response to CCL4 stimulation and decreases in response to exogenous MVC. (B) Average fold-change in pCCR5 MFI on day –6 (patient not yet on MVC) and day 0 (patient on MVC) CD8 T cells. Stimulation has an effect on day –6 but not day 0; exogenous MVC has an effect on day –6 that is ameliorated by day 0. (C) Representative flow plots and MFIs of sufficiently blocked patient 04712-018 (top) and insufficiently blocked patient 04712-005 (bottom). (D) Heterogeneity in %change in pCCR5 MFI on day 0 in response to exogenous MVC. Those patients whose MFI dropped by more than 20% compared with the unstimulated control were considered to have insufficient blockade, because additional MVC had an additional effect. ***P < .001. Biology of Blood and Marrow Transplantation 2018 24, 594-599DOI: (10.1016/j.bbmt.2017.10.028) Copyright © 2017 The American Society for Blood and Marrow Transplantation Terms and Conditions

Figure 2 Blockade insufficiency is predictive of worse outcomes. Insufficient blockade on day 0 is associated with increased risk of (A) death (HR, 10.6; P = .004), (B) GRFS (HR, 3.4; P = .04), (C) grades III to IV acute GVHD incidence (HR, 12; P = .009), and (D) NRM (HR, 146; P = .04). Biology of Blood and Marrow Transplantation 2018 24, 594-599DOI: (10.1016/j.bbmt.2017.10.028) Copyright © 2017 The American Society for Blood and Marrow Transplantation Terms and Conditions

Figure 3 Peritransplant increase in T cell CCR5 surface expression. CCR5 expression on (A) CD4 and (B) CD8 T cells. On both CD4 and CD8 T cells, recipient pretransplant CCR5 expression was elevated compared with healthy donor control, increased by day of transplant in response to MVC and chemotherapy and dropped to an intermediate level. (C) Representative CCR5 expression flow plots of pretransplant “CCR5lo” and “CCR5hi” patient CD8 T cells. *P < .05, **P < .01, ***P < .001. Biology of Blood and Marrow Transplantation 2018 24, 594-599DOI: (10.1016/j.bbmt.2017.10.028) Copyright © 2017 The American Society for Blood and Marrow Transplantation Terms and Conditions

Figure 4 Recipient pretransplant CD8 T cell CCR5 expression is predictive of outcomes. High CD8 T cell CCR5 surface expression is associated with increased risk of (A) death (HR, 3.9; P = .06), (B) GRFS (HR, 3.2; P = .03), and (C) NRM (HR, 6.2x108; P < .001). Biology of Blood and Marrow Transplantation 2018 24, 594-599DOI: (10.1016/j.bbmt.2017.10.028) Copyright © 2017 The American Society for Blood and Marrow Transplantation Terms and Conditions