PNH: A Review and an Update - Aplastic Anemia & MDS

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PNH: A REVIEW AND AN UPDATEPNH: A REVIEW AND AN UPDATE

Jamile M. Shammo MD, FASCP, FACP Associate Professor of Medicine and Pathology

Rush University Medical Center Chicago

Case study

A 37 year old man was referred to the hematology clinic for evaluation and management of MDS

He had anemia for 7 years, and was treated with iron supplements, epo, and had a bone marrow biopsy eventually which showed low risk MDS, and absent iron stores.

he had been evaluated for hematuria and was evaluated by a urologist who performed 2 cystoscopies, which were not revealing

Case study

At the time of his clinic visit, he complained of fatigue, and episodes of back pain

He also described episodes of dark urine

His iron studies were consistent with iron deficiency anemia

A flow cytometry of the peripheral blood was sent for RBC/Granulocytes testing to detect a possible PNH clone.

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Paroxysmal Nocturnal Hemoglobinuria:Paroxysmal Nocturnal Hemoglobinuria: A Chronic Disabling and LifeA Chronic Disabling and Life--Threatening DiseaseThreatening Disease

PNH is an acquired disorder of the PNH is an acquired disorder of the hematopoietic stem cellhematopoietic stem cell

Estimated 4,000 Estimated 4,000 –– 6,000 patients 6,000 patients in U.S.1in U.S.1

5 year mortality: 35%25 year mortality: 35%2

Diagnosed at all Diagnosed at all Ages Ages –– Median age early 30’sMedian age early 30’s

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 <30% clone, 1 in 7 patients died by 5 years.

de Latour et al. Blood. 2008; 112: 3099-3106.

Years After Diagnosis

Pa

tie

nts

Su

rviv

ing

(%

)

Actuarial Survival From the Time ofActuarial Survival From the Time of Diagnosis in 80 Patients With PNH2Diagnosis in 80 Patients With PNH2

100100

8080

6060

4040

2020

00

00 55 1010 1515 2020 2525

AgeAge-- and Genderand Gender-- Matched ControlsMatched Controls

Patients with PNHPatients with PNH

1. Hill A et al. Blood. 2006;108(11): 290a. Abstract 985. 2. Hillmen P et al. N Engl J Med. 1995;333:1253-1258. 3. Nishimura JI, et al. Medicine.

2004;83:193-207. 4. Socié G et al. Lancet. 1996;348:573-77. 5. Hill A et al. Br J Haematol. 2007;137:181-92.

CD55

The Defect in PNH

The Somatic Mutation of the XThe Somatic Mutation of the X--chromosome PIG A Gene Prevents chromosome PIG A Gene Prevents All GPI Anchored Proteins from Binding to Cell SurfaceAll GPI Anchored Proteins from Binding to Cell Surface

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

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

CD59

GPIGPI--anchoranchor

CD55CD55

Prevents formation and augments instability Prevents formation and augments instability of the C3 convertases, attenuating the of the C3 convertases, attenuating the complement cascade complement cascade

CD59CD59

Forms a defensive shield for RBCs from Forms a defensive shield for RBCs from complementcomplement--mediated lysismediated lysis

Inhibits the assembly of the membrane Inhibits the assembly of the membrane attack complexattack complex

Overview of Complement

C3C3 C3aC3a

C3bC3b

C5C5

Pro

xim

al

Te

rmin

al

C5bC5b--99 Cause of Cause of HemolysisHemolysis

in PNHin PNH

C5aC5a

C5bC5b

Complement CascadeComplement Cascade

Membrane AttackMembrane Attack ComplexComplex

Cause of Cause of HemolysisHemolysis in PNHin PNH

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Multimeric C9 Lesions on PNH Erythrocyte Membrane

