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Adipokine Concentrations and Adiposity in Hematopoietic Cell Transplant (HCT) Survivors
S56
Abstracts / Biol Blood Marrow Transplant 23 (2017) S18–S391
Figure 1. Distribution of vitamin D binding protein levels at Day 0 and Day 100 post-transplant. Median DBP level at Day 0 is 345.3 μg/mL with a range of (26.6-4900 μg/mL) Median DBP level at Day 100 is 680 μg/mL (range of 71.2-11,232 μg/mL).
LATE EFFECTS/QUALITY OF LIFE/PSYCHOSOCIAL ISSUES
52
Figure 2. Overall survival based on vitamin D binding protein level above or below the median at day 100.
Adipokine Concentrations and Adiposity in Hematopoietic Cell Transplant (HCT) Survivors Tyler G. Ketterl 1, Eric J. Chow 2, Wendy M. Leisenring 3, Pam Goodman 3, Ildi H. Koves 4, Anna Petryk 5, Julia Steinberger 6, K. Scott Baker 7. 1 Pediatric Hematology/ Oncology, Fred Hutch Cancer Research Center, Seattle, WA; 2 Pediatric Hematology-Oncology, Fred Hutchinson Cancer Research Center, Seattle, WA; 3 Fred Hutchinson Cancer Research Center, Seattle, WA; 4 Pediatric Endocrinology, Seattle Children’s Hospital, Seattle, WA; 5 Division of Pediatric Endocrinology, University of Minnesota Masonic Children’s Hospital, Minneapolis, MN; 6 University of Minnesota Masonic Children’s Hospital, Minneapolis, MN; 7 Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA Background: Adult survivors of acute leukemia in childhood have a higher than expected frequency of obesity, an increased risk for metabolic syndrome and early mortality from cardiovascular (CV) disease. Adipose tissue has been recognized as an endocrine and paracrine organ that produces adipokines (leptin and adiponectin) that are associated with
Table 1 HCT Survivor and Sibling Characteristics
Figure 3. Correlation of total 25OHD and CAMP expression at day 100 posttransplant (n = 18).
We report the novel finding of increased DBP levels after HSCT, sustained for more than a year, and associated with improved survival, likely due to association with freedom from GVHD. Our functional CAMP assay indicated a strong correlation with total 25OHD levels and DBP. These data indicate a complex and clinically significant relationship between DBP and transplant outcomes. We are further exploring immunomodulatory activity of DBP in this context.
Abstracts / Biol Blood Marrow Transplant 23 (2017) S18–S391
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Table 2 Adipokine and Anthropometric Adjusted Mean Values for HCT Survivors and Siblings
Transplant Service, Royal Melbourne Hospital, Parkville, Australia; 3 Australasian Leukaemia and Lymphoma Group, Melbourne, Australia; 4 Writesource Medical, Lane Cove, Australia; 5 Department of Haematology, Westmead Hospital, Westmead, Australia; 6 The Alfred Hospital, Prahran, Australia; 7 Haematology, Wellington Hospital, Wellington, New Zealand; 8 Christchurch Hospital, Christchurch, New Zealand; 9 Monash Health, Clayton, Australia; 10 Department of Clinical Haematology, Austin Hospital, Heidelberg, Australia Figure 1. BMI and Percent Fat Mass effect size (standardized mean difference) compared to siblings for all HCT Survivors as well as stratified by preparative regimen treatment group (TBI + cranial radiation (CRT), TBI alone, chemotherapy only). Adjusted for age, sex and Tanner stage.
