Paroxysmal Nocturnal Haemoglobinuria (PNH) Dr Conal McConville ...

Paroxysmal Nocturnal Haemoglobinuria 

(PNH) 

Dr Conal McConville 

SpR 

Belfast City Hospital 

August_12_2010Gbl

First Objective 

Describe the serious morbidities and mortality 

associated with chronic haemolysis in PNH patients 

August_12_2010Gbl 

2

Paroxysmal Nocturnal Haemoglobinuria: 

A Chronic Disabling and Life-Threatening Disease 

• Estimated 4,000 – 

6,000 patients in U.S. 1 

• 5 year mortality: 35% 2 

• Diagnosed at all 

Ages – Median age 

early 30’s 3,4 

• Quality of life 

diminished 5 

• Progressive disease 2-4 

Patients Surviving (%) 

100 

80 

60 

40 

20 

0 

Actuarial Survival From the Time of 

Diagnosis in 80 Patients With PNH 2 

0 5 10 15 20 25 

Years After Diagnosis 

Age- and sex- 

matched controls 

The expected survival of an age- and sex-matched control group is shown for comparison 

(Hillmen et al 1995). In a patient population where ½ the patients have

Paroxysmal Nocturnal Haemoglobinuria 

• Firstly, a few facts: 

• It’s s not paroxysmal 

– Even in the absence of symptoms, destructive 

progression of haemolysis is ongoing 

• It’s s not nocturnal 

– Haemolysis in PNH is subtle and constant, 

24 hours a day 

• Haemoglobinuria is a less commonly seen 

complication 

– ¾ patients present without haemoglobinuria 1 

1. International PNH Interest Group. Blood. 2005;106:3699-3709. 


4

The Defect in PNH 

The Somatic Mutation of the PIG A gene prevents 

all GPI anchored proteins from binding to cell surface 

CD59 

• Forms a defensive shield for RBCs 

from complement-mediated mediated lysis 

• Inhibits the assembly of the 

membrane attack complex 

CD55 

• Prevents formation and augments 

instability of the C3 convertases, 

attenuating the complement cascade 

CD59 

GPI-anchor 

CD55 

1. Adapted from: Johnson RJ et al. J Clin Pathol: Mol Pathol. 2002;55:145-152. 2. Brodsky R. Paroxysmal Nocturnal Haemoglobinuria. In: Hematology - Basic 

Principles and Practices. 4th ed. R Hoffman; EJ Benz; S Shattil et al, eds. Philadelphia, PA: Elsevier Churchill Livingstone; 2005; p. 419-427. 


5

Historically Viewed as a Hemolytic Anemia 

Normal red blood cells 

are protected from 

complement attack by 

a shield of terminal 

complement inhibitors 

Without this protective 

complement inhibitor 

shield, PNH red blood 

cells are destroyed 

Complement 

Activation 

Intact RBC 

Reduced Free Haemoglobin 

Red Cell Mass 

Anaemia 

1. International PNH Interest Group. Blood. 2005;106:3699-3709. 2. Brodsky R Paroxysmal Nocturnal Haemoglobinuria. In: Hematology - Basic Principles 

and Practices. 4th ed. R Hoffman; EJ Benz; S Shattil et al, eds. Philadelphia, PA: Elsevier Churchill Livingstone; 2005; p. 419-427. 3. Rother RP et al. JAMA. 

2005;293:1653-1662. 4. Socie G et al. Lancet. 1996;348:573-577. 5. Hill A et al. Br J Haematol. 2007;137:181-92. 


6

PNH is a Progressive Disease of 

Chronic Haemolysis 

Normal red blood cells 

Without this protective 

Thrombosis 

are protected from 

complement inhibitor 

complement attack by 

shield, PNH red blood 

a shield of terminal 

cells are destroyed 

Renal Failure 

complement inhibitors 

Pulmonary Hypertension 

Significant 

Impact on 

Survival 

Complement 

Activation 

Abdominal Pain 

Dyspnoea 

Intact RBC 

Free Haemoglobin 

Dysphagia 

Fatigue 

Significant 

Impact on 

Morbidity 

Haemoglobinuria 

Anaemia 

Erectile Dysfunction 

1. International PNH Interest Group. Blood. 2005;106:3699-3709. 2. Brodsky R Paroxysmal Nocturnal Haemoglobinuria. In: Hematology - Basic Principles 

and Practices. 4th ed. R Hoffman; EJ Benz; S Shattil et al, eds. Philadelphia, PA: Elsevier Churchill Livingstone; 2005; p. 419-427. 3. Rother RP et al. JAMA. 

