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Slide # 1
PNH: Complications and
Long-Term Issues
Carlos M. de Castro, MD
Duke University Center
July, 2011
AA&MDSIF Conference
PNH: Complications and
Long-Term Issues
What happens to PNH patients?
What are the long-term complications of PNH and can they be
prevented?
– Thrombosis (blood clots)
– Renal failure
– Pulmonary Hypertension
– Development of aplastic anemia, myelodysplastic syndrome, or AML
Long term complications of therapy
What are some special situations for PNH patients?
– Pregnancy
– Surgery
– Vaccinations
What is PNH and what is the long
term outlook?
Slide # 2
What is PNH?
A rare and unusual acquired hematologic disorder characterized by
– Intravascular hemolysis (breaking of red cells)
– Bone marrow failure (low blood counts)
– Thrombosis (blood clots)
There is a great deal of heterogeneity in the clinical presentation and course in patients with PNH
Signs & Symptoms of PNH
Episodic dark urine (hematuria)
Anemia
Fatigue
Abdominal pain
Esophageal spasms (heartburn)
Impotence
Low blood counts (cytopenias)
Blood clots
Paroxysmal Nocturnal Hemoglobinuria:
Long term outcomes
100
80
60
40
20
0
0 5 10 15 20 25
Years After Diagnosis
Pa
tie
nts
Su
rviv
ing
(%
)
Actuarial Survival From the Time of
Diagnosis in 80 Patients With PNH (1)
Age- and sex-
matched controls
Patients with PNH
(1) Hillmen P et al. NEJM 1995; 333:1253-8;
Slide # 3
Paroxysmal Nocturnal Hemoglobinuria:
Long term outcomes
Kaplan-Meier Survival Curve of patients with PNH from Duke University (n=173). Average survival was 19.4 years.
Nishimura et al Medicine 83: 193-207, 2004.
PNH – What do patients die from?
Cause of death Duke Japan
Thrombosis 16 (42%) 3 (8%)
Abd site 8 1
Other site 7 0
Arterial 3 2
Hemorrhage 4 (10.5%) 9 (24%)
Severe Infection 14 (36.5%) 14 (36.8%)
MDS/AML 3 (8%) 6 (16%)
Renal failure 3 (8%) 7 (18%)
Other malignancy 2 (5%) 2 (5%)
Unknown 2 (5%) 0
Nishimura et al Medicine 83: 193-207, 2004.
PNH - Thrombosis
Slide # 4
Thrombosis in PNH
• Recognized early as a problem
• Occurs in ~40% of European-descended populations
– less in East Asian populations
• Is the worst prognostic indicator
• Is the leading cause of death
• Once a thrombosis occurs, no clear evidence that any
anticoagulant will prevent further clots
Relationship of PNH Clone Size and
Thromboembolic Events
PNH Granulocyte Clone Size (%)
% T
E
Lee JW et al. Hematologica. 2010. 95 (s2): Abstract #505.
South Korean National Registry
Incidence of symptoms or complications of PNH
Correlation with clone size
International PNH Registry data – 524 patients
Urbano-Ispizua A, et al. EHA meeting 2010. Haematologica 95(s2): Abstract 1022
Slide # 5
Mesenteric / splenic
18%
Hepatic / portal
16%
PE
7%
Cerebral
6%
Superficial
4%
Arterial / CVA
14%
Arterial / MI
2% DVT: leg
18%
DVT: other
15%
Thrombosis in PNH
CVA, cerebrovascular accident; DVT, deep vein thrombosis; MI, myocardial infarction
Peculiarities of thrombosis in PNH
• Incidence may be much higher
– small, undetectable thromboses
– D-dimer data
• Once established, tends to recur and continue
– inexorable course of hepatic vein thrombosis
• Incidence lower in East Asian populations
– includes Mexican population
• Role of surgery and pregnancy in initiating thrombosis
Possible causes of thrombosis in PNH
Platelet activation by complement
Role for nitric oxide on platelets and endothelium
ADP release by hemolyzed RBC‟s
Reduced expression of urokinase plasminogen activator
receptor
Increased circulating microparticles from lysed RBC‟s
Slide # 6
How to manage thrombosis in PNH
Role of coumadin prophylaxis to prevent clots remains
controversial.
Patients presenting with an acute clot should undergo
treatment with a clot-busting drug – TPA, urokinase
Patients should then be on anticoagulant therapy
(coumadin, lovenox, etc).
Duration - Probably for their lifetime.
Patients with a thrombotic event should start eculizumab.
