Phase 1 study of quercetin, a natural antioxidant for children and young adults with Fanconi anemia
Abstract: Fanconi anemia (FA) is a rare inherited disorder characterized by progressive bone marrow failure (BMF) and a predisposition to malignancy. Systemic reactive oxygen species (ROS) and increased sensitivity of FA hematopoietic progenitors to ROS play a key role in the pathogenesis of BMF. Tr...
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| Format: | Article |
| Language: | English |
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Elsevier
2025-04-01
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| Series: | Blood Advances |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2473952925000308 |
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| author | Parinda A. Mehta Adam Nelson Sara Loveless Adam Lane Tsuyoshi Fukuda Ashley Teusink-Cross Deborah Elder Denise Lagory Erica Miller Jose A. Cancelas Jonathan Howell Junfang Zhao Kana Mizuno Kasiani C. Myers Kelly Lake Kelly McIntosh Kenneth D. R. Setchell Nathan Luebbering Stephanie Edwards Tafadzwa Chihanga Susanne I. Wells Stella M. Davies |
| author_facet | Parinda A. Mehta Adam Nelson Sara Loveless Adam Lane Tsuyoshi Fukuda Ashley Teusink-Cross Deborah Elder Denise Lagory Erica Miller Jose A. Cancelas Jonathan Howell Junfang Zhao Kana Mizuno Kasiani C. Myers Kelly Lake Kelly McIntosh Kenneth D. R. Setchell Nathan Luebbering Stephanie Edwards Tafadzwa Chihanga Susanne I. Wells Stella M. Davies |
| author_sort | Parinda A. Mehta |
| collection | DOAJ |
| description | Abstract: Fanconi anemia (FA) is a rare inherited disorder characterized by progressive bone marrow failure (BMF) and a predisposition to malignancy. Systemic reactive oxygen species (ROS) and increased sensitivity of FA hematopoietic progenitors to ROS play a key role in the pathogenesis of BMF. Treatment with antioxidants improve hematopoietic function in Fancc–/– mice. We report the safety, tolerability, and pharmacokinetics of quercetin, a naturally occurring antioxidant in the first dose-finding phase 1 study for patients with FA. Twelve patients (median age, 7 years [range, 3-21]) received oral quercetin twice daily for 4 months. Quercetin was well tolerated at all dose levels. Allometrically bodyweight-adjusted dose with a maximum adult daily dose of 4000 mg/d was established as the recommended dose of quercetin. Patients in an expansion cohort (n = 18) were treated using this recommended dose for 6 months. A subset of patients showed reduced ROS levels in the peripheral blood (PB) and bone marrow stem cell compartment. Patients in the analysis cohort treated with the recommended dose of quercetin achieved an a priori-defined optimal response of 25% reduction in the PB ROS level compared with baseline. Platelet counts remained stable to slightly improved over the study period (P = .06). Absolute neutrophil counts (P = .01) and hemoglobin levels gradually declined (P = .001). In those with evidence of BMF at baseline, 8 of 15 patients (53%) had a hematological response at some point after quercetin treatment. Fluctuations in counts are common in patients with FA, limiting accurate assessment of the impact of quercetin use in FA. This trial was registered at www.ClinicalTrials.gov as #NCT01720147. |
| format | Article |
| id | doaj-art-b43805ec2fd3401b8b60fa9d544559df |
| institution | OA Journals |
| issn | 2473-9529 |
| language | English |
| publishDate | 2025-04-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Blood Advances |
| spelling | doaj-art-b43805ec2fd3401b8b60fa9d544559df2025-08-20T02:09:26ZengElsevierBlood Advances2473-95292025-04-01981927193910.1182/bloodadvances.2024015053Phase 1 study of quercetin, a natural antioxidant for children and young adults with Fanconi anemiaParinda A. Mehta0Adam Nelson1Sara Loveless2Adam Lane3Tsuyoshi Fukuda4Ashley Teusink-Cross5Deborah Elder6Denise Lagory7Erica Miller8Jose A. Cancelas9Jonathan Howell10Junfang Zhao11Kana Mizuno12Kasiani C. Myers13Kelly Lake14Kelly McIntosh15Kenneth D. R. Setchell16Nathan Luebbering17Stephanie Edwards18Tafadzwa Chihanga19Susanne I. Wells20Stella M. Davies21Division of Bone Marrow Transplantation and Immune Deficiency, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH; Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH; Correspondence: Parinda A. Mehta, Division of Bone Marrow Transplantation and Immune Deficiency, Cincinnati Children’s Hospital Medical Center, 3333 Burnet Ave, Cincinnati, OH 45229;Bone Marrow Transplant MDT, Kids Cancer Centre, Sydney Children's Hospital Randwick, AustraliaDivision of Bone Marrow Transplantation and Immune Deficiency, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH; Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OHDivision of Bone Marrow Transplantation and Immune Deficiency, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH; Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OHDepartment of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH; Division of Translational and Clinical Pharmacology, Cincinnati Children's Hospital Medical Center, Cincinnati, OHDivision of Bone Marrow Transplantation and Immune Deficiency, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH; Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OHDepartment of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH; Division of Endocrinology, Cincinnati Children's Hospital Medical Center, Cincinnati, OHDepartment of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH; Division of Clinical Pharmacology, Investigational Pharmacy, Cincinnati Children's Hospital Medical Center, Cincinnati, OHDivision of Bone Marrow