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5/12/2011

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PNH Current Thinking on Disease,

Diagnosis and Treatment

Monica Bessler, MD, PhDBuck Family Professor in Hematology

Director Pediatric & AdultComprehensive Bone Marrow Failure Center

CHOP/UPENN

University of Pennsylvania School of Medicine

Email [email protected]

03/07

500

1000

2000

3000

8/93 1/99 5/00 9/01 2/03 6/04 11/05

AA PNH

Hem

oly

sis

(L

DH

)

Lacta

te d

eh

yd

rog

en

ase

Normal range

Packs o

f

red

blo

od

cells

12

8

4

Red cell transfusions

Eculizumab

Case Study:

31 year old woman with AA/PNH

Blood Clot

Aplastic

Anemia

I.

Hemoglobinuria

II.

Bone Marrow FailureIII.

Blood Clots

Clinical Manifestations of PNH

Blood clot

Thrombus

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Age Distribution of Patients with PNH

J Nishimura et. al. Medicine 2004

Institute of Hematology & Blood

Diseases Hospital

Chinese Academy of Medical

Science

Tianjin

China

Peking Union Medical College

Beijing

China

PNH Occurs in all Parts of the World

Hemoglobinuria

in PNH

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Hemoglobinuria = Hemoglobin in urine

≠ Blood in urine

Hemoglobin in urine

Hemoglobinuria

PNH !

Blood in urine

Hematuria

Not PNH !

centrifugation

microscopic examination

centrifugation

GPI-linked Proteins Deficient on

PNH Blood Cells

Monocytes B Cells T Cells NK CellsGranulocytesRed CellsPlatelets

CD55

CD58

CD59

CD109

(Gova/b- Ag )

PrPc

GP500

CD55 CD58

CD59 CD14

CD16 CD24

(NAB1-Ag)

CD48 CD66b

CD66c CD87

CD109 CD157

LAP NB1

PrPc ADP-RT

p50-80 GPI-80

C D55

CD58

CD59

CD14

{CD16 }

CD48

CDw52

CD87

CD109

CD157

Group-8

PrPc

GPI-80

CD55

CD58

CD59

CD24

CD48

CDw52

{CD73}

{CDw108}

PrPc

CD55

CD58

CD59

{CD16 }

CD48

CDw52

{CD73}

CD87

{CD90}

CDw108

{CD109}

PrPc

ADP-RT

CD55

CD58

CD59

CD16

CD48

CDw52

PrPc

HematopoieticStem Cell

CD59 CD109CD90

CD55, CD59

(Cromer Ag)

CD58, PrPc

AChE

(Cartwrigt-Ag)

CDw108

(John-Milton

-Hagen Ag )

Dombroch

residue

HolleyGregory AG

Bessler 2003

Complement Activation

C3b MAC

C5b-

9

C

5

C5

a

C6 C7 C8 C9

CD5

5

CD5

9

Classica

lLecti

nAlternativ

e

Normal

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Complement

activation

Complement

lysis

CD55

CD59

Red Blood Cell

CD55 and CD59 Protect Red Blood Cells

from Complement Lysis

Complement Mediated Lysis in PNH

PNHlC3b MAC

C5b-

9

C

5

C5

a

C6 C7 C8 C9

CD5

5

CD5

9

Classica

lLecti

nAlternativ

e

Activation -> Deposition on the surface -> Intravascular

Hemolysis

Complement

activation

Complement

lysis

CD55

CD59

Red Blood Cell

Lysis

Lack of CD55 and CD59 in PNH Causes

Complement Lysis of Red Blood Cells

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Complement Attack on PNH Red Blood Cells

Dourmashkin & Rosse WF.Am J Med. 1966 Humphrey & Dourmashkin Adv Immonol1969.