Classification of PNH

1. Classical PNH: Manifests with florid intravascular hemolysis and episodes of visible hemoglobinuria.

2. PNH in the setting of another BM failure state: This entity is characterized by mild hemolysis and a small clone size

3. Subclinical PNH: With <1% clone, and no clinical or biochemical evidence of intravascular hemolysis

9 AdBoard Master_Sept 14, 2010

PNH Clonal Expansion in an AA Representative Population

n = 75

At the start of follow up

At the last of follow up

Transitional pattern n (%)

(Classic PNH) (8) (11%)

Expansion 13 (17%)

Persistent 44 (59%)

Newly developed 5 (4%)

Disappearance 18 (24%)

PNH+ Patients

PNH-

Patients

109 (96%)

n = 114

Sugimori C et al. BJH. 2009; 147: 102-12

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Peripheral Blood Abnormalities at Presentation

Anemia aloneAnemia alone

Anemia and ThrombocytopeniaAnemia and Thrombocytopenia

Anemia and Anemia and NeutropeniaNeutropenia

PancytopeniaPancytopenia

% %

22.822.8

25.325.3

4.04.0

39.139.1

De Latour RP et al. Blood 2008;112:3099-3106

Paroxysmal Nocturnal Hemoglobinuria Clinical manifestations

Hemolytic anemia

paroxysmal

Even in the absence of symptoms, destructive progression of hemolysis is ongoing

nocturnal

Hemolysis in PNH is subtle and constant, 24 hours a day

Hemoglobinuria is a less commonly seen complication

¾ patients present without hemoglobinuria1

Bone marrow failure/pancytopenia

Thrombophilia/ Propensity for clots

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

Factors Determining Hemolysis Proportion of abnormal cells

Abnormality – type III vs type II

Activation of complement

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Definition of PNH type RBCs Type I cells

Normal RBC’s with normal CD59 expression

Circulating survival: 90-120 days1,2

Type III cells

PNH clone with complete CD59 deficiency

Circulating survival: 20 days1,2

Type II cells

PNH clone with complete deficiency (Type III cells) and partial CD59 deficiency

Circulating survival: 45 days1,2

1. Rosse WR Reviews in Molecular Medicine 1997; 76: 63. 2. Rosse WF Blood 1971; 37:556

Things That Activate Complement in Vivo

“Tick-over” spontaneous activation – Alternative pathway

Chronic hemolysis

Exposure to endotoxin from GI tract leads to increased risk of massive hemolysis

Other infections, surgery, trauma, pregnancy

Mastellos D et al. Immunologic Res. 2003; 3: 367-85; Mergenhagen STE et al. J of Inf Dis. 1973; 128:S86. Chenoweth DE et al. N Engl J Med. 1981; 304:497-503. Girardi G. Am J Reprod Immunol. 2008; 59:183–192

Common Symptoms in Patients With PNH

1. Meyers G et al. Blood. 2007;110(11):Abstract 3683.3. 2. Hill A et al. Br. J. Hematol. 2010;149(3):414-425. 3. Hillmen P et al. Am. J. Hematol. 2010; 85:553-559. 4. International PNH Interest Group. Blood. 2005;106(12):3699-3709. 5. Hillmen P et al. N Engl J Med. 1995;333:1253-8. 6. Nishimura J et al. Medicine. 2004;83(3):193-207.

41% Dysphagia1

47% Pulmonary Hypertension2

66% Dyspnea1

57% Abdominal Pain1

64% Chronic Renal Insufficiency3

47% Erectile dysfunction1

26% Hemoglobinuria4

40% Thrombosis5

89% Anemia6

96% Fatigue, Impaired QoL1

41% Dysphagia1

47% Pulmonary Hypertension2

66% Dyspnea1

57% Abdominal Pain1

64% Chronic Renal Insufficiency3

47% Erectile dysfunction1

26% Hemoglobinuria4

40% Thrombosis5

89% Anemia6

96% Fatigue, Impaired QoL1

Chronic Kidney Disease Chronic Kidney Disease Common Symptoms of PNH Common Symptoms of PNH Thrombosis Thrombosis

