Pyruvate Kinase Deficiency Natural History Study

Transcription

1 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

2 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

3 This talk is applicable for: Thalassemia Sickle cell disease Membrane disorders (e.g. spherocytosis) Enzyme defects (e.g. PKD, G6PD) PNH Other forms of hemolytic disease Definite Probable

4 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

5 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 PKD Natural History Study Sites 18 sites in the United States 3 sites in Canada 6 sites in Europe

7 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

8 Demographics n (% ); N=178 Age at enrollment (median, range) 19.9 y, 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, y

9 PK Deficiency Symptoms: Neonates Prenatal Complications in the Neonate with PKD Complications prior to birth in 33% (55/166) Preterm Delivery 16% (n=26) Preterm Labor 12% (n=20) 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

10 PK Deficiency Symptoms: Anemia Reported Hemolytic Triggers Transfusions Infections 60% Pregnancy 52% Stress 32% Other: aspirin, alcohol, menses Reported Reasons for Acute Transfusions (n=89): 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

11 PK Deficiency Treatments: Splenectomy Number of patients The majority of patients had a splenectomy: 65% (115/178) Indications for Splenectomy Median age at splenectomy: 3.7 y ( ) Outcomes of Splenectomy 92% To decrease transfusion 15% Remained transfusion dependent 90% To improve anemia after splenectomy 88% To improve quality of life 60% To reduce jaundice Infection Post-splenectomy bacterial infection in 25% (29/115) Deep Vein Thrombosis 7/ Pulmonary Embolism 2/ Stroke / Complications of Splenectomy Thrombosis Post-splenectomy thrombosis in 8% (9/115) Portal Vein Thrombosis 1/9 Age at splenectomy (years) 11

12 PK Deficiency Complications: Iron Overload Median Ferritin: Currently transfused: 1195 ng/ml (IQR ), n=32 Historically transfused: 606 ng/ml (IQR ), n=60 Acute Transfusions/Never Transfused: 321 ng/ml (IQR ), 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

13 Iron Monitoring in PKD Correlation of T2* MRI LIC with ferritin (mcg/l), r 2 =0.6, p<

14 Number of patients Treatment of Iron Overload Figure. Age when chelation was first prescribed Age at first chelation (years) 28% (n=51) have received Chelation Therapy Median age of chelation: 11.7 y (1-54 y) Deferoaxamine 54% Deferasirox 68% Deferiprone 3% Combination 16% 2% (n=4) have received Phlebotomy for chelation 14

15 Number of patients PKD Deficiency: Symptoms and Complications Gallstones Incidence of gallstones is 43% (n=75) Median Age 14.5 y (range y) Cholecystectomy 38% (n=68) Age at cholecystectomy (years) Extramedullary Hematopoiesis Extramedullary Hematopoiesis: 12% (21/178) Hepatic n=13 Splenic n=14 Paraspinous n=7 Mediastinal n=7 Osteopenia Bone Fractures: 17% (30/178) 15

16 PK Deficiency in Pregnancy 31 women with 102 pregnancies: Pregnancy Outcomes: Normal Birth 60% (61) Miscarriage 21% (21) Preterm (<37 weeks) 12% (12) Assisted Reproduction was rare (2%) Transfusions during Pregnancy: Prior to pregnancy 4% During 12% After delivery 21% 16

17 PKD NHS: Diversity of Genotypes 65 different mutations identified The majority were missense mutations 20 mutations not previously described Most Common Mutations 1529 G>A Homozygous: n=3 Heterozygous: n= C>T Homozygous: n=2 Heterozygous: n=17 Nonsense 14% 1436 C>T Homozygous: n= G>T Homozygous: n=1 Heterozygous: n=13 Splicing 11% In/Del 3% Promoter 1% Large deletion 6% Missense 65% Within the group of 1436 C>T homozygous patients, there was wide variability in the history of transfusions, baseline anemia, and history of gallstones. 17 With permission Bianchi and Fermo

18 PKD NHS: Diversity of Genotypes 42 Missense 9 Nonsense (6 Frameshift/3 Stop) 7 Splicing 2 Inframe Insertion/Deletion 1 Promoter 4 Large Deletion 18 With permission Bianchi and Fermo

19 Adult Patient Reported Outcomes Surveys Participants complete surveys which cover a number of domains o EuroQoL-5D Mobility, Self Care, Activities, Discomfort, and Anxiety/Depression n=71 o Functional Assessment of Cancer Therapy (FACT)-Anemia Physical, Social/Family, Emotional, Functional, and Fatigue n=71 o Patient Reported Outcome Measurement Information System (PROMIS) Fatigue n=45 o A latent variable regression model was used to assess the relationship between each domain and hemoglobin, gender, splenectomy status, and age 19

20 Adult Survey Results Associations with splenectomy: More likely to work (FACT-An, p=0.004) More likely to enjoy life, accept their illness, and be content with their lives (FACT-An, p=0.004) Associations with higher hemoglobin levels: Increased ability to work (FACT-An, p<0.001) Enhanced scores of emotional well-being (FACT-An, p=0.001) Higher report of emotional/family support (FACT-An, p=0.001) Associations with female gender Higher levels of fatigue (PROMIS, p=0.05) Associations with older age: Higher levels of fatigue (EQ, p=0.02) Lower physical health (p=0.01) and less emotional support (FACT-An, p=0.03) Decreased ability to work (FACT-An, p<0.001) 20

21 Classification Groups of Clinical Severity 21

22 Classification Groups of Clinical Severity Increased clinical severity was associated with: Younger age at diagnosis Higher rate of iron overload/chelation Iron overload was common in all groups regardless of transfusion history Reticulocyte counts and MCV were incrementally higher with increasing clinical severity, even after controlling for splenectomy status. Trend for increased rates of cholecystectomy with increased clinical severity 22

23 Summary and Conclusions PKD NHS is the largest assembly of patients with PK deficiency to date. We defined 4 severity groups base on transfusion history, anemia, and splenectomy status. Many complications correlate with disease severity. Monitoring for complications, such as gallstones and iron overload, is important even in patients with mild clinical characteristics. Prospective data from the NHS will provide additional guidance for monitoring and treatment in this rare anemia. 23

24 Acknowledgements PKD NHS Boston Children s Team Jill Falcone Dongjing Guo Krystle Benedict Wendy London PKD NHS Laboratories Patrick Gallagher Paola Bianchi Kimberly Lezon-Geyda Elisa Fermo PKD NHS Investigators and Participants 24