Pyruvate Kinase Deficiency Natural History Study - Enerca€¦ · Pyruvate Kinase Deficiency ... Dr. Bert Glader Stanford University, CA Dr. Joachim Kunz Heidelberg, ... Preterm (

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

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

2


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 ●


• 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

4


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


PKD Natural History Study Sites

• 18 sites in the United States • 3 sites in Canada • 6 sites in Europe

http://www.google.com/url?sa=i&rct=j&q=&esrc=s&frm=1&source=images&cd=&cad=rja&uact=8&ved=0CAcQjRxqFQoTCKHSipCf6MgCFYmPPgodnnkALw&url=http://geography.about.com/library/cia/blcitaly.htm&psig=AFQjCNHloUbNU---a0rKi0rY5A5L7Elb9g&ust=1446227407182916

http://www.google.com/url?sa=i&rct=j&q=&esrc=s&frm=1&source=images&cd=&cad=rja&uact=8&ved=0CAcQjRxqFQoTCL3OsPSd6MgCFULKPgodJI0HRQ&url=http://jolieblogz.blogspot.com/2010/12/map-of-holland-and-surrounding.html&psig=AFQjCNEz6U-tnuvoNZJZoNjY-kyQnUBiLQ&ust=1446227075112295

https://www.google.com/url?sa=i&rct=j&q=&esrc=s&frm=1&source=images&cd=&cad=rja&uact=8&ved=0CAcQjRxqFQoTCOfOz5md6MgCFYasPgodFGgNkg&url=https://chingsgeography.wikispaces.com/Unit+2-+Europe&bvm=bv.106130839,d.cWw&psig=AFQjCNEPmY8QlwRSK4bR_rkbj_2D72BWXA&ust=1446226878228419

http://www.google.com/url?sa=i&rct=j&q=&esrc=s&frm=1&source=images&cd=&cad=rja&uact=8&ved=0CAcQjRxqFQoTCLmOs_7158gCFcYdPgodVuYNuQ&url=http://www8.garmin.com/cartography/mapSource/MetroGuideNT.jsp&psig=AFQjCNGywYBmPuFI7roxfzbVRiGmOgBQ-A&ust=1446216311620824


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


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


PK Deficiency Symptoms: Neonates

9

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

http://www.google.com/url?sa=i&rct=j&q=&esrc=s&frm=1&source=images&cd=&cad=rja&uact=8&ved=0CAcQjRw&url=http://sudarmawan.wordpress.com/2011/12/14/phototeraphy-hiperbilirubinemia/&ei=XIy5VNPgO8ymyASCr4CICg&bvm=bv.83829542,d.aWw&psig=AFQjCNFOX2Z1StjZDGOSsJDwWlS8Jefseg&ust=1421532581692707


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)


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

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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


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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Iron Monitoring in PKD

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


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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Age at first chelation (years)

Figure. Age when chelation was first prescribed


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)

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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%

http://www.google.com/url?sa=i&rct=j&q=&esrc=s&frm=1&source=images&cd=&cad=rja&uact=8&ved=0CAcQjRw&url=http://zoominmedical.com/pregnant-woman-drawing/&ei=3pq5VKvjCpKwyQTCgYGgDg&bvm=bv.83829542,d.aWw&psig=AFQjCNFxQucwMyrID-5tCcTEgEtmqBGKoA&ust=1421536333268071


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/Del3%

Large deletion

6%


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


• 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

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Adult Patient Reported Outcomes Surveys


• 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 21

Classification Groups of Clinical Severity


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


• 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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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

Documents

Pyruvate Kinase Deficiency Natural History Study - Enerca€¦ · Pyruvate Kinase Deficiency ... Dr. Bert Glader Stanford University, CA Dr. Joachim Kunz Heidelberg, ... Preterm (