Whether one can stop anticoagulation once eculizumab is
started has not been well studied.
A bone marrow transplant can be considered.16
BMT is associated with significant morbidity and mortality
In a recent retrospective study in France examining PNH
patients1
– 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 transplant3,4
Historical Management of
PNH Bone Marrow Transplant
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.
16 patients treated with RIC
– 14 patients (87.1%) survive after median of nearly
6 years without evidence of PNH, (transfusion
independent and off anti-coagulation)
– Acute GVHD 50%, chronic GVHD 68.8%
Allogeneic BM Transplantation With RIC
RIC = reduced intensity conditioning.
Pantin J, et al. ASH 2010. Abstract 3505.
Slide # 7
What is the impact of eculizumab
on thrombosis?
• Equalized patient-years
• 92% fewer thrombotic events post eculizumab vs pre eculizumab
39
3
0
10
20
30
40
50
Pre-eculizumab
treatment
Eculizumab
treatment
P=0.0001
Th
rom
bo
tic e
ve
nts
(n
)
Hillmen P et al. Blood 2007; 110: 4123-4128
Effect of eculizumab on thromboembolic
event rate: concomitant antithrombotics
• Pre-eculizumab event rate elevated despite use of antithrombotics
• 91% reduction in event rate with eculizumab
10.61
0.62
0
2
4
6
8
10
12
Pre-eculizumab
treatment
Eculizumab treatment
P<0.0000000001
Th
rom
bo
sis
eve
nt ra
te
(pe
r 1
00
pa
tie
nt-
ye
ars
)
(n=103)
Hillmen P et al. Blood 2007; 110: 4123-4128
Will Eculizumab affect survival by lowering
the incidence of thrombosis?
We don‟t know but we certainly hope so.
Data from recent meetings is encouraging.
Please enroll in the International PNH registry.
Slide # 8
PNH – Renal Failure
Renal Damage in PNH: Background
Renal failure has been identified as
the cause of death in approximately
8 – 18% of PNH patients1,2
68% have a significant reduction in
creatinine clearance3
64% of patients with PNH have
chronic kidney disease2
Historically underappreciated in PNH
1. Nishimura JI, et al. Medicine. 2004;83:193-207. 2. Hillmen P et al. Am. J. Hematol. 2010; 85:553–559. 3. Rother RP, et al. JAMA. 2005;293:1653-1662
Renal Damage in PNH: Background
Chronic haemolysis and cell-free plasma haemoglobin lead to
several serious clinical sequelae in PNH1–3
Evidence of renal damage is highly prevalent in patients with
PNH5–9
May be acute renal failure, which is frequently reversible4
Associated with haemolysis and/or microvascular thrombosis2,4
Renal damage in PNH may be due to repetitive exposure of
tissue to cell-free haemoglobin9
1. Parker C et al. Blood 2005; 106:3699-709.; 2. Brodsky RA. Hematology: Basic Principles and Practice. Churchill Livingstone; 2005:419-27.; 3. Rother RP et
al. JAMA 2005;293:1653-62.; 4. Clark DA et al. Blood 1981;57:83-9.; 5. Hill A et al. Presented at the 48th ASH Annual Meeting, Dec 9, 2006.; 6. Mulopulos GP
et al. Am J Roentgenol 1986;146:51-2.; 7. Rimola J et al. Br J Radiol 2004;77:953-6.; 8. Tanaka YO et al. J Comput Assist Tomogr 1993;17:749-53; 9.
Nishimura J et al. Medicine 2004;83:193-207.