PNH Symptom Incidence Rate (%)PNH Symptom Incidence Rate (%) PNH Symptom Incidence Rate (%)PNH Symptom Incidence Rate (%)

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PNH and Hemolysis

1. International PNH Interest Group. Blood. 2005;106:3699-3709. 2. Brodsky R Paroxysmal Nocturnal Hemoglobinuria. In: Hematology - Basic Principles and Practices. 4th ed. R

Hoffman; EJ Benz; S Shattil et al, eds. Philadelphia, PA: Elsevier Churchill Livingstone; 2005;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.

Normal red blood cells Normal red blood cells

are protected from are protected from

complement attack by complement attack by

a shield of terminal a shield of terminal

complement inhibitorscomplement inhibitors

Without this protective Without this protective

complement inhibitor complement inhibitor

shield, PNH red blood shield, PNH red blood

cells are destroyedcells are destroyed

Intact RBCIntact RBC

Free HemoglobinFree Hemoglobin

ComplementComplement

ActivationActivation

Reduced Red Cell MassReduced Red Cell Mass

Anemia

Consequences of Chronic Hemolysis and Free Hemoglobin

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

4th ed. R Hoffman; EJ Benz; S Shattil et al, eds. Philadelphia, PA: Elsevier Churchill Livingstone; 2005;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.

Thrombosis

FatigueFatigue

Renal Failure

Abdominal Pain

Dyspnea

DysphagiaDysphagia

HemoglobinuriaHemoglobinuria

Erectile DysfunctionErectile Dysfunction

Normal red blood cells Normal red blood cells

are protected from are protected from

complement attack by complement attack by

a shield of terminal a shield of terminal

complement inhibitorscomplement inhibitors

Without this protective Without this protective

complement inhibitor complement inhibitor

shield, PNH red blood shield, PNH red blood

cells are destroyedcells are destroyed

Intact RBCIntact RBC

ComplementComplement

ActivationActivation

Significant Significant Impact on Impact on SurvivalSurvival

Significant Significant Impact on Impact on MorbidityMorbidity

Free Hgb/AnemiaFree Hgb/Anemia

Pulmonary Hypertension

NO↓NO↓

Thrombosis in PNH:

40% of patients experience clinical thrombotic events1

Leading cause of death2

Accounts for 40-67% of deaths1

First thrombotic event can be fatal1,3

Median time to TE was 2.1-2.3 years from diagnosis4

First TE increases risk for death 5- to 10-fold1

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.


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Common Sites of Thrombosis Occur Frequently in PNH

Higher proportion of PE and/or DVT sites of thrombosis consistently found in PNH patients Higher proportion of PE and/or DVT sites of thrombosis consistently found in PNH patients –– Socie et al. 1996 (29%)4 and Nishimura and Rosse. 2004 (27%)5Socie et al. 1996 (29%)4 and Nishimura and Rosse. 2004 (27%)5

1. Hillmen P et al. N Engl J Med. 1995;333:1253-8. 2. Hillmen P et al. Blood. 2007; 100:4123-8. 3. Fowkes FJI et al. Eur J Vasc Endovasc Surg. 2003;25:1-5. 4.

Socie G et al. Lancet. 1996;348:573-7. 5. Nishimura J et al. Medicine. 2004;83(3):193-207.

TE Type Hillmen P et al. 1995

(N=80) Hillmen P et al. 2007

(N=195)

DVT or PEDVT or PE 33%33% 40%40%

CVA/MICVA/MI 16%16% 15%15%

Typical VTE most common Typical VTE most common VTE in PNHVTE in PNH √√ √√

Atypical VTE more common in PNH Atypical VTE more common in PNH than in the general populationthan in the general population33 √√ √√


Clinical Symptoms Predictive of TE

South Korean National Registry.