2005;293:1653-1662. 4. Socie G et al. Lancet. 1996;348:573-577. 5. Hill A et al. Br J Haematol. 2007;137:181-92. 6. Lee JW et al. Hematologica 2010. 95 

(s2): Abstract #505 and 506. 7. Hill A et al. Br J Haematol. 2010; May;149(3):414-25. 8. Hillmen P et al. Am. J. Hematol. 2010; 85:553–559. 


7

Current Understanding of PNH: 

Chronic Haemolysis is the Underlying Cause of 

Progressive Morbidities and Mortality of PNH 

Thrombosis 

Venous 

Arterial 

• PE/DVT 

• Stroke/TIA 

• Cerebral 

• MI 

• Dermal 

• Hepatic/Portal 

• Abdominal ischemia 

Fatigue / Impaired 

Quality of Life 

• Abdominal pain 

• Dysphagia 

• Poor physical functioning 

• Erectile dysfunction 

Chronic Kidney Disease 

• Renal insufficiency 

• Dialysis 

• Hypertension 

End Organ Damage 

• Brain 

• Liver 

• GI 


• Dyspnoea 

• Cardiac Dysfunction 

Anaemia 

• Transfusions 

• Haemosiderosis 

1. International PNH Interest Group. Blood. 2005;106:3699-3709. 2. Brodsky R. Paroxysmal Nocturnal Haemoglobinuria. In: Hematology - Basic Principles 

and Practices. 4th ed. R Hoffman; EJ Benz;S Shattil et al, eds. Philadelphia, PA: Elsevier Churchill Livingstone; 2005; p. 419-427. 3. Hillmen P et al. N Engl J 

Med. 1995;333:1253-1258. 4. Rosse W et al. Hematology (Am Soc Hematol Educ Program). 2004:48-62. 5. Rother R et al. JAMA. 2005;293:1653-1662. 6. 

Socie G et al. Lancet. 1996;348:573-577. 7. Hill A et al. Br J Haematol. 2007;137:181-92. 8. Lee JW et al. Hematologica 2010. 95 (s2): Abstract #505 and 

506. 9. Hill A et al. Br J Haematol. 2010; May;149(3):414-25. 10. Hillmen P et al. Am. J. Hematol. 2010; 85:553–559. 


8

Thrombosis 


Fatigue / Impaired QOL 



Anemia 

Chronic Haemolysis is the Underlying Cause of 

Progressive Morbidities and Mortality of PNH 

Thrombosis 

Venous 

Arterial 

• PE/DVT 

• Stroke/TIA 

• Cerebral 

• MI 

• Dermal 

• Hepatic/Portal 

• Abdominal ischemia 

Fatigue / Impaired 

Quality of Life 

• Abdominal pain 

• Dysphagia 

• Poor physical functioning 

• Erectile dysfunction 


• Renal insufficiency 

• Dialysis 

• Hypertension 


• Brain 

• Liver 

• GI 


• Dyspnoea 

• Cardiac Dysfunction 

Anaemia 


• Haemosiderosis 

1. International PNH Interest Group. Blood. 2005;106:3699-3709. 2. Brodsky R. Paroxysmal Nocturnal Haemoglobinuria. In: Hematology - Basic Principles 

and Practices. 4th ed. R Hoffman; EJ Benz;S Shattil et al, eds. Philadelphia, PA: Elsevier Churchill Livingstone; 2005; p. 419-427. 3. Hillmen P et al. N Engl J 

Med. 1995;333:1253-1258. 4. Rosse W et al. Hematology (Am Soc Hematol Educ Program). 2004:48-62. 5. Rother R et al. JAMA. 2005;293:1653-1662. 6. 

Socie G et al. Lancet. 1996;348:573-577. 7. Hill A et al. Br J Haematol. 2007;137:181-92. 8. Lee JW et al. Hematologica 2010. 95 (s2): Abstract #505 and 

506. 9. Hill A et al. Br J Haematol. 2010; May;149(3):414-25. 10. Hillmen P et al. Am. J. Hematol. 2010; 85:553–559. 


9

Thrombosis 



Thrombosis in PNH 


• Is the leading cause of death 

• Occurs in typical and atypical site 

• All patients with PNH are at risk for 

thrombosis 


10

Thrombosis 




Thrombosis in PNH: 

Common and Frequent Cause of Death 

• 40% of patients experience clinical thrombotic events 1 

• Leading cause of death 2 

– Accounts for 40–67% of deaths 1 

– First thrombotic event can be fatal 1,3 

– Median time to TE was 2.1-2.3 2.3 years from diagnosis 4 

– First TE increases risk for death 5 to 10-fold 

1 

1. Hillmen et al. Blood 2007; 110: 4123-4128. 2. International PNH Group et al. Blood. 2005;106(12):3699-3709. 3. Audebert HJ et al. J Neurol. 