Slide # 9
Evidence of renal sequelae by MRI in PNH
MRI studies show virtually all PNH patients with
low-intensity signal in renal cortex, including PNH patients
with:
– low levels of hemolysis
– aplastic anemia
– MDS
– no hemoglobinuria
– smaller PNH clones
MRI findings are typical of intravascular hemolysis and are
not typically found with extravascular hemolysis
Mathieu D et al. Blood 1995; 85: 3283-3288;
Rimola J et al. Br J Radiol 2004; 77: 953-956;
Hakim F et al. Blood 1996; 88: 4725-4726;
Suzukawa K et al. Intern Med 1993; 32: 686-690
MDS, myelodysplastic syndrome; MRI, magnetic resonance imaging
Autopsy and functional findings in PNH
8–18% of mortality in PNH
Autopsy or biopsy findings with:
– heavy hemosiderin accumulation in the proximal tubules
– hemoglobin tubular casts
– signs of chronic interstitial nephritis and fibrosis
Functional tubular defects are commonly found with:
– impaired ability to concentrate urine
• medullary microinfarction or inability of tubular epithelium to sustain
maximum osmotic gradient
– renal tubular acidosis
– decreased reabsorption of phosphate
– aminoaciduria
Nishimura J et al. Medicine 2004; 83: 193-207; Mulopulos GP et al. AJR Am J Radiol 1986; 146: 51-52; Nguyen JS et al. N Engl J Med 2006; 355: 1048-1052;
Clark DA et al. Blood 1981; 57: 83-89; Riley AL et al. Am J Med 1977; 62: 125-129; Zachée P et al. Clin Nephrol 1993; 39: 28-31;
Nath K et al. Kidney Int 2001; 59: 106-117
Normal
tissue
on the right
Interstitial
scarring
on the left
Clark DA et al. Blood 1981; 57: 83-89
Renal pathology in PNH
Micrograph of a renal biopsy from a PNH patient,
indicative of vascular damage
Slide # 10
0 5 10 30 4020
100
90
80
70
60
50
40
30
20
0
10
Time to Major Clinical Kidney Event
Prior to Eculizumab Treatment
Pro
ba
bilit
y (
%)
of
Ma
inta
inin
g
No
rma
l K
idn
ey
Fu
nc
tio
n
Time Since PNH Diagnosis (years)
n 195 103 60 21 4
Kaplan-Meier probability of patients progressing to an MCK event.
Hillmen P et al. Am. J. Hematol. 2010; 85:553–559.
Chronic Kidney Disease Staging Identifies
Both Function and Damage
StageGFR
(ml/minute/1.73 m2)
Objective Measure of Kidney Damage
Description Action*
1 ≥ 90Evidence of proteinuria
Kidney damage with normal GFR
Diagnose and treat
Treat comorbid conditions;
Slow progression;
CVD risk reduction
2 60-89Evidence of proteinuria
Kidney damage with mild decreased GFR
Estimate progression
3 30-59No additional evidence necessary
Moderately decreased GFR
Evaluate and treat complications
4 15-29No additional evidence necessary
Severely decreased GFR
Prep for kidney replacement therapy; Predialysis
5 < 15 (or dialysis)No additional evidence necessary
Kidney FailureReplacement (if uraemiapresent); Dialysis
Chronic Kidney Disease (CKD) Stages 1-5
*Includes actions from preceding stages.Levey AS et al. Ann Intern Med. 2003;129:137-147.
How to manage renal complications
Stay well hydrated
Control other conditions which may affect the kidneys
(hypertension, diabetes)
Avoid drugs which may cause renal problems (eg. Non-
steroidal medications such as ibuprofen)
Monitor kidney function at least once per year.
Block hemolysis
30
Slide # 11
64% of Patients Exhibit stage 1-5 CKD
Among the 22 patients with minimal (0-1) transfusion history, 59% exhibited CKD
Hillmen et al. Long term effect of the complement inhibitor eculizumab on kidney function in patients with paroxysmal nocturnal Hemoglobinuria. Am J Hematol 85:553-559, 2010.
Kidney Function
Stage 3 - 5 CKD(n=40)
Stage 1 - 2 CKD(n=84)
No CKD (n=69)
20.5%
43.1%
35.4%
0
10
20
30
40
50
Pro
po
rtio
n o
f P
ati
en
ts (
%)
Renal Function with Eculizumab in Different
Baseline Populations – 12 Months
Hillmen et al. Long term effect of the complement inhibitor eculizumab on kidney function in patients with paroxysmal nocturnal
Hemoglobinuria. Am J Hematol 85:553-559, 2010.
58.1
23.4
76.9
35.2
71.4
20.5
6.7 5.22.6
0
10
20
30
40
50
60
70
80
90
Segment of PNH Population
Pro
po
rtio
n o
f P
ati
en
ts (
%)
P<0.001 P=0.02 P<0.001
No Change Improvement Worsening
Overall
(n=179)
Stage 1 – 2
(n=77)
Stage 3 - 5
(n=39)
Eculizumab Treatment Led to Rapid and
Sustained Improvement in Renal Function
6 Months Eculizumab
12 Months Eculizumab
18 Months Eculizumab
6X More Likely to Improve* (P<0.001)
14X More Likely to Improve* (P<0.001)
25X More Likely to Improve* (P<0.001)
CKD Stage 1-2
Duration of eculizumab treatment increased likelihood of renal function improvement
*When comparing likelihood of improvement versus deterioration in renal function
Hillmen P et al. Am. J. Hematol. 2010; 85:553–559.