Lee JW et al. Hematologica. 2010.95(s2):Abstract #505 and 506.


Potential Assessments to Identify Thrombosis Risk in PNH

Baseline Platelet Count Proportion with History of TE1

Thrombocytopenic <100,000 X 10Thrombocytopenic <100,000 X 1099/L/L 45%45%

NonNon--Thrombocytopenic ≥100,000 X 10Thrombocytopenic ≥100,000 X 1099/L/L 27%27%

Patients with thrombocytopenia have elevated incidence of TE1

Evidence of platelet consumption in PNH1,2

Platelet consumption may result from microthrombi1,3

D-dimer and other markers of elevated inflammatory response3,4

61% and 82% of PNH patients in French and US studies demonstrated an elevated risk for TE as indicated by increased D-dimer levels

Chronic terminal complement activation leads to systemic inflammatory and hypercoagulable state in PNH

1. Socie G et al. Blood. 2009;114:Abstract 4030. 2. Hill A et al. Br J Haematol. 2007;137:181-192. 3. Weitz I et al. Thrombosis Research. 2010;125:S106-107. 4. Helley D et al. Hematologica.2010;95(4):574-81.


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Kidney Pathology in PNH

Chronic hemolysis and cell-free plasma hemoglobin lead to chronic kidney disease in PNH1-4

Repetitive exposure of tissue to cell-free hemoglobin may lead to renal damage in PNH3,4

80% of PNH patients (median age of 31.5 years) had MRI evidence of significant renal hemosiderosis1,5

Marked hemosiderin deposits in the proximal renal tubule are a common feature in all autopsy and biopsy reports dealing with PNH

Demonstrable by MRI even when no overt hemoglobinuria is seen

Autopsy and biopsy often show interstitial nephritis and fibrosis3,4

1. Brodsky R. Hematology: Basic Principles and Practice. Churchill Livingstone; 2005:419-427. 2. Rother R et al. JAMA. 2005;293:1653-1662.

3. Clark DA et al. Blood. 1981;Jan;57(1):83-9. 4. Hillmen P et al. Am. J. Hematol. 2010; 85:553-559. 5. Hill A et al. Blood. 2006;108:Abstract 979.


64% of Patients Exhibit Clinical Chronic Kidney Disease (CKD)

59% of patients with minimal (0-1) transfusion history had CKD (n=22)

Hillmen P et al. Am. J. Hematol. 2010;85:553-559.


Impact of PNH on Quality of Life

59% patients were transfusion59% patients were transfusion--free for at least 12 mo or had never been transfusedfree for at least 12 mo or had never been transfused

76% were forced to modify their daily activities to manage their PNH76% were forced to modify their daily activities to manage their PNH

17% were unemployed due to PNH 17% were unemployed due to PNH

*Moderate to severe; N=29. Meyers G et al. Blood. 2007;110 (11): Abstract 3683.

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


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Two Independent International Groups Recommend Testing High Risk Patient for PNH

Borowitz MJ et al. International Clinical Cytometry Society. Part B Clin Cytometry. 2010;78B:211-230; International PNH Interest Group. Blood.

2005;106(12):3699-709.

Guidelines for the diagnosis and monitoring of paroxysmal

nocturnal hemoglobinuria and related disorders by flow cytometry Michael J. Borowitz *, Fiona E. Craig, Joseph A. DiGiuseppe, Andrea J. Illingworth, Wendell Rosse, D. Robert Sutherland,

Carl T. Wittwer, Stephen J. Richards, On behalf of the Clinical Cytometry Society

Standard Diagnostic Test for PNH

Flow cytometry performed on peripheral blood

Granulocytes and at least one additional cell line should be evaluated Red blood cells (RBCs)

Monocytes

Quantitative results Optimal-High sensitivity analysis: ≥0.01%

Routine analysis: ≥1%

Easy to understand PNH reports

Use more than one reagent against GPI-anchored proteins

Borowitz MJ et al. for International Clinical Cytometry Society. Part B Clin Cytometry. 2010;78B:211-230.

