Pyruvate Kinase Deficiency Natural History Study Rachael Grace, MD, - - PowerPoint PPT Presentation

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Pyruvate Kinase Deficiency Natural History Study Rachael Grace, MD, - - PowerPoint PPT Presentation

Oct 22, 2023 420 likes •685 views

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 Childrens Hospital, MA, USA 6 th EUROPEAN

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6th EUROPEAN SYMPOSIUM ON RARE ANAEMIAS 1st Dutch-Belgian meeting for patients and health professionals

21st - 22nd November 2015 Amsterdam - The Netherlands

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

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6th European Symposium on Rare Anaemias - 1st Dutch-Belgian meeting for patients and health professionals

  • 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

Disclosures

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6th European Symposium on Rare Anaemias - 1st 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

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6th European Symposium on Rare Anaemias - 1st Dutch-Belgian meeting for patients and health professionals

  • 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.

Key Points

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6th European Symposium on Rare Anaemias - 1st 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
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6th European Symposium on Rare Anaemias - 1st 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
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6th European Symposium on Rare Anaemias - 1st 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

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6th European Symposium on Rare Anaemias - 1st 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

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6th European Symposium on Rare Anaemias - 1st Dutch-Belgian meeting for patients and health professionals

PK Deficiency Symptoms: Neonates

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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

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6th European Symposium on Rare Anaemias - 1st Dutch-Belgian meeting for patients and health professionals

PK Deficiency Symptoms: Anemia

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Reported Hemolytic Triggers

  • Infections 60%
  • Pregnancy 52%
  • Stress 32%
  • Other: aspirin, alcohol, menses

Transfusions

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)
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6th European Symposium on Rare Anaemias - 1st Dutch-Belgian meeting for patients and health professionals

The majority of patients had a splenectomy: 65% (115/178) Median age at splenectomy: 3.7 y (0.6-28.1)

PK Deficiency Treatments: Splenectomy

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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

51 40 8 7 1 3 2 1 5 10 15 20 25 30 35 40 45 50 55 3 6 9 12 15 18 21 24 27 30

Number of patients Age at splenectomy (years)

Complications of Splenectomy Infection Post-splenectomy bacterial infection in 25% (29/115) Thrombosis Post-splenectomy thrombosis in 8% (9/115)

  • Deep Vein Thrombosis 7/9
  • Pulmonary Embolism 2/9
  • Stroke 2/9
  • Portal Vein Thrombosis 1/9
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6th European Symposium on Rare Anaemias - 1st Dutch-Belgian meeting for patients and health professionals

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)

PK Deficiency Complications: Iron Overload

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6th European Symposium on Rare Anaemias - 1st Dutch-Belgian meeting for patients and health professionals

Iron Monitoring in PKD

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Correlation of T2* MRI LIC with ferritin (mcg/L), r2=0.6, p<0.05

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6th European Symposium on Rare Anaemias - 1st Dutch-Belgian meeting for patients and health professionals

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

Treatment of Iron Overload

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10 3 5 8 1 2 3 1 1 1 2 2 4 4 1 1 2 3 4 5 6 7 8 9 10 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 51 54

Number of patients Age at first chelation (years)

  • Figure. Age when chelation was first prescribed
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6th European Symposium on Rare Anaemias - 1st Dutch-Belgian meeting for patients and health professionals

PKD Deficiency: Symptoms and Complications

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Gallstones

Incidence of gallstones is 43% (n=75) Median Age 14.5 y (range 2.2-60.4 y) Cholecystectomy 38% (n=68)

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)

2 12 7 8 4 7 4 4 4 4 1 4 0 0 1 0 0 3 0 0 1 2 4 6 8 10 12 14 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 51 54 57 60 63

Number of patients Age at cholecystectomy (years)

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6th European Symposium on Rare Anaemias - 1st Dutch-Belgian meeting for patients and health professionals

PK Deficiency in Pregnancy

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31 women with 102 pregnancies:

  • Pregnancy Outcomes:
  • Assisted Reproduction was rare (2%)
  • Transfusions during Pregnancy:

Normal Birth 60% (61) Miscarriage 21% (21) Preterm (<37 weeks) 12% (12) Prior to pregnancy 4% During 12% After delivery 21%

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6th European Symposium on Rare Anaemias - 1st Dutch-Belgian meeting for patients and health professionals

65 different mutations identified

  • The majority were missense mutations
  • 20 mutations not previously described

Most Common Mutations Within the group of 1436 C>T homozygous patients, there was wide variability in the history of transfusions, baseline anemia, and history of gallstones.

PKD NHS: Diversity of Genotypes

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1529 G>A Homozygous: n=3 Heterozygous: n=20 1436 C>T Homozygous: n=55 1456 C>T Homozygous: n=2 Heterozygous: n=17 721 G>T Homozygous: n=1 Heterozygous: n=13

With permission Bianchi and Fermo

Missense 65% Nonsense 14% Splicing 11%

Promoter 1% In/Del 3% Large deletion 6%

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6th European Symposium on Rare Anaemias - 1st Dutch-Belgian meeting for patients and health professionals

PKD NHS: Diversity of Genotypes

18 With permission Bianchi and Fermo

42 Missense 9 Nonsense (6 Frameshift/3 Stop) 7 Splicing 2 Inframe Insertion/Deletion 1 Promoter 4 Large Deletion

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6th European Symposium on Rare Anaemias - 1st Dutch-Belgian meeting for patients and health professionals

  • Participants complete surveys which cover a number of domains
  • EuroQoL-5D
  • Mobility, Self Care, Activities, Discomfort, and Anxiety/Depression
  • n=71
  • Functional Assessment of Cancer Therapy (FACT)-Anemia
  • Physical, Social/Family, Emotional, Functional, and Fatigue
  • n=71
  • Patient Reported Outcome Measurement Information System

(PROMIS) – Fatigue

  • n=45
  • A latent variable regression model was used to assess the

relationship between each domain and hemoglobin, gender, splenectomy status, and age

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Adult Patient Reported Outcomes Surveys

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6th European Symposium on Rare Anaemias - 1st Dutch-Belgian meeting for patients and health professionals

  • 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)

Adult Survey Results

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6th European Symposium on Rare Anaemias - 1st Dutch-Belgian meeting for patients and health professionals

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Classification Groups of Clinical Severity

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6th European Symposium on Rare Anaemias - 1st Dutch-Belgian meeting for patients and health professionals

Classification Groups of Clinical Severity

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  • 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

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6th European Symposium on Rare Anaemias - 1st Dutch-Belgian meeting for patients and health professionals

  • 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.

Summary and Conclusions

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6th European Symposium on Rare Anaemias - 1st Dutch-Belgian meeting for patients and health professionals

Acknowledgements

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