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PNH –izkušnje zdravljenja z ekulizumabom pri slovenskih bolnikih
PM
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Irena Preložnik Zupan
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PNH: Kronična, življenje ogrožajoča bolezen
Estimated prevalence is
15.9 /M in UK1
5 year mortality: ~ 35%2
Diagnosed at all
Ages – Median age
early 30s3
Quality of life (QoL)
diminished3,4
Progressive disease5
100
80
60
40
20
0
0 5 10 15 20 25
Years After Diagnosis
Pa
tie
nts
Su
rviv
ing
(%
)
The expected survival of an age- and sex-matched control group is shown for comparison2. In a patient population where ½ the patients have < 30% clone, 1 in 7 patients died by 5 years ( Peffault de Latour R et al. Blood 2008;112(8):3099-106)
Survival From the Time of
dg in 80 Patients With PNH2
Age- and sex-
matched controls
Patients with PNH
1. Hill A et al. Blood 2006;108: abstract 985. 2. Hillmen P et al. NEJM 1995;333:1253-58. 3. Socié G et al. Lancet 1996;348:573-7. 4. Hill A Br J Haematol
2007;137:181-92. 5. Lee JW et al. EHA 2010, abstract 506.
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CD55
Okvara pri PNH
Pridobljena somatska mutacija PIG A gena na X kromosomu prepreči vsem GPI vezanim proteinom vezavo na celično membrano
3
1. Johnson RJ et al. J Clin Pathol: Mol Pathol 2002;55:145-52. 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; pp 419-27.
CD59
GPI-vezalci
CD55
• Preprečuje nastanek in povečuje nestabilnost C3 konvertaze ter oslabi komplementno kaskado2
CD59
Tvori obrambno ovojnico ERI pred lizo komplementa1
GPI - Glycosylphosphatidylinositol; PIG A - phosphatidylinositol glycan anchor biosynthesis A
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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
Intact RBC
Free Hemoglobin
Complement
Activation
Reduced Red Cell Mass
Historically Viewed as a Hemolytic Anemia1-5
Anemia
1. Parker C et al. for the International PNH Interest Group. Blood 2005;106:3699-709. 2. Brodsky R Paroxysmal Nocturnal Hemoglobinuria. In: Hematology - Basic
Principles and Practices. 4th ed. R Hoffman et al. eds. Philadelphia, PA: Elsevier Churchill Livingstone; 2005; p. 419-27. 3. Rother RP et al. JAMA 2005;293:1653-62.
4.Socie G et al. Lancet 1996;348:573-7. 5. Hill A et al. Br J Haematol 2007;137:181-92.
RBC – Red blood cell
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Thrombosis
Fatigue
Renal Failure
Abdominal Pain
Dyspnea
Dysphagia
Hemoglobinuria
Erectile Dysfunction
Normal red blood cells
(RBCs) are protected
from complement attack
by a shield of terminal
complement inhibitors
Without this protective
complement inhibitor
shield, PNH red blood
cells are destroyed
Intact RBC
Complement
Activation
PNH je napredujoča bolezen s kronično hemolizo1,2
Significant
Impact on
Survival
Significant
Impact on
Morbidity
Free Hemoglobin
Anemia
Pulmonary Hypertension
1. Lee JW et al. EHA 2010, abstract 506. 2. Figure adapted from Rachidi S et al. Eur J Intern Med 2010;21:260-7.
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PNH – diagnoza je težavna
Delays in diagnosis range from 1 to more than 10 years1
Directly question patients for all potential symptoms
1. Hillmen P et al. N Engl J Med. 1995;333:1253-8. 2. Meyers G et al. Blood. 2007;110(11):Abstract 3683. 3. Hillmen P et al. Am. J. Hematol. 2010; 85: 553–559. 4. Nishimura J et al. Medicine. 2004;83(3):193-207. 5. International
PNH Interest Group. Blood. 2005;106(12):3699-3709. 6. Hill A et al. BJH. 2010; 149(3): 414-425.
Clinical Signs or Symptoms Incidence Rate (%)
Thrombosis 40%1
Dyspnea 66%2
Pulmonary Hypertension 47%6
Chronic Kidney Disease 64%3
Abdominal Pain 57%2
Anemia 88%4
Fatigue, impaired QOL 96%2
Hemoglobinuria (at presentation) 26%5
Dysphagia 41%2
Erectile Dysfunction 47%2
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Odkrivanje bolnikov z veliko verjetnostjo za PNH1-3
7
Unexplained
thrombosis
(venous or arterial)
Unexplained
cytopenias RA-MDS AA Hemoglobinuria
Coombs-negative
hemolytic anemia
Unexplained VTE/ATE Unexplained Cytopenias RA-MDS AA Hemoglobinuria Coombs-negative Hem A
1. Richards SJ et al. Cytometry B Clin Cytom 2009;76B:47-55. 2. Borowitz MJ et al. for the International Clinical Cytometry Society. Cytometry B Clin Cytom 2010; 78B: 211-30. 3. Parker C et al. for the International PNH Interest Group Blood
2005;106:3699-709.