Testing for PNH in Red Blood Cells

GPA = glycophorin A. Data Source - Dahl-Chase Diagnostic Services.

Normal RBC’s with normal CD59 expression (Type I cells)

PNH clone with complete CD59 deficiency (Type III cells) and partial CD59 deficiency (Type II cells)

PNH clone with complete CD59 deficiency (Type III cells)

Gating on GPA+ RBC’sGating on GPA+ RBC’s

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Testing for PNH: RBC’s and Granulocytes

Data Source - Dahl-Chase Diagnostic Services.

CD

24- G

ranu

locy

tes

FLAER- GPI Anchor Binding Marker CD59 – GPI Anchored Protein

80.1 % of Granulocytes lack GPI proteins 31.4% RBCs are Type III PNH cells

WBCWBC RBCRBC

Historical Management of PNH

Transfusions

Risk of iron overload

Transient treatment of anemia

Anticoagulants

Risk of hemorrhage

Ineffective in many patients2

Red cell supplements

ESAs may expand clones and elevate hemolysis

Folic acid, iron, erythropoiesis-stimulating agents

Steroids/androgen hormones

No controlled clinical trials

AE’s

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

PNH Bone Marrow Transplant

- BMT is the only potentially curative therapy for PNH1,

- Indications for transplant include

1. uncontrollable hemolysis

2.thrombosis

3. Bone marrow failure state

There is considerable morbidity and mortality associated with BMT for PNH.

Patient selection and timing of transplant are important variables in making

the decision.

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

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PNH Bone Marrow Transplant In a recent retrospective study in France examining PNH patients2

54% had GVHD

In another study examining PNH patients (n=23)1

50% chronic GVHD; 42% acute GVHD

BMT has a significant impact on quality of life post transplant3,4

Allogeneic BMT recommended for PNH patients with life-threatening cytopenias or possibly the rare patient with disabling

hemolysis or thrombosis not controlled with existing therapy5

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

Au

gu

st 1

2_1

0_2

010

Gb

l

BMT In PNH

Study Year Pub (N)

Age Median

(range) Study

Population Mortality GVHD Cause of Death Risk of Death

or GVHD

Santarone S et al. Hematologica + EBMT

2008 abstract

2009 26 33 (20-59)

PNH patients; 23 HLA matched

(22 identical

sib), 3 unmatched

42% ov erall

[34% at 6 mo.

(from abstract)]

n=10 of 20 ev aluable patients (50%) cGVHD

N=11 aGVHD (42%)

N=11: infections n=4, aGVHD n=1, cGVHD n=2 , multiorgan failure

n=2, EBV lymphoma n=1

At least 42%

De Latour et al.

EBMT, Abstract #316

2009

185 30 (23-38)

N=83 (54%) BMF;

N=69 (45%) PNH

31% treated v s. 17% controls at

5 years

N=100 (54%)

N=53 deaths

• 28 from infections

• 13 from GVHD

At least 31%

Ruggeri et al. EBMT, Abstract #O298

2009 58 12 51 SAA 7 PNH

53% 2 years (projected)

28 +/- 6% aGVHD

N=14 of 44 at risk

(32%) cGVHD

NA At least ~28%

de Latour et al. Blood 2008 52 42% (n=22) NA NA 42% (death)

de Latour et al. ASH abstract

2008 141 30 (23-36)

N=75 (54%) BMF;

N=62 (45%)PNH

~30% at 5 yrs vs. 32.2% at 10

years for

controls (n=401; 1950-2005)

n=45 (32%) cGVHD

n=35 (25%) aGVHD

N=39 (28%) Main causes:

•Infection (n=19)

•Gv HD (n=9)

•Hemorrhage (n=4)

At least 25%

Witherspoon et al 2007 14 32 (19-42)

