Pyruvate Kinase Deficiency Natural History Study Rachael Grace, MD, MMSc On behalf of the PKD NHS Investigators Assistant Professor, Harvard Medical School Director, Hematology Clinic, Boston Children’s Hospital, MA, USA 6 th EUROPEAN SYMPOSIUM ON RARE ANAEMIAS 1 st Dutch-Belgian meeting for patients and health professionals 21 st - 22 nd November 2015 Amsterdam - The Netherlands
Disclosures • The PKD Natural History Study is funded by Agios Pharmaceuticals • I am a Scientific Advisor for Agios Pharmaceuticals • I will not discuss off label use or investigational agents in my presentation 2 6 th European Symposium on Rare Anaemias - 1 st Dutch-Belgian meeting for patients and health professionals
This talk is applicable for: Definite Probable Thalassemia Sickle cell disease Membrane disorders (e.g. spherocytosis) Enzyme defects (e.g. PKD, G6PD) ● PNH Other forms of hemolytic disease ● 6 th European Symposium on Rare Anaemias - 1 st Dutch-Belgian meeting for patients and health professionals
Key Points • PKD NHS will allow us to learn more about the symptoms, complications, and treatment of PK Deficiency. • Monitoring for complications, such as gallstones and iron overload, is important even in patients with mild clinical characteristics. • Even among patients with the same genotype, there is wide phenotypic variability establishing that the clinical manifestations of PKD vary depending on many other factors. • Longitudinal data will provide additional important information about the natural history of PK deficiency. 4 6 th European Symposium on Rare Anaemias - 1 st Dutch-Belgian meeting for patients and health professionals
PKD Natural History Study • Goal is to increase our understanding of PK deficiency – Clinical information and surveys over 2 years – Blood sample for research genetic testing to confirm diagnosis • Coordinating Site: Boston Children’s Hospital • Current Sites: United States: 18 sites (n=121) Europe: 6 sites (n=63) Canada: 3 sites (n=11) • Laboratories: Paola Bianchi, Elisa Fermo (Milan, Italy) Patrick Gallagher, Kimberly Lezon-Geyda (CT, USA) • Current Enrollment: 195 participants to date, actively enrolling 6 th European Symposium on Rare Anaemias - 1 st Dutch-Belgian meeting for patients and health professionals
PKD Natural History Study Sites • 18 sites in the United States • 3 sites in Canada • 6 sites in Europe 6 th European Symposium on Rare Anaemias - 1 st Dutch-Belgian meeting for patients and health professionals
PKD Natural History Study Sites Site Investigator Site Site Investigator Site Dr. Jenny Despotovic Baylor Hospital, TX Dr. Eduard van Beers UMC, Utrecht, Netherlands Dr. Melissa Rhodes University of Mississippi, MS Dr. Wilma Barcellini Ospedale Maggiore di Milano, Italy Dr. Rachael Grace Boston Children’s Hospital, MA Dr. Stefan Eber University of Munich, Germany Dr. Christina Knoll Phoenix Children’s Hospital, AZ Dr. Marcin Wlodarski Freiburg, Germany Dr. Bert Glader Stanford University, CA Dr. Joachim Kunz Heidelberg, Germany Dr. Holmes Morton Lancaster General Hospital, PA Dr. Nina Kollmar Kassal, Germany Dr. Peter Newburger University of Massachusetts, MA Dr. Vicky Breakey Hamilton, ON Dr. Winifred Wang St Jude’s Hospital, TN Dr. Yves Pastore Montreal, QC Dr. Jennifer Rothman Duke Children’s Hospital, NC Dr. Kevin Kuo Toronto, ON Dr. Heather Bradeen University of Vermont, VT Dr. Yaddanapudi Ravindranath Wayne State, Detroit, MI Dr. Hassan Yaish Salt Lake City, UT Dr. Heng Wang DCC Clinic, Middlefield, OH Dr. John Chapin Cornell, New York, New York Dr. Melissa Rose Nationwide Hospital, Ohio Dr. Alexis Thompson Lurie Children’s, Chicago, IL Dr. Janet Kwiatkowski University of Pennsylvania, PA Dr. Mukta Sharma Children’s Mercy Hospital, MO 6 th European Symposium on Rare Anaemias - 1 st Dutch-Belgian meeting for patients and health professionals
Demographics n (% ); N=178 Age at enrollment (median, range) 19.9 y, 0.1-70.7 y <18 years (n) 83 (47%) ≥18 years (n) 95 (53%) Gender Male 80 (46%) Race White 168 (94%) Black/African American 3 (2%) Asian 3 (2%) Hispanic 14 (8%) Amish 54 (30%) Age at Diagnosis (median, range) 0.2 y, 0-60.3 y 6 th European Symposium on Rare Anaemias - 1 st Dutch-Belgian meeting for patients and health professionals
