Selective Depletion of αβ T Cells and B Cells for Human Leukocyte Antigen– Haploidentical Hematopoietic Stem Cell Transplantation. A Three-Year Follow-Up.

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Selective Depletion of αβ T Cells and B Cells for Human Leukocyte Antigen– Haploidentical Hematopoietic Stem Cell Transplantation. A Three-Year Follow-Up of Procedure Efficiency Giuseppina Li Pira, David Malaspina, Elia Girolami, Simone Biagini, Elisabetta Cicchetti, Gianpiero Conflitti, Manuel Broglia, Stefano Ceccarelli, Stefania Lazzaro, Daria Pagliara, Antonella Meschini, Alice Bertaina, Mauro Montanari, Franco Locatelli Biology of Blood and Marrow Transplantation Volume 22, Issue 11, Pages 2056-2064 (November 2016) DOI: 10.1016/j.bbmt.2016.08.006 Copyright © 2016 The American Society for Blood and Marrow Transplantation Terms and Conditions

Figure 1 Preapheresis CD34+ HSC counts. (A) shows CD34+ HSC counts/µL on day 4 in donors mobilized with G-CSF, plus or minus MZ. (B) shows the increase of CD34+ HSC counts from day 4 to day 5 (2.7 fold, P, .0001) in 152 donors receiving G-CSF alone. (C) shows the increase of CD34+ HSC counts from day 4 to day 5 (8.3 fold, P: .0001) in 48 donors receiving MZ 9 hours before apheresis. For a better evaluation, (D) shows CD34+ HSC counts on days 4 and 5 in 56 donors not treated with MZ, who had CD34+ cell counts <40/µL (but with a predicted apheresis yield >12.0 × 106 CD34+ HSC/kg recipient's body weight) on day 4 and, thus, were comparable to the group of MZ-treated donors in Panel C. Biology of Blood and Marrow Transplantation 2016 22, 2056-2064DOI: (10.1016/j.bbmt.2016.08.006) Copyright © 2016 The American Society for Blood and Marrow Transplantation Terms and Conditions

Figure 2 Effect of MZ on cell subsets in apheresis samples. The panels show the percentage of different subsets referred to total nucleated cells, in donors treated or not with MZ. (A) CD34+ cells, (B) CD3 T cells, (C) αβ T cells, (D) γδ T cells, (E) NK cells, and (F) CD20 B cells. A highly significant effect of MZ (P: .0001) was observed on B cells only. Biology of Blood and Marrow Transplantation 2016 22, 2056-2064DOI: (10.1016/j.bbmt.2016.08.006) Copyright © 2016 The American Society for Blood and Marrow Transplantation Terms and Conditions

Figure 3 Evaluation of depletion efficiency. Depletion efficiency of αβ T cells, CD20 B cells, and CD3 T cells, referred to the values observed in the pre-column samples. Depletion efficiency is given as median log10 depletion (with ranges in parentheses) as described in Methods. The inset table indicates the log depletion mean values in donors who received or did not receive MZ. Biology of Blood and Marrow Transplantation 2016 22, 2056-2064DOI: (10.1016/j.bbmt.2016.08.006) Copyright © 2016 The American Society for Blood and Marrow Transplantation Terms and Conditions

Figure 4 PMNC effect on cell depletion and recovery. Plotting PMNC percentages in apheresis samples versus αβ T cell log depletion (A) and versus B cell log depletion (B) shows a moderate and weak correlation respectively, according to the Pearson correlation coefficient. Biology of Blood and Marrow Transplantation 2016 22, 2056-2064DOI: (10.1016/j.bbmt.2016.08.006) Copyright © 2016 The American Society for Blood and Marrow Transplantation Terms and Conditions

Figure 5 Median composition of the grafts. (A) shows the different cell subsets determined in the 200 grafts on a log scale as median numbers of cells present in the final products (grafts). Ranges are shown on top of the bars. (B) indicates the median cell composition and ranges of infused graft products per kg recipient body weight. Biology of Blood and Marrow Transplantation 2016 22, 2056-2064DOI: (10.1016/j.bbmt.2016.08.006) Copyright © 2016 The American Society for Blood and Marrow Transplantation Terms and Conditions

Figure 6 Monitoring of cell depletion and cell recovery. Data were analyzed at 6-month intervals. (A) Shows depletion efficiency for αβ T cells, B cells, and CD3 T cells over 6 semesters. The trend towards higher depletion efficiency for αβ T cells and B cells was not significant. (B) Shows percent cell recovery for CD34+ HSC, γδ T cells, and NK cells. Also in this case fluctuations were not significant. (C) Shows CD34+ HSC recovery in comparison with apheresis samples and with precolumn samples. The initial discrepancy, highly significant for the first 2 semesters (P, .0005 and .0008, respectively), vanished at later time points (P > .05). Biology of Blood and Marrow Transplantation 2016 22, 2056-2064DOI: (10.1016/j.bbmt.2016.08.006) Copyright © 2016 The American Society for Blood and Marrow Transplantation Terms and Conditions

Figure 7 Nomogram to estimate reduction of depletion efficiency as a function of contamination with unlabeled cells. The nomogram was constructed to estimate the influence of unlabeled cells on cell depletion efficiency. Theoretical or expected log depletion is given on the Y axis. The X axis shows the µL of cells that escaped labeling and contaminated the processed product, with reference to a total manipulated volume of 100 mL. As an example, if a log depletion of 5 is expected with 0 µL contaminating cells, 10 µL of residual unlabeled cells that contaminate the final product decrease depletion efficiency by 1 log. This theoretical calculation is independent of the actual cell concentration in the bag. It can be noted that reduction of final log depletion correlates positively with the amount of contaminating cells and negatively with the expected depletion efficiency. Biology of Blood and Marrow Transplantation 2016 22, 2056-2064DOI: (10.1016/j.bbmt.2016.08.006) Copyright © 2016 The American Society for Blood and Marrow Transplantation Terms and Conditions