Hemolytic PNH 43% < 6 months 50% N=6: GVHD n=2, infections n=2, other n=2

At least 43%

9 20 (14-38)

Non-Hemolytic PNH

33% 44% N=3: infections n=2, other n=1 At least 33%

Parker 2005 121 30 PNH Patients 44% (10 yr) NA NA 44% (death)

Hegenbart et al. 2003 7 34 (25-49)

Hemolytic PNH; 2 BMF

43% n=5 (71%) n=3: Infection n=1; GVHD n=1; Organ failure n=1

At least 43%

Saso et al. 1999 57 28 (10-47)

32% SAA 44% at 2 yr n=16 (34%) aGVHD 21d engraftment;

n=13/39 cGVHD with

90d engraftment

• 19/48 (40%) died in HLA identical cohort

•Gv HD (n=3)

At least 33%

33

?

PNHPNH

AA/PNHAA/PNH

Moderate AA Moderate AA with hemolysiswith hemolysis

Moderate AA Moderate AA without hemolysiswithout hemolysis

Severe AA Severe AA without hemolysiswithout hemolysis

EculizumabEculizumab ISTIST BMTBMT

ProphylacticProphylactic

AnticoagulaionAnticoagulaion

PNH with hemolysisPNH with hemolysis PNH Intermediate + hemolysisPNH Intermediate + hemolysis

Considerations for Managing the PNH/AA Patient

De Latour RP, Amoura Z, and Socie G. La revue de medecine interne. 2010; 200-207.

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Eculizumab ( Soliris)

C3C3 C3aC3a

C3bC3b

C5C5

Pro

xim

al

Te

rmin

al

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.

C5bC5b--99 Cause of HemolysisCause of Hemolysis

in PNHin PNH

C5aC5a

C5bC5b

SOLIRISSOLIRIS®®

• Proximal functions of complement remain intact

• Weak anaphylatoxin

• Immune complex clearance

• Microbial opsonization

• Terminal complement - C5a and C5b-9 activity blocked

• SOLIRIS® binds with high affinity to C5

Complement CascadeComplement Cascade

Pilot Study Pilot Study –– NEJMNEJM. 2004. 2004 N = 11N = 11

Primary endpoint: reduction of hemolysisPrimary endpoint: reduction of hemolysis

TRIUMPH – NEJM. 2006 Pivotal Phase III, Double-Blind,

Placebo-Controlled Trial, N = 87

SHEPHERD – Blood. 2008 Broader patient population, including

those receiving minimal transfusions or with thrombocytopenia, N = 97

Eculizumab Clinical Trials in PNH

LongLong--Term Extension Trial Term Extension Trial

Hillmen Hillmen BloodBlood. 2007. 2007 Evaluated longEvaluated long--term safety, term safety,

efficacy and effect on efficacy and effect on

thrombosis; Placebo patients thrombosis; Placebo patients switched to SOLIRISswitched to SOLIRIS®®

N = 187N = 187

Dosing Schedule

In clinical trials all patients received a meningococcal vaccination

SOLIRIS® should be administered via IV infusion over 35 minutes every 7 days during induction and every 14 days during maintenance

SOLIRIS® dose adjustment to every 12 days may be necessary for some patients to maintain LDH reduction

Concomitant medications allowed

Steroids, immunosuppressant drugs, anti-clotting agents and hematinics1

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

1. Hillmen P et al. N Engl J Med. 2004;350(6):552-9.

Pretreatment Induction Phase Maintenance Phase

2 weeks before induction

Week →

1 2 3 4 5 6 7 8

9 and every

2 weeks thereafter

Neisseria meningitidis vaccination

SOLIRIS® dose, mg

→ 600 600 600 600 900 X 900 X 900

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TRIUMPH and SHEPHERD: Response

P<0.001 at all measured time points. Hillmen P et al. Blood. 2007;110(12):4123-8.