obesity, insulin secretion, and insulin resistance as well as endothelial function, vascular homeostasis and atherogenesis. Methods: > 2-year survivors of HCT for hematologic malignancies during childhood were recruited from 2 institutions along with a control population of siblings (Table 1). Participants underwent a comprehensive evaluation for body composition, anthropometrics and blood samples for measurement of CV risk factors and adipokines. Cases were stratified by preparative regimen (TBI + cranial radiation (CRT), TBI alone, chemotherapy only) and adjusted least square means were estimated for each adipokine and adjusted by age, sex, race, Tanner Score, and percent fat mass (PFM) percentiles (0-24, 25-74, 75+). Results: 151 HCT survivors and 91 siblings underwent evaluation (insufficient blood samples obtained from 10 cases). As shown in Table 2, significant differences were detected in mean adipokine levels between survivors and siblings: leptin was significantly higher and adiponectin significantly lower in HCT survivors who received TBI with or without CRT compared with siblings. Of note, despite finding that BMI was similar between survivors and controls, PFM was significantly higher in all groups of HCT survivors compared with siblings (Figure 1). Conclusion: Significant differences exist in the adipokines leptin and adiponectin among HCT survivors compared with sibling controls, despite a similar BMI between the two groups. The higher PFM we observed supports previous studies that HCT survivors have a lean mass deficit and increased fat mass (sarcopenic obesitiy) associated with abnormalities in adipokine levels. These data may provide insight into underlying mechanisms that contribute to the high risk of developing metabolic syndrome and cardiovascular complications in HCT survivors.
53 A Risk-Adapted Protocol of Prophylactic Zoledronic Acid Prevents Bone Mineral Density Loss Post Allograft: Results of the ALLG Bm07 Phase II Prospective Trial Eric Wong 1,2,3, Belinda Butcher 4, Bereha Khodr 3, Ashish Bajel 2,3, Mark Hertzberg 3,5, Sushrut Patil 3,6, Alwyn D’Souza 3,7, Peter Ganley 3,8, Peter Ebeling 9, Andrew Grigg 3,10. 1 The University of Melbourne, Parkville, Australia; 2 Clinical Haematology and Bone Marrow
Bone loss occurs frequently following alloSCT and likely contributes to increased fracture risk after alloSCT. We previously demonstrated that monthly pamidronate reduced bone loss post-alloSCT and small studies have suggested that zoledronic acid (ZA) does likewise. However, bisphosphonates are expensive and not all patients require frequent prophylaxis. The Australasian Leukemia & Lymphoma Group (ALLG) conducted a prospective study evaluating the efficacy of pretransplant ZA and individualized post-transplant ZA to prevent bone loss in patients undergoing alloSCT. Methods: A phase II multicenter study was conducted in adult alloSCT recipients. All patients received ZA 4 mg prior to conditioning. Bone mineral density (BMD) was measured prealloSCT and at days 100, 180, 270 and 365 post-alloSCT. Administration of post-transplant ZA was determined by a risk-adapted algorithm. Following each assessment, patients with any of: i) reduction in BMD >5% compared with baseline, ii) who received ≥1 mg/kg/day prednisolone for 2 weeks, iii) ≥ 10 mg/d prednisolone for 6 weeks were given ZA. All patients received vitamin D and calcium supplementation. Pre-menopausal women received hormone replacement therapy. The primary endpoint was the change in femoral neck (FN) BMD at days 100 (d100) and 365 (d365) post-alloSCT compared with baseline. The secondary objective was a comparison of FN BMD with 35 historical untreated controls at d100 and d365. Results: Of 82 patients enrolled, 70 were alive without relapse at d100. By d100, 44 (62.9%) received glucocorticosteroids, including 35 (50%) with mean prednisolone dose >10 mg/d. At d100, FN BMD change was -2.6 ± 4.6% compared to baseline (P = n.s) (Figure 1). Factors significantly associated with BMD loss at d100 included acute GVHD (P = .040 ANOVA overall difference grades 0-4) and busulfan/cyclophosphamide (Bu/Cy) conditioning (vs Cy/TBI mean difference -4.1%, P = .023; vs other regimens -3.5%, P = .034). BMD did not significantly change between d100 and d365. Factors associated with change in BMD at d365 included extensive chronic GVHD (vs no chronic GVHD mean difference -6.9%, P = .008) and Bu/ Cy conditioning (vs Cy/TBI -6.0%, P = .007). Age, sex, cyclosporin duration and mean glucocorticoid dose stratified into low (<10 mg/d), medium (10-50 mg/d) or high (>50 mg/d) groups were not associated with change in BMD at d100 or d365. Compared with historical controls receiving no ZA, BMD loss at d100 and d365 was significantly less in patients who received ZA (d100 -2.6% vs -6.0%, P = .001; d365 -2.9% vs -10.5%, P < .0001). There were no serious adverse events attributed to ZA. Conclusion: Prophylactic ZA pre-alloSCT minimizes loss of FN BMD by d100 post-alloSCT. A risk-adapted algorithm based on
Abstracts / Biol Blood Marrow Transplant 23 (2017) S18–S391
Figure 1. Distribution of vitamin D binding protein levels at Day 0 and Day 100 post-transplant. Median DBP level at Day 0 is 345.3 μg/mL with a range of (26.6-4900 μg/mL) Median DBP level at Day 100 is 680 μg/mL (range of 71.2-11,232 μg/mL).