Diagnosis of PNH by the Ham Test

PNH Control

S HS S HSPNH patient

HamTest: 1938

Diagnosis of PNH Today

Deficiency of GPI-Linked Proteins

on PNH-Granulocytes

Bessler 1991

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Flow cytometry

on peripheral white blood cells:

% of Granulocytes deficient for CD59 or FLAER

= Size of the PNH Clone

PNH Testing

PNH Type I Type II Type III

Intermediate No expression

of CD59

I

CD59

PNH Red Blood Cells

PNH

IIIIIIIII III

Co

un

ts

CD59

I

Flow Cytometric Analysis of Red Blood Cells

PNH

PNH I PNH IIPNH I + III PNH I + II + III

PNH PNH

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Bone Marrow Failure

Normal bone marrow Bone Marrow Failure (BMF)

Aplastic Anemia (AA)

The Bone Marrow is the Site of Blood Cell Production

Red

Blood Cells

White

Blood Cells

Platelets

Bone Marrow

Granulocytes

Neutrophils

Lymphocytes

Bone Marrow Biopsy

Iliac Crest

Bone Marrow

5/12/2011

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Bone marrow biopsyBone marrow

aspirate

Bone Marrow Examination

Giemsa Wright

Courtesy of J Choi CHOP 400x100x

Bone Marrow in PNH

H&E

Courtesy of J Choi

CHOP

Bone Marrow in PNH

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03/07

500

1000

2000

3000

8/93 1/99 5/00 9/01 2/03 6/04 11/05

AA PNH

Hem

oly

sis

(L

DH

)

Lacta

te d

eh

yd

rog

en

ase

Normal range

Packs o

f

red

blo

od

cells

12

8

4


Eculizumab

Case Study:


Blood Clot

Aplastic

Anemia

Hemolytic / Classical PNH AA/ PNH

AA/PNHPNHPNH

Pe

rip

he

ral b

loo

d

ce

ll co

un

t

Normal Normal Normal

Cytopenia

Relationship of PNH with Aplastic Anemia (AA)

Adapted from Rotoli & Luzzatto 1989

AA

AA

MDS within PNH PNH and MDS PNH within MDS

PNH

cloneMDS

% B

loo

d C

ells

MDS

PNH clone

%B

loo

d C

ells

%B

loo

d C

ells MDS

PNH

clone

Relationship of PNH with

Myelodysplastic Syndrome (MDS)

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Red blood cell

Platelet Blood clot

Thrombus

Healthy blood flow Obstructed blood flow

Blood Clots in PNH

Blood Clot in the Liver and Brain

in a Patient with PNH

Courtesy of University of Wisconsin Medical School, Madison, WI.

Sagittal Sinus

Blood clot in the liver vein

Blood Clot in the brain

with a small stroke

The bigger the PNH Clone

The more likely a Blood Clot

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Blood Clots are more Frequent

in Patients With a Large PNH Clone

Nishimura J et al. Medicine. 2004;83:193-207.Hall C et al. Blood. 2003;102:3587-3591.

No Blood Clots Blood Clot

Moyo VM et al. BJH. 2004;126:133-138.

0 5 10 15 200

10

20

30

40

50

60

Incid

en

ce o

fblo

od c

lots

, %

Granulocyte

clone size

>50% (n=67)

Granulocyte clone size

>50% (n=55)0

20

40

60

80

100

CD

59

(-)P

MN

, %

100

80

60

40

20

0P<0.0001

PN

H c

ells

,

%

No Blood Clots Blood Clots

P=0.0001

Follow-up (years)