Rule PNH in or out
using flow cytometry
and clinical assessment
AA – aplastic anemia; RA-MDS – Refractory anemia – myelodysplastic syndrome
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SOLIRIS® (ekulizumab) humanizirano prvo v razredu, protitelo1 proti - C5
Hinge
CH
3
CH
2
Human IgG4 Heavy Chain
Constant Regions 2 and 3
(Eliminates complement activation)
Complementarity Determining Regions
(murine origin)
Human Framework Regions
• No mutations
• Germline
Human IgG2 Heavy Chain
Constant Region 1 and Hinge
(Eliminates Fc receptor binding)
1. Rother R et al. Nat Biotech 2007;25:1256
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SOLIRIS® zavira zadnji del komplementa1
C3 C3a
C3b
C5
Pro
xim
al
Term
inal
1. Rother RP et al. Discovery and development of the complement inhibitor eculizumab for the treatment of paroxysmal nocturnal hemoglobinuria. Nature Biotech. 2007;25(11):1256-64. 2..SOLIRIS® SmPC: SOLIRIS® (eculizumab)
summary of product characteristics. Alexion Europe SAS 2007.
C5b-9 Cause of Hemolysis
in PNH
C5a
C5b
SOLIRIS®
• Proximal functions of complement remain
intact1
• Weak anaphylatoxin
• Immune complex clearance
• Microbial opsonization
• Terminal complement activity is blocked1
• SOLIRIS® binds with high affinity to C51,2
Complement Cascade1
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Shema doziranja1
In clinical trials all patients were vaccinated against Neisseria meningitidis2
Concomitant medications allowed:
– Steroids, immunosuppressant drugs, anti-clotting agents and hematinics2
SOLIRIS® should be administered via IV infusion within 25-45 minutes every 7 days during induction and every 14 days during maintenance1
SOLIRIS® dose adjustment to every 12 days may be necessary for some patients to maintain LDH reduction1
1. SOLIRIS® SmPC: SOLIRIS® (eculizumab) summary of product characteristics. Alexion Europe SAS 2007 2. Hillmen P et al. Effect of Eculizumab on Hemolysis and Transfusion Requirements in Patients with Paroxysmal Nocturnal
Hemoglobinuria N Engl J Med. 2004;350(6):552-9.
Pretreatment Induction Phase Maintenance Phase*
≥ 2 weeks before
induction:
Neisseria
meningitidis
vaccination
Week 1 2 3 4 5 6 7 8
9 and
every 2
weeks
thereafter
Soliris®
Dose
600
mg
600
mg
600
mg
600
mg
900
mg x
900
mg x
900
mg *Dose within ± 2 days
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86% zmanjšanje LDH: TRIUMPH in SHEPHERD1
P<0.001 at all measured time points.
1. Hillmen P et al. The Complement Inhibitor Eculizumab in Paroxysmal Nocturnal Hemoglobinuria. NEJM 2006; 355:1233-1243. 2. Brodsky RA et al. Multicenter phase 3 study of the complement inhibitor eculizumab for the treatment of
patients with paroxysmal nocturnal hemoglobinuria. Blood 2008; 111:1840-1847
TRIUMPH placebo patients switched to SOLIRIS® after week 262
All TRIUMPH patients entered the long-term extension study1
TRIUMPH – Placebo/Extension
TRIUMPH – SOLIRIS®/Extension
SHEPHERD – SOLIRIS®
Lacta
te D
eh
yd
rog
en
ase (
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 dose2
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73% zmanjšanje srednje vrednosti enot koncentriranih eritrocitov: TRIUMPH1
*P<0.001.
◘Transfusion data obtained during 12 months before treatment; values were normalized for a 6-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.