TRIUMPH placebo patients switched to SOLIRIS®® after week 26. All TRIUMPH patients entered the long-term extension study.

TRIUMPH – Placebo/Extension

TRIUMPH – SOLIRIS®/Extension

SHEPHERD – SOLIRIS®®

Lac

tate

De

hy

dro

ge

nas

e (U

/L)

0

500

1000

1500

2000

2500

3000

Time, Weeks

0 4 8 12 16 20 24 28 32 36 40 44 48 52

100% response after the first dose

73% Reduction in Mean Units Transfused Across all Subgroups: TRIUMPH

**PP<0.001. <0.001. ††Transfusion data obtained during 12 months before treatment; values were normalized for a 6Transfusion data obtained during 12 months before treatment; values were normalized for a 6--month period.month period. 1. Hillmen P et al. N Engl J Med. 2006;355;1233-1243. 2. Schubert J. Br. J Haematol. 2008;142(2):263-72.

OverallOverall 44--1414 1515--2525 >25>25

PrePre--treatment Transfusion Stratatreatment Transfusion Strata††

Patients not on SOLIRISPatients not on SOLIRIS®® (n=44)(n=44)

SOLIRIS (n=43)SOLIRIS (n=43)

**

** **

**

(n=87)(n=87) (n=30)(n=30) (n=35)(n=35) (n=22)(n=22) 00

22

44

66

88

1010

1212

1414

1616

Med

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Un

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M

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1818

•• 51% of SOLIRIS patients achieved transfusion independence vs 0% of patients not on SOLIRIS51% of SOLIRIS patients achieved transfusion independence vs 0% of patients not on SOLIRIS11

•• Patients with concomitant bone marrow dysfunction may continue to require minimal transfusionsPatients with concomitant bone marrow dysfunction may continue to require minimal transfusions

Patients Report Rapid and Sustained Improvement Across Broad Range of Measures

*P<0.05. †P<0.001. 1. Brodsky R et al. Blood. 2006;108(11): Abstract 3770. 2. Data on file. Alexion Pharmaceuticals.

Moderate Moderate ImpactImpact

Small Small ImpactImpact

Large Large ImpactImpact

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Sta

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EORTC EORTC FunctioningFunctioning

EORTC EORTC SymptomsSymptoms

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14

Eculizumab therapy and Thrombotic Events

63% of patients received concomitant anticoagulants1

The effect of anticoagulant withdrawal was not studied2

Events observed in both venous and arterial sites3

PI: There were fewer thrombotic events with SOLIRIS treatment than during the same period of time prior to treatment. 1. Brodsky R et al. Blood. 2008;111(4):1840-47. 2. SOLIRIS® (eculizumab) [package insert]. Alexion Pharmaceuticals; 2009. 3. Hillmen P, et al. Blood. 2007;110:4123-4128.

39

3

0

5

10

15

20

25

30

35

40

45

Pre-SOLIRIS® Treatment SOLIRIS Treatment

Th

rom

bo

tic

Eve

nts

(#)

P=0.0001

N=195

Renal Function change with Renal Function change with eculizumabeculizumab®® At 6 MonthsAt 6 Months

Hillmen P et al. Am. J. Hematol. 2010; 85:553–559.

60.3

24.7

75.0

31.7

64.2

20.0

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5.0

0

10

20

30

40

50

60

70

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Overall (n=189)

Stage 1 – 2 (n=81)

Stage 3 - 5 (n=40)

Segment of PNH Population

Pro

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No Change Improvement Worsening

Chronic Kidney DiseaseChronic Kidney Disease Chronic Kidney DiseaseChronic Kidney Disease Common Symptoms of PNHCommon Symptoms of PNH ThrombosisThrombosis

42

Eculizumab has a Major Impact on Survival in PNH Survival is comparable to age and sex matched control population

• 96% (76/79) patient survival.