Blood Clots in Patients with PNH

Blood clots in the

veins

~ 32-40%

Belly ~ 1/3

Head ~ 6%

Legs / Embolus ~ 1/3

Other ~ 1/3

Stroke ~ 14%

Bone Marrow Failure Occurrence of PNH blood cells

Anemia

Infections

Gallstones

Bleeding

Inappropriate complement

activation

Extravascular Hemolysis

Low blood cell counts

Blood Clot

Abdominal pain

Bloating

Back pain

Headache

Erectile dysfunction

Esophagospasm

Fatigue

Hemoglobinuria

Kidney failure

Intravascular Hemolysis

The Mechanisms of Disease in PNH

5/12/2011

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Anemia

Infections

Bleeding


The Two Components Causing PNH

Anemia


Infections

Bleeding

Gallstones


activation



The Mechanisms of Disease in PNH

AnemiaBlood Clot

Abdominal pain

Bloating

Back pain

Headache


Esophagospasm

Fatigue

Hemoglobinuria

Kidney failure


Anemia


Infections

Bleeding

Gallstones


activation



Thrombosis in PNH

AnemiaBlood Clot

Abdominal pain

Bloating

Back pain

Headache


Esophagospasm

Fatigue

Hemoglobinuria

Kidney failure


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Treatment for PNH

Personalized Treatment PlanCure

Stem Cell Transplant

Spontaneous remission

SupportiveAnticoagulation (blood thinner)

Red cell transfusion

Iron (only in non-transfused patients)

Folate 5mg daily

Erythropoietin (with Soliris)

Pain management

Disease ModifyingImmunosuppression

Complement inhibitors (Eculizumab, Soliris™)

Only Cure(Exception: Spontaneous Remission ~15%)Anemia

Occurrence of PNH blood cells

Gallstones


activation


Blood Clot

Abdominal pain

Bloating

Back pain

Headache


Esophagospasm

Fatigue

Hemoglobinuria

Kidney failure


Bone Marrow Failure

Infections

Bleeding


Anemia

Treatment of PNH:

• Hematopoietic Stem Cell Transplant

Improves

Blood cell counts

Anemia

Occurrence of PNH blood cells

Gallstones


activation


Blood Clot

Abdominal pain

Bloating

Back pain

Headache


Esophagospasm

Fatigue

Hemoglobinuria

Kidney failure


Treatment of Bone Marrow Failure in PNH:

• IVIG, Cyclosporine, Growth Factors

Bone Marrow Failure

Infections

Bleeding


Anemia

5/12/2011

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Eculizumab (humanized anti-C5 antibody)

Soliris

FDA/ EMEA approval

2007

•100 ml over 30 minutes

•Intravenous

•Initially every week (4x)

•then every other week

Complement

activation

Complement

lysis

CD55

CD59

Red Blood Cell

Soliris Blocks Complement Lysis

of PNH Red Blood Cells

Soliris

03/07

500

1000

2000

3000

8/93 1/99 5/00 9/01 2/03 6/04 11/05

AA PNH

Hem

oly

sis

(L

DH

)

Lacta

te d

eh

yd

rog

en

ase

Normal range

Packs o

f

red

blo

od

cells

12

8

4


Eculizumab

Case Study:


Blood Clot

Aplastic

Anemia

5/12/2011

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Eculizumab Reduces the Frequency of

Transfusions

0

2

4

6

8

10

12

0

2

4

6

8

10

12

Sugar pill Eculizumab

Before After

Median transfusions Mean transfusions

P < 0.000000001

Hillmen et al NEJM 2006:355(12):1233-43.

Before After

Sugar pill Eculizumab

Before After Before After

0

2

4

6

8

10

12

14

16

Before Eculizumab Treatment After Eculizumab Treatment

Th

rom

bo

sis

Even

t R

ate

(TE

per

100 p

t-y

ears

)

P = 0.0001

(n=195) (n=195)

Eculizumab Reduces the Risk of Blood Clots

39 events

3 events

Hillmen P et al. 2007 Blood;110:4123.

Eculizumab Improves but does not

Normalize Hemoglobin Levels

0 5 10 15 20 25Time, weeks

He

mo

glo

bin

g/d

L

Sugar pill

+ red cell

transfusion

Eculizumab

Hillmen et al NEJM 2006:355(12):1233-43.