2005;252:1379-1386. 4. De Latour. Blood. 2008; 112:3099-3106. 


11

Thrombosis 




Does transfusion history or clone size impact the 

risk for thrombosis? 


12

Thrombosis 




Evidence of Thrombosis in 

Never-Transfused PNH Patients* 

Parameter 

% of Patients 

Evidence of Thromboembolism (n=43) 28% 

TE events per 100 patient years 7.85 

TE rate in patients with PNH clone ≤50% (n=8) 33% 

TE rate in patients with PNH clone >50% (n=24) 30% 

15% of this patient cohort had LDH levels

Thrombosis 



Thrombosis in PNH 


• 40-67% mortality in PNH results from thrombosis 1 

– Thrombosis is the leading cause of death in PNH 2 

– First TE increases risk for death 5 to 10-fold 1 

• DVT or PE most common clinical presentation 1 

• Arterial thromboses are also common 3 

– 39% of TE events occur at arterial sites 

• Clinical thrombosis evident in all PNH patients: 1 

– Minimal haemolysis 

– No transfusion history 

– Smaller clone size 3 

1. Hillmen P et al. Blood. 2007;110:12:4123-4128. 2. International PNH Group et al. Blood. 2005;106(12):3699-3709. 3. Lee JW et al. Hematologica 2010. 95 

(s2): Abstract #506. 4. Hall C et al. Blood. 2003;102:3587-3591. 


14

Thrombosis 




39% of TE Events Occur at Arterial Sites 

Renal vein 

6% 

Dermal 

2% 

Gangrene 

2% 

Cerebral venous 

occlusion 

2% 

RUL infarction* 

2% 

Hepatic portal 

8% 

PE 

10% 

Arterial 

39% 

Cerebral arterial occlusion 

14% 

Coronary arterial 

occlusion 

13% 

Mesenteric/visceral 

12% 

DVT 

17% 

Mesenteric/visceral 

artery 

10% 

Retinal artery 

obstruction 

2% 

*RUL; right upper lobe 

Lee JW et al. Hematologica 2010. 95 (s2): Abstract #505. 

Arterial TE events were common in a large, 

retrospective analysis 

South Korean National Registry 


15

Thrombosis 



Kidney Disease 


• 8-18% mortality in PNH results from renal failure 1 

• Kidney disease in PNH is caused by haemolysis 2 

• 64% of patients with PNH exhibit chronic kidney disease at 

any one time 3 

– Renal insufficiency prevalence in PNH is 6.6 times 

higher than reported for the general population 4 

• Kidney disease is underappreciated in PNH 3 

1. Nishimura JI et al. Medicine. 2004;83:193-207. 2. Clark DA et al. Blood. 1981 Jan;57(1):83-9. 3. Hillmen P et al. Am. J. Hematol. 2010; 85:553–559. 

4. Stevens LA et al. N Engl J Med. 2006;354:2473-83. 


16

Thrombosis 



Impact of PNH on Quality of Life 


~75% of Patients Reported Symptoms as Moderate to Very Severe 

59% patients were transfusion-free free for at least 12 mo or had never been transfused 

76% were forced to modify their daily activities to manage their PNH 

17% were unemployed due to PNH 

*Moderate to severe; N=29. 

Meyers G et al. Blood. 2007;110 (11): Abstract 3683. 


17

Thrombosis 



Haemolysis Causes Fatigue 

Independent of Anemia 


• Rosse (Hoffman-Haematology) 1 

– “Many patients note a feeling of fatigue that may be 

disabling during periods of haemoglobinuria.” 

– This is not related to haemoglobin level (anaemia), as it 

disappears when the haemoglobinuria stops.” 

• Brodsky (Hoffman-Haematology) 2 

– “PNH patients frequently complain of disabling fatigue 

that is often out of proportion to the degree of anaemia.” 

• Multivariate analysis indicates haemolysis drives fatigue in 

PNH – not anaemia 3 

1. Rosse W. Paroxysmal nocturnal haemoglobinuria In: R Hoffman; EJ Benz; SJ Shattil et al., eds. Hematology: Basic Principles and Practice. 3rd ed. New 

York: Churchill-Livingstone; 2000:331-342. 2. Brodsky RA. Paroxysmal nocturnal haemoglobinuria. In: R Hoffman; EJ Benz; SJ Shattil et al., eds. Hematology. 

