Biol Blood Marrow Transplant xxx (2015) 1e5
1 2 3 4 5 journal homepage: www.bbmt.org 6 7 8 9 10 þ 11 Q 1 12 13 1, 2, * 14 , Johan Törlén 2, Olle Ringdén 2, Mats Engström 1, 2, Emma Watz 1, 3, Q 9 Mats Remberger 15 1, 2 Michael Uhlin , Jonas Mattsson 1, 2 16 1 17 Department of Oncology and Pathology, Karolinska Institutet, Stockholm, Sweden 2 Center for Allogeneic Stem Cell Transplantation, Karolinska University Hospital Huddinge, Stockholm, Sweden 18 3 Department of Clinical Immunology and Transfusion Medicine, Karolinska University Hospital Huddinge, Stockholm, Sweden 19 20 21 a b s t r a c t Article history: 22 Received 4 November 2014 During more recent years only few studies have analyzed the effect of total nucleated cell (TNC) and CD34þ 23 Accepted 26 January 2015 cell dose in allogeneic hematopoietic stem cell transplantation (HSCT). A single-center analysis included 544 24 patients, 227 with a sibling donor and 317 with an unrelated donor. Most patients (n ¼ 292) were treated 25 Key Words: with myeloablative conditioning, whereas the remaining patients (n ¼ 252) received reduced-intensity 26 Cell dose conditioning. Bone marrow (BM) (n ¼ 121) and peripheral blood stem cell (PBSC) grafts (n ¼ 423) were 27 CD34 analyzed separately. Median TNC and CD34þ cell dose was 3.2 108/kg versus 11.6 108/kg in BM and 3.9 HSCT 28 106/kg versus 8.1 106/kg in PBSC. In the BM group we found a higher TNC and CD34þ cell dose was GVHD 29 associated with a faster neutrophil engraftment (P < .001 and P ¼ .02). In the PBSC group we found patients BM 30 given a very high (11 106/kg) CD34þ cell dose had decreased rates of survival (P ¼ .001) and increased PBSC Q2 relapse (P ¼ .02). A high CD34þ cell dose correlated with faster platelet engraftment (P < .01). In HSCT using 31 PBSCs, the CD34þ cell doses should be kept below 11 106/kg but over 2.5 106/kg. 32 Ó 2015 American Society for Blood and Marrow Transplantation. 33 34 35 36 37 [4,14-16]. Hence, it is important to establish which cell dose INTRODUCTION 38 is optimal for outcome when using BM or PBSC in the Hematopoietic stem cell transplantation (HSCT) is a 39 modern era of HSCT. potentially curative treatment for several hematological 40 malignancies, bone marrow (BM) failure syndromes, and 41 METHODS some inherited metabolic disorders [1]. An adequate number 42 Patients of nucleated or CD34þ cells in the graft are of utmost 43 The effect of the graft cell dose was studied in 544 consecutive HSCT importance to achieve sustained engraftment and good 44 patients transplanted between January 2000 and December 2011 at Karsurvival [2]. Historically, the approach of more is better has 45 olinska University Hospital, Sweden. Only patients with a malignant disease been applied at many centers. This is 1 contributory rationale receiving either BM or PBSCs from a HLA-identical sibling or a HLA-A, -B, and 46 -DR matched unrelated donor were included. Patients transplanted because for the increasing use of peripheral blood stem cells (PBSCs) 47 of solid tumors (n ¼ 62) were excluded because this was an experimental in HSCT, becasue a PBSC graft contains approximately 5 to 10 48 treatment. times more CD34þ and T cells compared with a BM graft [3]. 49 Patient characteristics are displayed in Table 1. Patients receiving a BM Higher cell numbers in the graft decrease the risk of rejection 50 or PBSC graft were analyzed separately because the cell dose differs considerably between these 2 types of grafts and BM is preferentially given and shorten the phase of aplasia [4-10]. However, many 51 to children. The study was approved by the Research Ethics Committee of studies have shown the risk for chronic graft-versus-host 52 Karolinska Institutet. The procedures were in accordance with the Helsinki disease (GVHD) is increased in patients receiving PBSC 53 Declaration. compared with BM, probably because of the higher cell 54 content [11-13]. More recently, only a few studies have 55 HLA Typing evaluated the effect of cell dose on outcome after HSCT 56 All patients and donors were typed using PCResequence-specific primer high-resolution typing for both HLA class I and II alleles [17]. 57 58 Conditioning Regimen and GVHD Prophylaxis Financial disclosure: See Acknowledgments on page 4. 59 * Correspondence and reprint requests: Mats Remberger, Professor, Reduced-intensity conditioning was given to 252 patients and consisted 60 of fludarabine 30 mg/m2/d for 3 to 6 days in combination with (1) cycloCAST-unit, Karolinska University Hospital, SE-14186 Stockholm, Sweden. 61 phosphamide 60 mg/kg/d for 2 days (n ¼ 26), (2) 2 3 Gy total body E-mail address: [email protected] (M. Remberger). 62 63
Biology of Blood and Marrow Transplantation
Effect of Total Nucleated and CD34 Cell Dose on Outcome after Allogeneic Hematopoietic Stem Cell Transplantation
http://dx.doi.org/10.1016/j.bbmt.2015.01.025 1083-8791/Ó 2015 American Society for Blood and Marrow Transplantation.