Normal12

10

8

6

4

2

0

5/12/2011

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Intravascular

Hemolysis

Extravascular

Hemolysis

--> Hemoglobinuria

--> High LDH--> No Hemoglobinuria

--> Low LDH


C3b MAC

C5b-

9

C

5

C5

a

C6 C7 C8 C9

CD5

5

CD5

9

Classica

lLecti

nAlternativ

e

PNH

Activation -> Deposition on the surface Intravascular

Hemolysis


C3b MAC

C5b-

9

C

5

C5

a

C6 C7 C8 C9 CD5

5

CD5

9

Classica

lLecti

nAlternativ

e

Activation -> Deposition on the surface Extravascular

Hemolysis

So

liris

Soliri

s

5/12/2011

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Blood Clott

Blocks intravascular hemolysis

and associated symptoms

Anemia


Infections

Bleeding

Gallstones


activation



Complement Inhibition in PNH: Eculizumab

AnemiaBlood Clot

Abdominal pain

Bloating

Back pain

Headache


Esophagospasm

Fatigue

Hemoglobinuria

Kidney failure


Meningococcal Bacterial Infection

• Fever >101

• Chills

• Altered mental status

• Headache

• See your doctor!

• Go to nearest emergency room!

• Start emergency antibiotics!

• Show your “Patient Safety Card” !

• Keep your vaccination up-to-date !

– Meningococcal quadrivalent conjugate vaccine (MCV4

or MenactraT) for adolescents and adults every 5 years

for individuals 2-55 years.

– Meningococcal quadrivalent polysaccharide vaccine

(MPSV4 or Menomune®) for individuals older than 55

years.

– Does not protect against all meningococcal strains!

– In some countries different strains are more abundant. -

> prophylactic antibiotics (Penicillin 250mg 2/day)

Meningococcal Vaccines

5/12/2011

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Pregnancy in PNH

Risks of Pregnancy in PNH

Mother:

Anemia

Low platelets and bleeding

Infection (urinary tract)

Recurrence of aplastic anemia

Blood clots during and after pregnancy !

Child:

Early and late fetal death

PNH is not inherited

Management of Pregnancy in PNH

Discuss

Plan

Verify

Prevent

Monitor

Treat early

• Hematologist familiar with PNH

• Obstetrician familiar with

high risk pregnancy

• Neonatologist

5/12/2011

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Alternatives to Pregnancy in PNH

• Adoption

• Surrogate pregnancy (legal contract)

– Laws differ from state to state and country to country

– Egg donation (gestational surrogacy)• Risk of bleeding during oocyte harvest

• Risk of thrombosis (hyperstimulation syndrome)

– In vitro fertilization (embryos may be stored)

– Surrogate pregnancy• Gestational contracted motherhood

Sponsored by:

PNH Registry Overview

The PNH Registry is an ongoing global,

observational, non-interventional study collecting

safety, effectiveness, clinical characteristic and

quality of life data on patients with PNH irrespective

of clone size or treatment.

The PNH Registry has been established in order to

describe the real world outcomes of PNH, capturing

a wide range of patients from all over the world.

5/12/2011

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PNH Registry Objectives

• Enhance the understanding of PNH demographics

and real world outcomes

• Provide real world data characterizing clinical and

subject-reported outcomes associated with PNH

treatment regimens

• Raise disease awareness in the medical community

and PNH patient population

Highlights from the 2010 American Society of Hematology Meeting:

Paroxysmal Nocturnal Hemoglobinuria (PNH)

Longterm Eculizumab Results

639: Long Term Treatment with Eculizumab In Paroxysmal Nocturnal

Hemoglobinuria (PNH): Sustained Efficacy and Improved Survival. Richard J Kelly, M.B.Ch.B., MRCP(UK), FRCPath, Anita Hill, M.B.Ch.B., MRCP(UK), FRCPath,

Ph.D., Lindsay D Mitchell, M.B.Ch.B., MRCP(UK), FRCPath, Stephen John Richards, Ph.D.,

FRCPath, Louise M Arnold, R.N., B.Sc., Gemma L Valters, R.N., B.Sc., Matthew Cullen, M.Sc.,

Dena R Cohen, M.Sc., Walter M Gregory, Ph.D., and Peter Hillmen, M.B.Ch.B., FRCP, FRCPath,

Ph.D.