• There was no difference in mortality between patients on eculizumab and the normal population (P=0.46)

• 2 patients over 70 years of age had worse survival (P=0.0042). No patients under the age of 50 years died

Kelly R et al. Blood. 2010;116(21) Abstract #639

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Warning WARNING: SERIOUS MENINGOCOCCAL INFECTION

SOLIRIS® increases the risk of meningococcal infections. Meningococcal infection may become rapidly life-threatening or fatal if not recognized and treated early.

Vaccinate patients with a meningococcal vaccine at least 2 weeks prior to receiving the first dose of SOLIRIS®

Revaccinate according to current medical guidelines for vaccine use

Monitor patients for early signs of meningococcal infections, evaluate immediately if infection is suspected, and treat with antibiotics if necessary


Safety: Warnings and Precautions

The effect of withdrawal of anticoagulant therapy during SOLIRIS® treatment has not been established. Therefore, treatment with SOLIRIS should not alter anticoagulant management

Patients who discontinue SOLIRIS must be monitored closely for signs of serious hemolysis

If serious hemolysis occurs after SOLIRIS discontinuation, consider the following procedures/treatments: blood transfusion (packed RBCs), or exchange transfusion if the PNH RBCs are >50% of the total RBCs by flow cytometry; anticoagulation; corticosteroids; or reinstitution of SOLIRIS

In clinical trials, 16 of 196 PNH patients discontinued SOLIRIS treatment; no serious hemolysis was observed


Serious Adverse Events: Clinical Trial Experience

Meningococcal infections are the most important adverse events that may be experienced by patients receiving SOLIRIS®

In clinical studies, 2 out of 196 patients developed serious meningococcal infections while receiving treatment with SOLIRIS Both patients had been vaccinated

In clinical studies among non-PNH patients, meningococcal meningitis occurred in one patient, who was unvaccinated

In post-marketing experience, cases of serious or fatal meningococcal infections have been reported


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Adverse Reactions Reported in ≥ 5% of SOLIRIS® Treated Patients in TRIUMPH

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

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


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.

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PNH Registry Data Collection

Physician-Reported Data Data collected at study enrollment and every six months thereafter

Data entry minimally includes: demographics, medical history, PNH diagnosis, flow cytometry results, symptoms, and clinical outcomes

All necessary information can be gathered from patient medical records

Patient Reported Outcomes Patients complete questionnaires at study enrollment and every six

months thereafter EORTC QLQ-30*

FACIT-F-fatigue scale*

Overall health status

Symptom frequency and bother

Healthcare utilization

Work Status

*validated quality-of-life instruments in other disease states

PNH Registry: Future Research Topics

PNH and Thrombotic Events

PNH and Renal Dysfunction

PNH in the Pediatric Setting

Association of Clinical & Patient Characteristics with PNH Treatment

Evolution of PNH Clones

Survival / Mortality

Correlation of PNH with Laboratory Markers

PNH: Conclusions PNH is a rare and life threatening disease Delays in diagnosis range from 1 to more than 10

years1

high-risk patients should be identified and tested for PNH2

Reliable testing and reporting procedures matter2 Granulocyte analysis in all cases PNH testing on RBCs alone is not adequate

Adding quantitative results to report forms is essential

With the advent of treatment options for PNH, there is a compelling reason to identify patients3

1. Hillmen P et al. N Engl J Med. 1995;333:1253-8. 2. Borowitz MJ et al. for International Clinical Cytometry Society. Part B Clin Cytometry. 2010;78B:211-230.

3. Brodsky R et al. Blood. 2008;111(4):1840-47.

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PNH: CONCLUSIONSPNH: CONCLUSIONS

The commercial availability of Eculizumab has certainly made a positive impact on patients quality of life, and survival

Bone marrow transplantation is the only curative modality for bone marrow failure states.

Other therapeutic options for PNH are being currently evaluated in

clinical trials (TT30)

Documents

PNH: A Review and an Update - Aplastic Anemia & MDS