Basic Principles and Practice. 4th ed. Philadelphia: Elsevier Churchill Livingstone; 2005:419-427. 3. Hill A et al. Haematologica. 2008;93(s1):359. Abstract 

0903 and Presentation at: European Hematology Association 15 th Annual Meeting; June 15 th , 2008; Copenhagen, Denmark. 


18

Thrombosis 




Pain is a Common Symptom in PNH 

Patients 

Pain, 

No treatment 

Medical Intervention 

Pain, 

Treatment 

Opioids 

Other 

No pain 

NSAID 

(n=286) 

Almost 3 out of 5 (58%) patients reported significant pain 

47% of patients with pain required medical intervention 

South Korean National Registry 

Lee JW et al. Hematologica 2010. 95 (s2): Abstract #506. 


19

Thrombosis 




Fatigue and Quality of Life Conclusions 

• 96% of patients report fatigue 1 

– Fatigue/QoL independent of anemia/transfusion requirements 

• 76% of patients with PNH have disruptions in daily 

activities 1 

– 17% of patients were unemployed due to PNH 

• Fatigue, QoL and abdominal pain are linked by 

underlying haemolysis and the threat of ischemia and 

mortality 2 

– 66% of patients report shortness of breath 

– 57% of patients report abdominal pain 

• 2.2-fold increased risk of mortality 

• 3.6-fold increased risk of developing TE 

• PNH symptoms are independent of clone size 3 

1. Meyers G et al. Blood. 2007;110(11):Abstract 3683. 2. Lee JW et al. Hematologica 2010. 95 (s2): Abstract #506. 3. Urbano-Ispizua A et 

al. Hematologica 2010. 95 (s2): Abstract #1022. 


20

Thrombosis 


Fatigue / / Impaired QOL 

Is Dyspnoea in PNH Linked to Pulmonary 

Hypertension? 

• 66% of PNH patients report dyspnoea 1 


• Haemolysis results in cell-free haemoglobin and NO 

consumption leading to pulmonary hypertension 2,3 

1. Meyers G et al. Blood. 2007;110(11):Abstract 3683. 2. Rother R. et al. JAMA. 2005; 293: 1653-1662. 3. Hill A et al. Br J Haematol. 2010; May;149(3):414-25. 


21

Thrombosis 


Fatigue / / Impaired QOL 

Evidence of 

Pulmonary Hypertension in PNH 


Study 1: 

47% of patients (34/73) had elevated NT-proBNP 

≥160 

pg/ml, indicating PHT in these patients 1 

Study 2: 

43% of haemolytic PNH patients (12/28) had mild to 

moderate PHT and 7% (2/28) had severe PHT, measured 

by doppler echocardiography 2 

Study 3: 

80% of PNH patients with elevated BNP levels had 

reduced right ventricular ejection fraction (RVEF) 3 

1. Hill A et al. Blood. 2008;112 (11):Abstract 486. 2. Hill et al. Br J Haematol. 2006;133 (suppl 1):119:Abstract 316. 3. Hill et al. Blood. 2006;108(11): Abstract 979. 


22

Common Symptoms of Haemolysis 

Signal the Underlying Threat of Catastrophic Consequences 

Dyspnoea 

Dysphagia 

Abdominal Pain 

Impaired QoL 

Fatigue 

Haemoglobinuria 

Erectile Dysfunction 

Anaemia 

DVT 

Acute Renal Failure 

Hepatic Failure 

Chronic 

Kidney Disease 

Cardiac 

Dysfunction 

Stroke / TIA 


Ischemic Bowel 


23

ESA=erythropoietin stimulating agents 

Historical Management of PNH 

Palliative options do not impact progression and risk 

for severe morbidities and mortality 1 


– Risk of iron overload 

– Transient treatment of anaemia 

• Anticoagulants 

– Risk of haemorrhage 

– Ineffective in many patients 2 

• Red cell supplements 

– ESAs may expand clones and elevate haemolysis 

– Folic acid, iron, erythropoiesis-stimulating stimulating agents 

• Steroids/androgen hormones 

– No controlled clinical trials 

– AE’s 

1. International PNH Interest Group. Blood. 2005;106:3699-3709. 2. Hillmen P et al. Blood. 2007;110:4123-8. 


24

Historical Management of PNH 

Bone Marrow Transplant 

BMT is associated with significant morbidity and mortality 

Haemolysis and thrombosis are risk factors for poor outcomes 

• In a recent retrospective study in France examining PNH 

patients: 1 

– 54% had GVHD 

• In another study examining PNH patients (n=23 )2 

– 50% chronic GVHD; 42% acute GVHD 

• BMT has a significant impact on quality of life post 

transplant 3,4 

• Allogeneic BMT recommended for PNH patients with life- 

threatening cytopenias or possibly the rare patient with 

disabling haemolysis or thrombosis not controlled with 

existing therapy 5 

1. De Latour PF et al. Abstract #316. EBMT 2009. 2. Santarone S et al. Haematologica. 2010; Jun;95(6):983-8 . 3. Bieri S et al. Bone Marrow Transplantation. 