4237: Long Term Safety and Efficacy of Sustained Eculizumab Treatment

In Patients with Paroxysmal Nocturnal Hemoglobinuria (PNH). Robert A Brodsky, M.D., Carlos de Castro III, M.D., Hubert Schrezenmeier, M.D., Antonio M.

Risitano, M.D., Ph.D., Joerg Schubert, M.D., Jaroslaw P Maciejewski, M.D., Ph.D., FACP, Ulrich

Duehrsen, M.D., Lucio Luzzatto, M.D., FRCP, FRCPath, Petra Muus, M.D., Ph.D., Jeffrey Szer,

BMedSc, M.B.B.S., FRACP10, Gérard Socié, M.D., Ph.D., and Peter Hillmen, M.B.Ch.B., FRCP,

FRCPath, Ph.D.

5/12/2011

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Highlights from the 2010 American Society of Hematology Meeting:

Paroxysmal Nocturnal Hemoglobinuria (PNH)


4240 Low Level Residual Extravascular Haemolysis Is Common

Following Eculizumab Treatment In Paroxysmal Nocturnal

Haemoglobinuria (PNH), but Does Not Affect Transfusion Requirement Austin G Kulasekararaj, Dupe Odunsi, Pramila Krishnamurthy, Hayden Janet, Ibrahim Momoh,

Ghulam J. Mufti, D.M., FRCP, FRCPath, Judith C. W. Marsh, M.D. and Modupe Elebute,

M.B.B.S., M.D., M.R.C.P., FRCPath

New Therapeutics

638 TT30, a Novel Human Complement Inhibitor in Development for Paroxysmal Nocturnal

Hemoglobinuria and Other Hemolytic Disorders, Demonstrates Red Blood Cell Surface

Targeting and Retention in a Model of Complement Alternative Pathway-Mediated

Hemolysis

Masha Fridkis-Hareli, Ph.D., Michael Storek, Ph.D., Antonio M. Risitano, M.D., Ph.D., Ante S.

Lundberg, M.D., Christopher J Horvath, D.V.M., M.S., DACVP, and V. Michael Holers, M.D.

Complement

activation

Complement

lysis

CD55

CD59

Red Blood Cell

TT30 Blocks Complement Activation

on PNH Red Blood Cells

TT

30


C3b MAC

C5b-

9

C

5

C5

a

C6 C7 C8 C9

CD5

5

CD5

9

Classica

lLecti

nAlternativ

e

Activation -> Deposition on the surface Intravascular

Hemolysis

PNH

TT

30

TT

30

5/12/2011

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T30 Stops Complement Deposition & Hemolysis

C3b MAC

C5b-

9

C

5

C5

a

C6 C7 C8 C9

CD5

5

CD5

9

Classica

lLecti

nAlternativ

e

Activation ->T

T3

0T

T30

Pediatric & Adult

Comprehensive BMF CenterChildren's Hospital of Philadelphia (CHOP) &

Hospital of the University of Pennsylvania (HUP/UPENN)

University of Pennsylvania School of Medicine

Monica Bessler MD PhD

Email: [email protected]

July 1, 2010

We are always looking for

study participants

For further information

Contact

Monica Bessler MD, PhD

[email protected]

5/12/2011

23

We thank all patients and physicians for

participating in our studies

For Information Contact

Thank You !

Monica Bessler MD, PhD

[email protected]

The Children’s Hospital of Philadelphia &

Hospital of the University of Pennsylvania

Acknowledgements

We thank the Aplastic Anemia & MDS

International Foundation

For their support of our research!

Thank You !

Acknowledgements

Florentine Camenish Bursary Research Award 2003 to MB

Kazuhiko Ikeda MD PhD , Aplastic Anemia & MDS International Foundation

Fellowship 2009

mailto:[email protected]

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