Slide # 12
Renal Function in PNH: Conclusions
Changes in renal function are common in PNH (65% of PNH
patients; 6.6-fold more common than in the general population)1
Severe CKD is observed in 21% of PNH patients and appears to
be under-diagnosed in this patient population
21% of patients with CKD prior to eculizumab were no longer
classified with CKD during eculizumab treatment
Administration of eculizumab to patients with more mild baseline
kidney disease was associated with the greatest likelihood of
improvement and prevention of worsening in kidney function
Long-term eculizumab treatment resulted in a significant
improvement and prevention of worsening in CKD at all initial
stages of renal disease
Pulmonary Hypertension in PNH
Hemolysis-associated pulmonary
hypertension
An important complication in hereditary hemolytic anemias
such as thalassemia, stomatocytosis, and spherocytosis
A common morbidity in sickle cell disease
Linked to intravascular hemolysis, leading to the term
„hemolysis-associated pulmonary hypertension‟ (PHT)
An independent risk factor for death in sickle cell disease
Gladwin MT et al. N Engl J Med 2004; 350: 886-895
Slide # 13
Brain natriuretic peptide
Elevated levels of BNP:
– released from stretched right heart chambers
– reflect cardiac chamber volume and pressure overload
– indicate increased PHT and right ventricular dysfunction
In patients with hemolytic syndrome, NT-proBNP >160 pg/mL:1
– is a highly positive predictive value for diagnosis of PHT
– is an independent predictor of mortality
TRIUMPH study: 47% of PNH patients had baseline levels of
NT-proBNP >160 pg/mL2
Suggestive of PHT
1Machado RF et al. JAMA 2006; 296: 310-318;2Hillmen P et al. N Engl J Med 2006; 355: 1233-1243 BNP, brain natriuretic peptide
Change in BNP during eculizumab
treatment
PHT with NT-proBNP ≥160 pg/mL1
Eculizumab vs placebo (P<0.001)
50% reduction
14% increase
Baseline BaselineWeek 26 Week 26
52.5
39.4
26.3
43.8
0
10
20
30
40
50
60
Placebo EculizumabTreatment group: TRIUMPH (n=73)
Pro
po
rtio
n o
f p
ati
en
ts
wit
h e
vid
en
ce
of
PH
T
Hill A et al. British J Haematol 149: 414-425, 2010
Pulmonary Hypertension - Summary
PHT is a serious and life-threatening complication of hemolytic
disorders
PHT and PNH symptoms are common in patients with hemolytic PNH
PHT may be under-diagnosed clinically in patients with PNH
Hemoglobinemia, NO consumption, and disruption of vasomotor tone
contribute to PHT in patients with PNH
Eculizumab treatment significantly reduces PHT, as measured by BNP,
and PHT-related symptoms in patients with PNH
Eculizumab treatment dramatically reduces hemolysis,
hemoglobinemia, and NO consumption in patients with PNH
Slide # 14
PNH – development of AA or MDS
Sir John V. Dacie (1911 - )
Lewis SM, Dacie JV. The aplastic anemia-paroxysmal nocturnalhemoglobinuria syndrome. Br J Haematol 13:236, 1967.
William Dameshek 1900-1962Dameshek W. Riddle:What do aplastic anemia, paroxysmal nocturnal hemoglobinuria
(PNH), and “hypoplastic” leukemia have in common? Blood 30:251, 1967
Slide # 15
PNH – Aplastic anemia and MDS/leukemia
A fairly sizable proportion of patients with aplastic anemia
may later develop PNH (20-40%).
Patients with PNH may often have bone marrow failure and
some will develop aplastic anemia.
Patients with PNH may develop myelodysplastic syndrome
and or acute myelogenous leukemia (<5%).
Patients with MDS may have a small PNH clone present
and these patients may respond better to
immunosuppressive therapy with ATG and/or cyclosporine.
Models of pathogenesis
Normal Aplastic PNH MDSMarrow Anemia_________________________
ImmuneAssault
ImmuneAssault
PNH (hemolysis)
PNH (hypoplasia)
Stromal cellDysregulation,ImmuneAssault
Treatment of AA or MDS/AML
Aplastic anemia when severe enough is treated with either
immunosuppressive therapy (ATG, cyclosporine) or with a
stem cell transplant.
Myelodysplastic syndrome has multiple different therapies
depending on the severity.
AML is treated with chemotherapy and/or stem cell
transplant.
