Targeted Chemoprevention of Progressive Marrow Failure in Patients with Fanconi Anemia using Quercetin, a Pilot study Parinda Mehta, M.D. Division of Bone Marrow Transplantation and Immune Deficiency Cincinnati Children s Hospital Medical Center
Treatment options for Fanconi Anemia Diagnosis Early marrow failure Moderate marrow failure End-stage Marrow failure Comprehensive Care Clinic Complementation Watchful waiting Newer Androgens Radiation-free Hematopoietic Transplantation Need for an effective novel therapy with a better toxicity profile
Reactive Oxygen Species (ROS) in FA Studies in both animals and human subjects indicate that high levels of and increased sensitivity to ROS plays an important role in pathogenesis of bone marrow failure in patients with FA
ROS
Reactive oxygen species (ROS) Reactive oxygen species (ROS) refer to a variety of molecules and free radicals derived from molecular oxygen The biologically relevant ROS, such as hydrogen peroxide (H2O2), superoxide (O2), and the hydroxyl radical (HO), are generated from the precursor superoxide anion
Consequences of increased oxidative stress/ros Oxidative stress is detrimental to cells due to oxidative damage to lipids, proteins, and DNA This leads to a cascade of events that leads to apoptosis (cell death) or uncontrolled proliferation
Consequences of increased oxidative stress/ros Marrow Failure MDS/Leukemia/ other cancers
What can we do about this?
Quercetin (antioxidant) reduces TNFgenerated ROS Normal Control FA-A
Quercetin prevents marrow failure and leukemia in Fanconi mice Quercetin improves stem cell compartment increases cells that make blood cells in mice with FA Cells from Fanconi mice do not turn into leukemia after treatment with Quercetin
Mice with Fanconi anemia have prediabetes (similar to children with FA) quercetin also makes this better
So, what happens in patients? Patients with FA produce increased ROS levels compared to normal controls ROS levels decrease to baseline with addition of Quercetin in in-vitro studies, using both BM and peripheral blood samples from patients with FA
Reversal of ROS with Quercetin in patients with FA
Quercetin in FA patients These data suggest a possible benefit in supporting hematopoiesis and preventing progressive marrow failure with Quercetin
What is Quercetin? Quercetin (3, 30, 40, 5, 7- pentahydroxyflavone) is a naturally occurring flavonoid Richest dietary sources include onions, apples, berries, tea and red wine Common ingredient in dietary supplements and multivitamin preparations
Quercetin Has a wide range of biological activities - free radical scavenging - iron chelating - anti-inflammation - antioxidant - antineoplastic properties
ROS suppression and marrow failure/mds/aml in FA
Clinical Implications Reversal of marrow failure will obviate or delay the need for stem cell transplantation If found to be effective, treatment with Quercetin can be included in standard clinical care of this patient population for many years
Clinical trial of Quercetin in patients with FA In adult studies oral Quercetin has been well tolerated without any side effects Our study of Quercetin in patients with FA is now open and enrolling!
Clinical trial of Quercetin in Three goals: patients with FA 1. Establish safety 2. Establish feasibility of long term administration 3. Obtain pharmacokinetic data/drug level meaning how the drug is handled by patients with FA
Quercetin in FA This study will enroll 12 patients in different stages of marrow failure Inclusion Criteria - Diagnosis of FA proven by DEB test - Able to take enteral medication Major Exclusion Criteria - Patients with morphological evidence of MDS or leukemia
Quercetin Administration Quercetin will be supplied as a liquid suspension, to be taken twice a day Patients will be treated with Quercetin twice a day for 4 months
Monitoring for safety and feasibility of Quercetin in FA patients Patients will be monitored closely for any side effects Weekly phone calls from study co-ordinator Pre-treatment testing, regular blood tests Follow up visit with bone marrow testing at 4 months and again at 1 year
Monitoring for Quercetin effects We will measure levels of Quercetin in the blood to see if we can get optimal levels We will measure ROS levels in blood and bone marrow to see if it is in fact decreasing after Quercetin We will also follow blood counts, growth and blood sugars closely to see the effects of the supplement
Progress on the study First three patients (>12 years of age) are enrolled! Tolerating Quercetin very well No major side effects We are seeing improvement in the colony count of baby blood cells.
AUC is better, the peak glucose is not as high, and there is no hypoglycemia at the end of the test
Quercetin suppresses tumor growth in mice ** *
What do we expect? Our pilot study will show that long term oral Quercetin therapy is feasible, safe and can achieve biologically relevant blood levels in patients with FA These results will form the basis of our next efficacy study, which will demonstrate that Quercetin therapy delays or prevents progressive marrow failure in children with FA Assess safety, feasibility and pharmacokinetics (PK) of oral Quercetin therapy in pediatric patients with FA Role of Quercetin therapy in patients with Fanconi Anemia Prevention of progressive marrow failure in FA Efficacy in improving hematopoiesis To assess efficacy of Quercetin in improving hematopoiesis (i.e. peripheral counts) and insulin sensitivity/glucose tolerance Measure the impact of Quercetin on reduction of ROS, and maintenance or improvement of hematopoietic stem cell (HSC) reserve
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