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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.
Chronic Kidney Disease Chronic Kidney Disease Common Symptoms of PNH Common Symptoms of PNH Thrombosis Thrombosis
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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 √√ √√
Chronic Kidney Disease Chronic Kidney Disease Common Symptoms of PNH Common Symptoms of PNH Thrombosis Thrombosis
Clinical Symptoms Predictive of TE
South Korean National Registry.
Lee JW et al. Hematologica. 2010.95(s2):Abstract #505 and 506.
Chronic Kidney Disease Chronic Kidney Disease Common Symptoms of PNH Common Symptoms of PNH Thrombosis Thrombosis
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.
Chronic Kidney Disease Chronic Kidney Disease Common Symptoms of PNH Common Symptoms of PNH Thrombosis Thrombosis
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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.
Chronic Kidney Disease Chronic Kidney Disease Common Symptoms of PNH Common Symptoms of PNH Thrombosis Thrombosis
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.
Chronic Kidney Disease Chronic Kidney Disease Common Symptoms of PNH Common Symptoms of PNH Thrombosis Thrombosis
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
Chronic Kidney Disease Chronic Kidney Disease Common Symptoms of PNH Common Symptoms of PNH Thrombosis Thrombosis
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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
ian
Un
its T
ran
sfu
sed
M
ed
ian
Un
its T
ran
sfu
sed
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
Sta
nd
ard
Eff
ect S
ize (
SE
S)
Sta
nd
ard
Eff
ect S
ize (
SE
S)
EORTC EORTC FunctioningFunctioning
EORTC EORTC SymptomsSymptoms
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bal
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11
1.21.2
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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
7.9 11.1
5.0
0
10
20
30
40
50
60
70
80
Overall (n=189)
Stage 1 – 2 (n=81)
Stage 3 - 5 (n=40)
Segment of PNH Population
Pro
po
rtio
n o
f P
atie
nts
(%
)
P<0.001 P=0.05 P<0.001
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
SOLIRIS® (eculizumab) [package insert]. Alexion Pharmaceuticals; 2009.
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
SOLIRIS® (eculizumab) [package insert]. Alexion Pharmaceuticals; 2009.
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
SOLIRIS® (eculizumab) [package insert]. Alexion Pharmaceuticals; 2009.
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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
SOLIRIS® (eculizumab) [package insert]. Alexion Pharmaceuticals; 2009.
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)