45
Slide # 16
Complications of PNH Therapy
Complications of PNH Therapy
Eculizumab
– Neisseria infection
– Cost and convenience
– Extravascular hemolysis
ATG/Cyclosporine
– Hospitalization
– Anaphylactic reactions
– Serum sickness
– Immunosuppression / Infection
Bone marrow transplantation
– Allogeneic bone marrow transplant
– Prolonged hospitalization
– Up to 44% mortality at 2 yrs with HLA-matched
sibling donor
– Acute GVHD in 34%; chronic GVHD in 33%
– GVHD-free survival in 14% of patients
Serious Adverse Events:
Clinical Trial Experience
Meningococcal infections are the most important adverse
events that may be experienced by patients receiving
Eculizumab
In PNH clinical studies, 2 patients experienced
meningococcal sepsis
– Both patients had received a meningococcal vaccine
In clinical studies among patients without PNH,
meningococcal meningitis occurred
in 1 unvaccinated patient
Slide # 17
Special Situations in PNH
Vaccinations
– May activate complement
– Role for Eculizumab
Surgery
– May activate complement
– May lead to thrombosis
– Role for Eculizumab
Pregnancy
PNH and Pregnancy
PNH is a known hypercoagulable state
Pregnancy is a hypercoagulable state
High estrogen levels
Compression of abdominal and pelvic veins by the enlarging uterus
PNH and Pregnancy
23 women: 19 with PNH, 4 with AA/PNH
38 pregnancies
11 miscarriages
Pregnancy: 6 hemolysis, 6 hemorrhage Labor: 5 hemolysis, 3 hemorrhage
1 thrombosis, 1 sepsis
No maternal deaths
Uncomplicated in one-third of pregnanciesDe Gramond et al., Lancet 1987;1:868
Slide # 18
Women with PNHEffects on Pregnancy
Thrombosis: 5 women
2 with previous clots (Budd-Chiari syndrome, pulmonary embolus)
1 during pregnancy (phlebitis)
2 post-partum (hepatic, intracranial)
Hemolysis: 24 pregnancies (73%)
20 required PRBC transfusions
Thrombocytopenia: 9 cases
Obstetrical complications: 4 women
Hypertension, pre-eclampsia, eclampsia
Ray et al., Haemostasis 2000;30:103-117
Women with PNHEffects on Infants
Perinatal outcomes of 33 pregnancies
45% of the babies were pre-term
Average birthweight 2800g
Three infant deaths
Two had hemolytic disease of the newborn, not related to PNH
No infant thrombosis
Ray et al., Haemostasis 2000;30:103-117
PNH and PregnancySummary
Pregnancy is possible for women with PNH, with or without aplastic anemia, but is potentially hazardous for mother and infant.
Pregnancy leads to complications in up to 50% of women: worse cytopenia, transfusion dependency, thrombosis, and the need for anticoagulation or immunosuppressants
Pregnancy for women with PNH is risky, and should be planned carefully with an experienced hematologist and high-risk OB.
There is emerging data on the use of Eculizumab in pregnancy.
Slide # 19
Special situations for patients with PNH
Surgery– Singer A et al. Successful Liver Transplantation for Budd-Chiari Syndrome
in a Patient with Paroxysmal Nocturnal Hemoglobinuria Treated with the
Anti-Complement Antibody Eculizumab. Liver Transplant 15: 540-543, 2009.
Pregnancy– Kelly R, et al. The management of pregnancy in paroxysmal nocturnal
haemoglobinuria on long term eculizumab. Br J Haematol 149: 446-450,
2010.
– Danilov AV, et al. Managing a pregnant patient with paroxysmal nocturnal
hemoglobinuria in the era of eculizumab. Leukemia Research 34: 566-571,
2010.
Clinical Impact of Extravascular Haemolysis
Consequences
Increased LDH
Anemia
Fatigue?
Complement-mediated Intravascular Haemolysis
PNH RBC Survival
No Eculizumab Treatment
Eculizumab Treatment
PNH RBC
C3b Deposition, Possible Extravascular
Haemolysis
1. Hill, A et al. Haematologica. 2010; 95:567-573. 2. Risitano, AM. Blood. 2009;113:4094-4100. 3. Hillmen P et al. N Engl J Med. 1995;333:1253-1258.
Consequences
Increased LDH
Anemia
Hemoglobinuria
Nitrous Oxide Squelching
Fatigue
Does Eculizumab improve survival?
57
Slide # 20
De Latour RP et al., Blood, 2008;112:3099-3106.