LATE EFFECTS/QUALITY OF LIFE/PSYCHOSOCIAL ISSUES
52
Figure 2. Overall survival based on vitamin D binding protein level above or below the median at day 100.
Adipokine Concentrations and Adiposity in Hematopoietic Cell Transplant (HCT) Survivors Tyler G. Ketterl 1, Eric J. Chow 2, Wendy M. Leisenring 3, Pam Goodman 3, Ildi H. Koves 4, Anna Petryk 5, Julia Steinberger 6, K. Scott Baker 7. 1 Pediatric Hematology/ Oncology, Fred Hutch Cancer Research Center, Seattle, WA; 2 Pediatric Hematology-Oncology, Fred Hutchinson Cancer Research Center, Seattle, WA; 3 Fred Hutchinson Cancer Research Center, Seattle, WA; 4 Pediatric Endocrinology, Seattle Children’s Hospital, Seattle, WA; 5 Division of Pediatric Endocrinology, University of Minnesota Masonic Children’s Hospital, Minneapolis, MN; 6 University of Minnesota Masonic Children’s Hospital, Minneapolis, MN; 7 Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA Background: Adult survivors of acute leukemia in childhood have a higher than expected frequency of obesity, an increased risk for metabolic syndrome and early mortality from cardiovascular (CV) disease. Adipose tissue has been recognized as an endocrine and paracrine organ that produces adipokines (leptin and adiponectin) that are associated with
Table 1 HCT Survivor and Sibling Characteristics
Figure 3. Correlation of total 25OHD and CAMP expression at day 100 posttransplant (n = 18).
We report the novel finding of increased DBP levels after HSCT, sustained for more than a year, and associated with improved survival, likely due to association with freedom from GVHD. Our functional CAMP assay indicated a strong correlation with total 25OHD levels and DBP. These data indicate a complex and clinically significant relationship between DBP and transplant outcomes. We are further exploring immunomodulatory activity of DBP in this context.
Abstracts / Biol Blood Marrow Transplant 23 (2017) S18–S391
S57
Table 2 Adipokine and Anthropometric Adjusted Mean Values for HCT Survivors and Siblings
Transplant Service, Royal Melbourne Hospital, Parkville, Australia; 3 Australasian Leukaemia and Lymphoma Group, Melbourne, Australia; 4 Writesource Medical, Lane Cove, Australia; 5 Department of Haematology, Westmead Hospital, Westmead, Australia; 6 The Alfred Hospital, Prahran, Australia; 7 Haematology, Wellington Hospital, Wellington, New Zealand; 8 Christchurch Hospital, Christchurch, New Zealand; 9 Monash Health, Clayton, Australia; 10 Department of Clinical Haematology, Austin Hospital, Heidelberg, Australia Figure 1. BMI and Percent Fat Mass effect size (standardized mean difference) compared to siblings for all HCT Survivors as well as stratified by preparative regimen treatment group (TBI + cranial radiation (CRT), TBI alone, chemotherapy only). Adjusted for age, sex and Tanner stage.
obesity, insulin secretion, and insulin resistance as well as endothelial function, vascular homeostasis and atherogenesis. Methods: > 2-year survivors of HCT for hematologic malignancies during childhood were recruited from 2 institutions along with a control population of siblings (Table 1). Participants underwent a comprehensive evaluation for body composition, anthropometrics and blood samples for measurement of CV risk factors and adipokines. Cases were stratified by preparative regimen (TBI + cranial radiation (CRT), TBI alone, chemotherapy only) and adjusted least square means were estimated for each adipokine and adjusted by age, sex, race, Tanner Score, and percent fat mass (PFM) percentiles (0-24, 25-74, 75+). Results: 151 HCT survivors and 91 siblings underwent evaluation (insufficient blood samples obtained from 10 cases). As shown in Table 2, significant differences were detected in mean adipokine levels between survivors and siblings: leptin was significantly higher and adiponectin significantly lower in HCT survivors who received TBI with or without CRT compared with siblings. Of note, despite finding that BMI was similar between survivors and controls, PFM was significantly higher in all groups of HCT survivors compared with siblings (Figure 1). Conclusion: Significant differences exist in the adipokines leptin and adiponectin among HCT survivors compared with sibling controls, despite a similar BMI between the two groups. The higher PFM we observed supports previous studies that HCT survivors have a lean mass deficit and increased fat mass (sarcopenic obesitiy) associated with abnormalities in adipokine levels. These data may provide insight into underlying mechanisms that contribute to the high risk of developing metabolic syndrome and cardiovascular complications in HCT survivors.