FLA 5.2.0 DTD YBBMT53773_proof 21 February 2015 3:12 pm ce PT
64 65 66 67 68 69 70 71 72 73 74 75 76 77 78 79 80 81 82 83 84 85 86 87 88 89 90 91 92 93 94 95 96 97 98 99 100 101 102 103 104 105 106 107 108 109 110 111 112 113 114 115 116 117 118 119 120 121 122 123 124 125 126
2
127 128 129 130 131 132 133 134 135 136 137 138 139 140 141 142 143 144 145 146 147 148 149 150 151 152 153 154 155 156 157 158 159 160 161 162 163 164 165 166 167 168 169 170 171 172 173 174 175 176 177 178 179 180 181 182 183 184 185 186 187 188 189 190 191
M. Remberger et al. / Biol Blood Marrow Transplant xxx (2015) 1e5
Table 1 Patient Characteristics Receiving Either BM or PBSCs
Median age, yr (range) Sex (male/female) Diagnose Acute leukemia Chronic leukemia Lymphoma MDS Other Late stage (>CR1/CP1) Donor Sibling MUD Median donor age, yr (range) Female to male Median TNC dose, 108/kg (range) Median CD34 dose, 106/kg (range) Conditioning MAC/RIC TBI-based Chemotherapy-based ATG GVHD prophylaxis CsAþMTX Tacrolimusþsirolimus Other
BM (n ¼ 121)
PBSCs (n ¼ 423)
14 (11 106 cells/kg in our analysis) after allogeneic HSCT. One explanation may be that grafts with very high numbers of CD34þ cells also are very rich in regulatory T cells with the capacity to down-regulate the antileukemic effect. This theory is supported by the fact that the CD34þ cell dose did not correlated to chronic GVHD in our study. In our study, unmanipulated grafts were used and all donors were HLA-A, -B, and -DR matched. Compared with
many other studies, our cell doses were relatively high, with at least 10% of patients receiving a very high cell dose. Some patients received a CD34þ cell dose of up to 50 106/kg. A study from the European Group for Blood and Marrow Transplantation showed that a “rich BM” gave better outcome than PBSCs or less rich BM, linked to a diminution of the relapse incidence [44]. We could not verify these results. Overall, PBSCs showed a nonsignificantly better OS rate compared with BM, 62% versus 53% (P ¼ .22). Furthermore, a PBSC graft containing
1 2 3 4 5 journal homepage: www.bbmt.org 6 7 8 9 10 þ 11 Q 1 12 13 1, 2, * 14 , Johan Törlén 2, Olle Ringdén 2, Mats Engström 1, 2, Emma Watz 1, 3, Q 9 Mats Remberger 15 1, 2 Michael Uhlin , Jonas Mattsson 1, 2 16 1 17 Department of Oncology and Pathology, Karolinska Institutet, Stockholm, Sweden 2 Center for Allogeneic Stem Cell Transplantation, Karolinska University Hospital Huddinge, Stockholm, Sweden 18 3 Department of Clinical Immunology and Transfusion Medicine, Karolinska University Hospital Huddinge, Stockholm, Sweden 19 20 21 a b s t r a c t Article history: 22 Received 4 November 2014 During more recent years only few studies have analyzed the effect of total nucleated cell (TNC) and CD34þ 23 Accepted 26 January 2015 cell dose in allogeneic hematopoietic stem cell transplantation (HSCT). A single-center analysis included 544 24 patients, 227 with a sibling donor and 317 with an unrelated donor. Most patients (n ¼ 292) were treated 25 Key Words: with myeloablative conditioning, whereas the remaining patients (n ¼ 252) received reduced-intensity 26 Cell dose conditioning. Bone marrow (BM) (n ¼ 121) and peripheral blood stem cell (PBSC) grafts (n ¼ 423) were 27 CD34 analyzed separately. Median TNC and CD34þ cell dose was 3.2 108/kg versus 11.6 108/kg in BM and 3.9 HSCT 28 106/kg versus 8.1 106/kg in PBSC. In the BM group we found a higher TNC and CD34þ cell dose was GVHD 29 associated with a faster neutrophil engraftment (P < .001 and P ¼ .02). In the PBSC group we found patients BM 30 given a very high (11 106/kg) CD34þ cell dose had decreased rates of survival (P ¼ .001) and increased PBSC Q2 relapse (P ¼ .02). A high CD34þ cell dose correlated with faster platelet engraftment (P < .01). In HSCT using 31 PBSCs, the CD34þ cell doses should be kept below 11 106/kg but over 2.5 106/kg. 32 Ó 2015 American Society for Blood and Marrow Transplantation. 