PK Deficiency Symptoms: Neonates Complications prior to birth in 33% (55/166) Prenatal • Preterm Delivery 16% (n=26) Complications in the • Preterm Labor 12% (n=20) • Neonate with PKD Prenatal Transfusion 12% (n=20) • IUGR/Fetal Distress 6% (n=10) • Hydrops 4% (n=7) Jaundice Jaundice in 88% of babies (n=144) • Phototherapy 91% • Exchange Transfusion 45% Need for exchange transfusion does not predict later clinical severity 9 6 th European Symposium on Rare Anaemias - 1 st Dutch-Belgian meeting for patients and health professionals
PK Deficiency Symptoms: Anemia • Infections 60% Reported Hemolytic • Pregnancy 52% Triggers • Stress 32% • Other: aspirin, alcohol, menses Reported Reasons for Acute Transfusions (n=89): Transfusions • Infections 71% • Pregnancy 35% • Surgery 32% • Stress 12% Transfusion History (n=178) • Regular Transfused 21% (n=37) • Previously Regularly Transfused 46% (n=81) • Transfused Intermittently 18% (n=32) • Never Transfused 16% (n=28) 10 6 th European Symposium on Rare Anaemias - 1 st Dutch-Belgian meeting for patients and health professionals
PK Deficiency Treatments: Splenectomy The majority of patients had a splenectomy: 65% (115/178) Indications for Splenectomy Outcomes of Splenectomy 92% To decrease transfusion 15% Remained transfusion dependent after splenectomy 90% To improve anemia 88% To improve quality of life 60% To reduce jaundice Median age at splenectomy: 3.7 y (0.6-28.1) 55 51 Complications of Splenectomy 50 45 40 Number of patients Infection Post-splenectomy bacterial infection in 25% (29/115) 40 35 30 Thrombosis Post-splenectomy thrombosis in 8% (9/115) 25 • Deep Vein Thrombosis 7/9 20 15 • Pulmonary Embolism 2/9 8 7 10 3 • Stroke 2/9 2 5 1 1 0 0 0 • Portal Vein Thrombosis 1/9 3 6 9 12 15 18 21 24 27 30 Age at splenectomy (years) 11 6 th European Symposium on Rare Anaemias - 1 st Dutch-Belgian meeting for patients and health professionals
PK Deficiency Complications: Iron Overload Median Ferritin : Currently transfused: 1195 ng/ml (IQR 688-1733), n=32 Historically transfused: 606 ng/ml (IQR 410-1099), n=60 Acute Transfusions/Never Transfused: 321 ng/ml (IQR 160-570), n=36 Ferritin is higher in those who had a splenectomy even after adjusting for transfusion status. MRI was performed in 46% (n=81) of participants • Hepatic T2* Median: 5.2 mg/g DW liver 63% had hepatic iron overload (>4 mg/g DW liver) 70% with no or few transfusions had hepatic iron overload • Cardiac T2* Median: 36.2 ms 3% had cardiac iron overload (<20 ms) 12 6 th European Symposium on Rare Anaemias - 1 st Dutch-Belgian meeting for patients and health professionals
Iron Monitoring in PKD Correlation of T2* MRI LIC with ferritin (mcg/L), r 2 =0.6, p<0.05 13 6 th European Symposium on Rare Anaemias - 1 st Dutch-Belgian meeting for patients and health professionals
Treatment of Iron Overload Figure. Age when chelation was first prescribed 28% (n=51) have received Chelation Therapy 10 10 Median age of chelation: 9 11.7 y (1-54 y) 8 8 • Deferoaxamine 54% 7 Number of patients • Deferasirox 68% 6 5 • 5 Deferiprone 3% 4 4 4 • Combination 16% 3 3 3 2 2 2 2 1 1 1 1 1 2% (n=4) have received 1 0 0 0 Phlebotomy for chelation 0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 51 54 Age at first chelation (years) 14 6 th European Symposium on Rare Anaemias - 1 st Dutch-Belgian meeting for patients and health professionals
PKD Deficiency: Symptoms and Complications Incidence of gallstones is 43% (n=75) Gallstones Median Age 14.5 y (range 2.2-60.4 y) Cholecystectomy 38% (n=68) 14 12 12 Number of patients 10 8 8 7 7 6 4 4 4 4 4 4 4 3 2 2 1 1 1 0 0 0 0 0 0 0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 51 54 57 60 63 Age at cholecystectomy (years) Extramedullary Hematopoiesis: 12% (21/178) Extramedullary Hepatic n=13 Hematopoiesis Splenic n=14 Paraspinous n=7 Mediastinal n=7 Bone Fractures: 17% (30/178) Osteopenia 15 6 th European Symposium on Rare Anaemias - 1 st Dutch-Belgian meeting for patients and health professionals
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