53 A Risk-Adapted Protocol of Prophylactic Zoledronic Acid Prevents Bone Mineral Density Loss Post Allograft: Results of the ALLG Bm07 Phase II Prospective Trial Eric Wong 1,2,3, Belinda Butcher 4, Bereha Khodr 3, Ashish Bajel 2,3, Mark Hertzberg 3,5, Sushrut Patil 3,6, Alwyn D’Souza 3,7, Peter Ganley 3,8, Peter Ebeling 9, Andrew Grigg 3,10. 1 The University of Melbourne, Parkville, Australia; 2 Clinical Haematology and Bone Marrow
Bone loss occurs frequently following alloSCT and likely contributes to increased fracture risk after alloSCT. We previously demonstrated that monthly pamidronate reduced bone loss post-alloSCT and small studies have suggested that zoledronic acid (ZA) does likewise. However, bisphosphonates are expensive and not all patients require frequent prophylaxis. The Australasian Leukemia & Lymphoma Group (ALLG) conducted a prospective study evaluating the efficacy of pretransplant ZA and individualized post-transplant ZA to prevent bone loss in patients undergoing alloSCT. Methods: A phase II multicenter study was conducted in adult alloSCT recipients. All patients received ZA 4 mg prior to conditioning. Bone mineral density (BMD) was measured prealloSCT and at days 100, 180, 270 and 365 post-alloSCT. Administration of post-transplant ZA was determined by a risk-adapted algorithm. Following each assessment, patients with any of: i) reduction in BMD >5% compared with baseline, ii) who received ≥1 mg/kg/day prednisolone for 2 weeks, iii) ≥ 10 mg/d prednisolone for 6 weeks were given ZA. All patients received vitamin D and calcium supplementation. Pre-menopausal women received hormone replacement therapy. The primary endpoint was the change in femoral neck (FN) BMD at days 100 (d100) and 365 (d365) post-alloSCT compared with baseline. The secondary objective was a comparison of FN BMD with 35 historical untreated controls at d100 and d365. Results: Of 82 patients enrolled, 70 were alive without relapse at d100. By d100, 44 (62.9%) received glucocorticosteroids, including 35 (50%) with mean prednisolone dose >10 mg/d. At d100, FN BMD change was -2.6 ± 4.6% compared to baseline (P = n.s) (Figure 1). Factors significantly associated with BMD loss at d100 included acute GVHD (P = .040 ANOVA overall difference grades 0-4) and busulfan/cyclophosphamide (Bu/Cy) conditioning (vs Cy/TBI mean difference -4.1%, P = .023; vs other regimens -3.5%, P = .034). BMD did not significantly change between d100 and d365. Factors associated with change in BMD at d365 included extensive chronic GVHD (vs no chronic GVHD mean difference -6.9%, P = .008) and Bu/ Cy conditioning (vs Cy/TBI -6.0%, P = .007). Age, sex, cyclosporin duration and mean glucocorticoid dose stratified into low (<10 mg/d), medium (10-50 mg/d) or high (>50 mg/d) groups were not associated with change in BMD at d100 or d365. Compared with historical controls receiving no ZA, BMD loss at d100 and d365 was significantly less in patients who received ZA (d100 -2.6% vs -6.0%, P = .001; d365 -2.9% vs -10.5%, P < .0001). There were no serious adverse events attributed to ZA. Conclusion: Prophylactic ZA pre-alloSCT minimizes loss of FN BMD by d100 post-alloSCT. A risk-adapted algorithm based on