33 34 35 36 37 [4,14-16]. Hence, it is important to establish which cell dose INTRODUCTION 38 is optimal for outcome when using BM or PBSC in the Hematopoietic stem cell transplantation (HSCT) is a 39 modern era of HSCT. potentially curative treatment for several hematological 40 malignancies, bone marrow (BM) failure syndromes, and 41 METHODS some inherited metabolic disorders [1]. An adequate number 42 Patients of nucleated or CD34þ cells in the graft are of utmost 43 The effect of the graft cell dose was studied in 544 consecutive HSCT importance to achieve sustained engraftment and good 44 patients transplanted between January 2000 and December 2011 at Karsurvival [2]. Historically, the approach of more is better has 45 olinska University Hospital, Sweden. Only patients with a malignant disease been applied at many centers. This is 1 contributory rationale receiving either BM or PBSCs from a HLA-identical sibling or a HLA-A, -B, and 46 -DR matched unrelated donor were included. Patients transplanted because for the increasing use of peripheral blood stem cells (PBSCs) 47 of solid tumors (n ¼ 62) were excluded because this was an experimental in HSCT, becasue a PBSC graft contains approximately 5 to 10 48 treatment. times more CD34þ and T cells compared with a BM graft [3]. 49 Patient characteristics are displayed in Table 1. Patients receiving a BM Higher cell numbers in the graft decrease the risk of rejection 50 or PBSC graft were analyzed separately because the cell dose differs considerably between these 2 types of grafts and BM is preferentially given and shorten the phase of aplasia [4-10]. However, many 51 to children. The study was approved by the Research Ethics Committee of studies have shown the risk for chronic graft-versus-host 52 Karolinska Institutet. The procedures were in accordance with the Helsinki disease (GVHD) is increased in patients receiving PBSC 53 Declaration. compared with BM, probably because of the higher cell 54 content [11-13]. More recently, only a few studies have 55 HLA Typing evaluated the effect of cell dose on outcome after HSCT 56 All patients and donors were typed using PCResequence-specific primer high-resolution typing for both HLA class I and II alleles [17]. 57 58 Conditioning Regimen and GVHD Prophylaxis Financial disclosure: See Acknowledgments on page 4. 59 * Correspondence and reprint requests: Mats Remberger, Professor, Reduced-intensity conditioning was given to 252 patients and consisted 60 of fludarabine 30 mg/m2/d for 3 to 6 days in combination with (1) cycloCAST-unit, Karolinska University Hospital, SE-14186 Stockholm, Sweden. 61 phosphamide 60 mg/kg/d for 2 days (n ¼ 26), (2) 2 3 Gy total body E-mail address: [email protected] (M. Remberger). 62 63
Biology of Blood and Marrow Transplantation
Effect of Total Nucleated and CD34 Cell Dose on Outcome after Allogeneic Hematopoietic Stem Cell Transplantation
http://dx.doi.org/10.1016/j.bbmt.2015.01.025 1083-8791/Ó 2015 American Society for Blood and Marrow Transplantation.
FLA 5.2.0 DTD YBBMT53773_proof 21 February 2015 3:12 pm ce PT
64 65 66 67 68 69 70 71 72 73 74 75 76 77 78 79 80 81 82 83 84 85 86 87 88 89 90 91 92 93 94 95 96 97 98 99 100 101 102 103 104 105 106 107 108 109 110 111 112 113 114 115 116 117 118 119 120 121 122 123 124 125 126
2
127 128 129 130 131 132 133 134 135 136 137 138 139 140 141 142 143 144 145 146 147 148 149 150 151 152 153 154 155 156 157 158 159 160 161 162 163 164 165 166 167 168 169 170 171 172 173 174 175 176 177 178 179 180 181 182 183 184 185 186 187 188 189 190 191
M. Remberger et al. / Biol Blood Marrow Transplant xxx (2015) 1e5
Table 1 Patient Characteristics Receiving Either BM or PBSCs
Median age, yr (range) Sex (male/female) Diagnose Acute leukemia Chronic leukemia Lymphoma MDS Other Late stage (>CR1/CP1) Donor Sibling MUD Median donor age, yr (range) Female to male Median TNC dose, 108/kg (range) Median CD34 dose, 106/kg (range) Conditioning MAC/RIC TBI-based Chemotherapy-based ATG GVHD prophylaxis CsAþMTX Tacrolimusþsirolimus Other
BM (n ¼ 121)
PBSCs (n ¼ 423)
14 (11 106 cells/kg in our analysis) after allogeneic HSCT. One explanation may be that grafts with very high numbers of CD34þ cells also are very rich in regulatory T cells with the capacity to down-regulate the antileukemic effect. This theory is supported by the fact that the CD34þ cell dose did not correlated to chronic GVHD in our study. In our study, unmanipulated grafts were used and all donors were HLA-A, -B, and -DR matched. Compared with
many other studies, our cell doses were relatively high, with at least 10% of patients receiving a very high cell dose. Some patients received a CD34þ cell dose of up to 50 106/kg. A study from the European Group for Blood and Marrow Transplantation showed that a “rich BM” gave better outcome than PBSCs or less rich BM, linked to a diminution of the relapse incidence [44]. We could not verify these results. Overall, PBSCs showed a nonsignificantly better OS rate compared with BM, 62% versus 53% (P ¼ .22). Furthermore, a PBSC graft containing