Transplantation and Immune Deficiency, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH; Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OHDepartment of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH; Division of Experimental Hematology and Cancer Biology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH; Hoxworth Blood Center Academic Unit, University of Cincinnati College of Medicine, Cincinnati, OH; Reilly and O’Connell Families Cell Manipulation Core Facility and Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MADepartment of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH; Division of Endocrinology, Cincinnati Children's Hospital Medical Center, Cincinnati, OHDepartment of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH; Division of Pathology and Laboratory Medicine, Cincinnati Children’s Hospital Medical Center, Cincinnati, OHDepartment of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH; Division of Translational and Clinical Pharmacology, Cincinnati Children's Hospital Medical Center, Cincinnati, OHDivision of Bone Marrow Transplantation and Immune Deficiency, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH; Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OHDivision of Bone Marrow Transplantation and Immune Deficiency, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH; Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OHDivision of Bone Marrow Transplantation and Immune Deficiency, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH; Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OHDepartment of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH; Division of Pathology and Laboratory Medicine, Cincinnati Children’s Hospital Medical Center, Cincinnati, OHDivision of Bone Marrow Transplantation and Immune Deficiency, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH; Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OHDivision of Bone Marrow Transplantation and Immune Deficiency, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH; Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OHDepartment of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH; Division of Oncology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OHDepartment of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH; Division of Oncology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OHDivision of Bone Marrow Transplantation and Immune Deficiency, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH; Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OHAbstract: Fanconi anemia (FA) is a rare inherited disorder characterized by progressive bone marrow failure (BMF) and a predisposition to malignancy. Systemic reactive oxygen species (ROS) and increased sensitivity of FA hematopoietic progenitors to ROS play a key role in the pathogenesis of BMF. Treatment with antioxidants improve hematopoietic function in Fancc–/– mice. We report the safety, tolerability, and pharmacokinetics of quercetin, a naturally occurring antioxidant in the first dose-finding phase 1 study for patients with FA. Twelve patients (median age, 7 years [range, 3-21]) received oral quercetin twice daily for 4 months. Quercetin was well tolerated at all dose levels. Allometrically bodyweight-adjusted dose with a maximum adult daily dose of 4000 mg/d was established as the recommended dose of quercetin. Patients in an expansion cohort (n = 18) were treated using this recommended dose for 6 months. A subset of patients showed reduced ROS levels in the peripheral blood (PB) and bone marrow stem cell compartment. Patients in the analysis cohort treated with the recommended dose of quercetin achieved an a priori-defined optimal response of 25% reduction in the PB ROS level compared with baseline. Platelet counts remained stable to slightly improved over the study period (P = .06). Absolute neutrophil counts (P = .01) and hemoglobin levels gradually declined (P = .001). In those with evidence of BMF at baseline, 8 of 15 patients (53%) had a hematological response at some point after quercetin treatment. Fluctuations in counts are common in patients with FA, limiting accurate assessment of the impact of quercetin use in FA. This trial was registered at www.ClinicalTrials.gov as #NCT01720147.http://www.sciencedirect.com/science/article/pii/S2473952925000308 |
| spellingShingle | Parinda A. Mehta Adam Nelson Sara Loveless Adam Lane Tsuyoshi Fukuda Ashley Teusink-Cross Deborah Elder Denise Lagory Erica Miller Jose A. Cancelas Jonathan Howell Junfang Zhao Kana Mizuno Kasiani C. Myers Kelly Lake Kelly McIntosh Kenneth D. R. Setchell Nathan Luebbering Stephanie Edwards Tafadzwa Chihanga Susanne I. Wells Stella M. Davies Phase 1 study of quercetin, a natural antioxidant for children and young adults with Fanconi anemia Blood Advances |
| title | Phase 1 study of quercetin, a natural antioxidant for children and young adults with Fanconi anemia |
| title_full | Phase 1 study of quercetin, a natural antioxidant for children and young adults with Fanconi anemia |
| title_fullStr | Phase 1 study of quercetin, a natural antioxidant for children and young adults with Fanconi anemia |
| title_full_unstemmed | Phase 1 study of quercetin, a natural antioxidant for children and young adults with Fanconi anemia |
| title_short | Phase 1 study of quercetin, a natural antioxidant for children and young adults with Fanconi anemia |
| title_sort | phase 1 study of quercetin a natural antioxidant for children and young adults with fanconi anemia |
| url | http://www.sciencedirect.com/science/article/pii/S2473952925000308 |
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