Effects of the NK Cell Recovery on Outcomes of Unmanipulated Haploidentical Blood and Marrow Transplantation for Patients with Hematologic Malignancies

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Effects of the NK Cell Recovery on Outcomes of Unmanipulated Haploidentical Blood and Marrow Transplantation for Patients with Hematologic Malignancies Ying-Jun Chang, Xiang-Yu Zhao, Xiao-Jun Huang Biology of Blood and Marrow Transplantation Volume 14, Issue 3, Pages 323-334 (March 2008) DOI: 10.1016/j.bbmt.2007.12.497 Copyright © 2008 American Society for Blood and Marrow Transplantation Terms and Conditions

Figure 1 Kinetics reconstitution of NK and its subsets after HLA-mismatched/haploidentical HCT without in vitro T cells depletion. Donors (D) or donor-derived patients NK cells and its subsets, CD56bright and CD56dim NK cells, as well as T cells after transplantation (30, 60, 90, 120, and 180 days) were monitored by cytometry. The median, 25 to 75 percentile ranges, and extreme values of the absolute numbers of NK and its subsets (A1 and A2), or ratio of CD56dim/CD56bright NK cells (B1 and B2) and T/NK (C1 and C2) were shown in the box plot. Cells/μL indicates the absolute number in WBC of overall NK cells and its subset. The reconstruction kinetics of the 16 patients without II-IV aGVHD were shown in A1, B1, and C1; those of the overall 43 patients were presented in A2, B2, and C2. ∗Represent P < .05 compared to their donors. ∗∗Represent P < .01 compared to their donors. Biology of Blood and Marrow Transplantation 2008 14, 323-334DOI: (10.1016/j.bbmt.2007.12.497) Copyright © 2008 American Society for Blood and Marrow Transplantation Terms and Conditions

Figure 2 The functionality recovery of cytokine and cytotoxicity of NK cells after transplantation. The capability of NK cells to produce IFN-γ in response to PMA plus inomycin stimulation was analyzed by intracellular flow cytometry. The ability of the patient-derived NK cells with (□) or without IL-2 (▪) preactivation to produce IFN-γ was similar to those of donor-derived NK cells by day 30 after transplantation (A). The cytotoxicity capability of purified patient- or donor-derived NK cells and patient- or donor-derived PBMNCs against K562 cells was assessed by LDH release assay. The spontaneous or activated (IL-2 activated) killing potential of patient-derived NK cells or PBMNCs were lower than those of donor-derived by day 30 after transplantation (B,C; P < .01). Biology of Blood and Marrow Transplantation 2008 14, 323-334DOI: (10.1016/j.bbmt.2007.12.497) Copyright © 2008 American Society for Blood and Marrow Transplantation Terms and Conditions

Figure 3 Interrelationship of day 14 NK recovery and doses of CD34+, CD3+ cells, and CD56dim NK cells in allograft. The dose of CD34+ cells in the allograft inversely correlated with the ratio of T/NK cells (A) and CD56dim/CD56bri cells (B) by day 14 after HSCT. The dose of CD3+ T cells also inversely correlated with the ratio of CD56dim/CD56bright cells by day 14 after HSCT (C). The dose of CD56dim NK cells positively associated with the absolute number of the day 14 CD56bright NK cell (E), therefore inversely correlating with the ratio of CD56dim/CD56bright cells by day 14 after HSCT (F). Biology of Blood and Marrow Transplantation 2008 14, 323-334DOI: (10.1016/j.bbmt.2007.12.497) Copyright © 2008 American Society for Blood and Marrow Transplantation Terms and Conditions

Figure 4 The occurrence of aGVHD delays the recovery of the NK subset. Donors (D) or donor-derived patient NK cells and its subsets, as well as T cells after transplantation (30, 60, 90,120, and 180 days) were monitored by cytometry. Results were presented for donors or patients separated by 0-I and II-IV aGVHD. The median, 25 to 75 percentile ranges, and extreme values of the percentages or absolute number of NK and its subsets, as well as T cells or ratio of T/NK cells (A-F) are shown in the box plot. TNC% indicates the absolute proportion in WBC of overall NK cells and its subset, or of T cells (A-D); cells/μL indicates the absolute number in WBC of T cells (E); black and white column represent the groups of 0-I and II-IV GVHD, respectively. ∗Represents P < .05 between patients with 0-I and II-IV aGVHD; ∗∗represents P < .01 between patients with 0-I and II-IV aGVHD. Biology of Blood and Marrow Transplantation 2008 14, 323-334DOI: (10.1016/j.bbmt.2007.12.497) Copyright © 2008 American Society for Blood and Marrow Transplantation Terms and Conditions

Figure 5 The high ratio of T/NK cells correlated with the increased occurrence of aGVHD and cGVHD after HSCT. Patients were subgrouped into the “low ratio of T/NK cells (≤1.0)” and the “high ratio of T/NK cells (>1.0)” groups based on less or more than the ratio of 1.0, and subgrouped into the “low” and “high” CD3+ T cells group according to the median circulating CD3+ T cells counts of 31.36 cells/μL by day 14 after transplantation. Cumulative incidence estimates of II-IV aGVHD (A), III-IV aGVHD (B), and cGVHD (C) in these 2 and 4 cohorts, respectively. Biology of Blood and Marrow Transplantation 2008 14, 323-334DOI: (10.1016/j.bbmt.2007.12.497) Copyright © 2008 American Society for Blood and Marrow Transplantation Terms and Conditions

Figure 6 The high number of circulating CD56bright NK cells correlated with better OS and less TRM. Patients were subgrouped into the “high,” “middle,” and “low” group based on the 33 and 67 percentage of circulating CD56bright NK cell count by day 14 after transplantation. Kaplan-Meier survival estimates OS (A) in these 3 groups and cumulative incidence estimates TRM (B). Biology of Blood and Marrow Transplantation 2008 14, 323-334DOI: (10.1016/j.bbmt.2007.12.497) Copyright © 2008 American Society for Blood and Marrow Transplantation Terms and Conditions