2008; 42: 819–827. 4. Fraser CJ et al. Blood. 2006;108: 2867-2873. 5. Brodsky RA. Blood. 2009 113: 6522-6527 


25

SOLIRIS ® ▼(eculizumab) 

• Soliris® is indicated for the treatment of patients with 

paroxysmal nocturnal haemoglobinuria. Evidence of 

clinical benefit of Soliris® in the treatment of patients 

with PNH is limited to patients with history of 

transfusions. 


26

SOLIRIS ® Blocks Terminal Complement 

Complement Cascade 

SOLIRIS® 

C3 

C3a 

• 

SOLIRIS® binds with high affinity to C5 

Proximal 

C3b 

• 

Terminal complement - C5a and C5b-9 

activity blocked 

C5 

C5a 

• 

Proximal functions of complement 

remain intact 

Terminal 

C5b 

C5b-9 

Cause of Haemolysis 

in PNH 

• 

Weak anaphylatoxin 

• 

Immune complex clearance 

• 

Microbial opsonization 

1. Figueroa JE, Densen P. Clin Microbiol Rev. 1991;4(3):359-395. 2. Walport MJ. N Engl J Med. 2001;344(14):1058-66. 3. SOLIRIS® (eculizumab) [package insert]. Alexion Pharmaceuticals; 2009. 4. Rother RP et al. Nature 

Biotech. 2007;25(11):1256-64. 

August 12_10_2010Gbl 

27

Summary of Clinical Efficacy 

In clinical trials, SOLIRIS ® significantly reduced haemolysis 1 

the underlying cause of morbidity and mortality in PNH 

• 86% sustained reduction in haemolysis as measured by LDH 2 

• 92% reduction in thrombotic events across all patient types 3 

• 94% reduction in thrombotic events in patients treated with 

anticoagulants 3 

• Patients treated with SOLIRIS experienced improvement in CKD and 

pulmonary hypertension 4,5 

• 78% clinically meaningful improvement in fatigue 

– Fatigue in PNH impacted by haemolysis 

– Significant improvement noted in pain and dyspnoea along with a 

broad range of QoL measures 5 

• 73% reduction in need for transfusions across all patient populations 

2 

1. SOLIRIS® (eculizumab) [package insert]. Alexion Pharmaceuticals; 2009. 2. Hillmen P et al. N Engl J Med. 2006;355:1233-43. 3. Hillmen P et al. Blood. 2007;110(12):4123-8. 4. Hillmen P et al. Am. J. Hematol. 2010; 85:553–559 5. 

Hill A, et al. BJH. doi:10.1111/j.1365-2141.2010 5. Socie G et al. Blood. 2007;110(11)::Abstract 3672. 


28

Adverse Reactions Reported in ≥ 5% of 

SOLIRIS ® Treated Patients in TRIUMPH 

SOLIRIS® (eculizumab) [package insert]. Alexion Pharmaceuticals; 2009. 

Patients, n (%) 

Reaction SOLIRIS ® (n = 43) Placebo (n = 44) 

Headache 19 (44) 12 (27) 

Nasopharyngitis 10 (23) 8 (18) 

Back pain 8 (19) 4 (9) 

Nausea 7 (16) 5 (11) 

Fatigue 5 (12) 1 (2) 

Cough 5 (12) 4 (9) 

Herpes simplex virus infections 3 (7) 0 

Sinusitis 3 (7) 0 

Respiratory tract infection 3 (7) 1 (2) 

Constipation 3 (7) 2 (5) 

Myalgia 3 (7) 1 (2) 

Pain in extremity 3 (7) 1 (2) 

Influenza-like illness 2 (5) 1 (2) 


29

Patient Safety Card 

• Patients should be informed 

that they will be provided with 

a Patient Safety Card 

• Patients should carry the card 

with them at all times 

• The card describes symptoms, 

which if experienced, should 

prompt the patient to seek 

immediate medical attention 

• Instruct patients to show the 

card to all health care 

providers involved in 

their care 

SOLIRIS® (eculizumab) [package insert]. Alexion Pharmaceuticals; 2009. 


30


Thank you 

Thank you 

31

Paroxysmal Nocturnal Haemoglobinuria (PNH) Dr Conal McConville ...

You also want an ePaper? Increase the reach of your titles

Delete template?

Save as template?