Mortality Rates in PNH:
Data from French Patients
n 454 211 120 58 22 11 2 1
1
8
6
4
2
0
0 5 10 25 30 4015 20 35
Time after diagnosis (years)
O/N* 10-year Survival Rate (SE)
96/454 0.75 (0.03)
Su
rviv
al
Uncontrolled
Complement
Activation
Increased
Mortality
• TE
Renal
Gastrointestinal
Pulmonary
Cardiac
Hepatic
End Organ DamageHaemolysis
Complications
Associated
With Elevated
Haemolysis
(LDH)
Poor Outcomes
What is the Impact of Eculizumab on
Survival?
Long-term Treatment With Eculizumab in PNH:
Sustained Efficacy and Improved Survival
79 consecutive patients with PNH,
between May 2002 and July 2010
Mortality and disease symptoms were
evaluated
Kelly RJ et al. Blood in press
Slide # 21
Patient Characteristics
Presenting Features Number (%)
Male 40 (51%)
Age at diagnosis (median) 37 years (12-79)
Documented history of AA 24 (30%)*
Haemoglobinuria 50 (63%)
Abdominal pain 24 (30%)
Dysphagia 9 (11%)
Thrombosis 4 (5%)
Anaemia 70 (95%)†
*1 patient had MDS; †HB at presentation not available in 5 cases.Kelly RJ et al. Blood. In press.
Patient Characteristics
At Start of Eculizumab Median (range)
Age 46 years (14-84)
LDH level (normal range up to 430IU/L) 2872 (587-10300)
Neutrophils 2.2x109/L (0.6-11.9)
Platelets 149x109/L (11-507)
Reticulocytes (absolute) 171x109/L (57-415)
PNH granulocyte clone 96.4% (41.8-100)
Type II erythrocyte clone 3.8% ( 0-77.4)
Type III erythrocyte clone 25.0% (2.4-79.6)
Concurrent Treatment at Start of Eculizumab
Anticoagulation 46 (58%)
Ciclosporin 14 (18%)
Androgens 2 (3%)
Kelly RJ et al. Blood. In press.
Thrombotic Events
Patients (n) 79
Pre-treatment
Thrombotic events (n) 34
Proportion occurring on anticoagulation (%) 47
Patient years (n) 608
Thrombotic event rate
(n per 100 patient years)
5.60
Eculizumab Treatment
Thrombotic events (n) 2
Patient years (n) 260
Thrombotic event rate
(n per 100 patient years)
0.8(P<0.001)
Kelly RJ et al. Blood. In press.
Slide # 22
Thrombosis Data
2 thromboses while on eculizumab
– 71yo female, CVA prior to starting eculizumab – retinal
vein thrombosis , Tx- warfarin and eculizumab
– 65yo male thrombosis in AV fistula, Tx- aspirin and
eculizumab
Kelly RJ et al. Blood. In press.
Eculizumab Has a Major Impact on Survival in PNH
• 96% (76/79) patient survival
• There was no difference in mortality between patients on eculizumab
and the normal population (P=0.46)
Survival is comparable to age and gender-matched control population out to 8 years
Cu
mu
lati
ve
su
rviv
ing
(%
)
Time (years)
100
80
60
40
20
0
0 1 2 6 7 94 5 83
n = 79
Age- and sex-matched normal population
Eculizumab treated
Kelly RJ et al. Blood. In press.
Mortality in Patients on Eculizumab
3 Patients Died in the 8 Year Study Period
1. 55 year old man died from metastatic caecal carcinoma
which was diagnosed prior to eculizumab treatment
2. 76 year old woman died from pneumonia following a long
history of recurrent bronchopneumonia prior to starting
eculizumab
3. 79 year old man with a preceding history of ischaemic
heart disease died from congestive cardiac failure
Kelly RJ et al. Blood. In press.
Slide # 23
Improved Overall Survival in Patients
Treated With Eculizumab
Time (years)
Cu
mu
lati
ve S
urv
ivin
g (
%)
1 2 3 4 5 6 7 8 9
20
40
60
80
100
0
Kelly RJ et al. Blood. In press.
On Eculizumab, n=79
Pre-eculizumab, n=30
Overall survival was 97.6% (95%CI 93.7-99.1) at 3 years and was maintained
through 5.5 years of ongoing eculizumab treatment (N=195)
Patient Survival in the Eculizumab Study Population
Brodsky R et al. Blood. 2010;116(21) Abstract #4237.
69
The End – Thank you