Patients not on SOLIRIS® (n=44)
SOLIRIS® (n=43)
*
* *
*
(n=87) (n=30) (n=35) (n=22)
0
2
4
6
8
10
12
14
16
Overall 4-14 15-25 >25
Pre-treatment Transfusion Requirement (RBC units)◘
Med
ian
Un
its T
ran
sfu
sed
18
• 51% of SOLIRIS patients achieved transfusion independence vs 0% of patients not on SOLIRIS1
• Patients with concomitant bone marrow dysfunction may continue to require minimal transfusions2
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92% zmanjšanje trombotičnih dogodkov2
PI: There were fewer thrombotic events with SOLIRIS® treatment than during the same period
of time prior to treatment. 1. SOLIRIS® SmPC: SOLIRIS® (eculizumab) summary of product characteristics. Alexion Europe SAS 2007 . 2.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
Soliris® reduced the rate of thrombosis by 94% in patients receiving antithrombotics2
The effect of anticoagulant withdrawal was not studied1
Events observed in both venous and arterial sites2
N=195
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Disabling Disabling
Prikaz primera – prva
28 let-ženska
Brez predhodnih bolezni
november 2000 (17 let) -Pediatrična klinika
pancitopenija
Dg: Aplastična anemija
Zdravljenje: konjski antitimocitni globulin (Atgam), kortikosteroidi,
ciklosporin
Prikaz primera
Januar 2004 – prvič v naši ambulanti
– L 4,0 x109/L; Hb 118 g/L; MCV 105 fl; Plt 93 x109/L
– LDH 6,99 µkat/L
– Fe 9,3; TIBC 64; feritin 177µg/L
– Kreat 71 µmol/L
– Pretočna citometrija: PNH + NG 10,3%
– Coombsovi testi neg
Prikaz primera
27 avgust 2004 – hepatitis B virus vakcinacija (3x)
– L 3,4 x109/L; Hb 118 g/L; MCV 105 fl; Tr 89 x109/L
– Pretočna citometrija: PNH + NG 10,3%
– September 21st 2004
• Pretočna citometrija: PNH + NG 26%
Prikaz primera
2005
– Ni znakov tromboze
– PNH+ NG – 25-37%
– LDH 10-20 µkat/L
Toda
– Ponovno pancitopenija (L 3,1, Hb 86; Plt 59– začela cyclosporin
v septembru 2005
– ERI transfuzije -prvič
Prikaz primera
2006
– blaga anemija (Hb 103-110 g/L)
-Th: železo, B12, folati
– Ni znakov tromboze
– PNH+ NG – 32%
– Ciklosporin prenehala v juniju
Klinični potek in zdravljenje
2008-2010
– ↑ večja pogostost zmernih hemolitičnih epizod
– ↑ odvisnost od transfuzij - 2-3 mesece
– Ni bilo znakov progresa v KM
– Allo PKMC? Nima sorodnega darovalca.
– PNH+ NG – 50-90% (nov 2010- 92%)
– LDH 50-70 µkat/L
– Th: warfarin, folna kislina, transfuzije
– Začeli smo pogajanja z zavarovalnico za ekulizumab
Klinični potek in zdravljenje
2011
Začetek zdravljenja z Ekulizumabom (7 junij 2011)
(standardna shema)
Meningococcal vaccination -14 dni prej
Dodatna th: warfarin, folna kislina
LDH vrednost pred in po zdravljenju z EKULIZUMABOM
LDH, µkat/L (2010, 2011)
0
10
20
30
40
50
60
70
80
90
nov.10
dec.10
jan.11
feb.11
mar.11
apr.11
maj.11
jun.11
jul.11
avg.11
sep.11
okt.11
nov.11
dec.11
jan.12
feb.12
EKULIZUMAB
Transfuzije (št enot)/ leto
Ekulizumab
Vrednost feritina pred in po zdravljenju z EKULIZUMABOM
Ferritin, µg/L(30-315) 2010-2011
Transferin saturation, % (14-52)
0
50
100
150
200
250
300
350
nov dec jan feb apr june july sep
Series1
Series2
Transf sat
Ferritin
Flow cytometry before and after Eculizumab
2.6.2011 23.9.2011
PRED PO
PNH klon
+
(Type II)
++ (Type III)
PNH klon
+
(Type II)
++
(Type III)
FLAER-
/CD15+ CD33
granulociti
93% 95,6%
ERI 18,5% 18,2 0,3 98,2% 40,5 57,7
0
2
4
6
8
10
12
14
avg.11 sep.11 okt.11 nov.11 dec.11 jan.12 feb.12 mar.12
LD
H
µ
kat/
L
Vrednosti LDH
EKULIZUMAB
Drugi bolnik
10
2
4 4 4
2 2
4
avg.11 sep.11 okt.11 nov.11 dec.11 jan.12 feb.12 mar.12
Št. enot konc. ERI po mesecih
Drugi bolnik
EKULIZUMAB
Zaključki
Hitro delovanje
Deloma zmanjšana potreba po transfuzijah
– 50-60% -neodvisni od transfuzij
– 35% potreba po transfuzijah se zmanjša
– 15% še vedno potrebujejo transfuzije
Razrešitev pomembnega simptoma(fatigue)
Dobro prenašanja
Ni pomembnih stranskih učinkov
Primeri indikacij za EKULIZUMAB
Bolnik 1 Bolnik 2 Bolnik 3
Spol/starost Moški/ 20 Moški/ 25 Ženska/ 31
Hb (preko 6 mes)/g/L 110-128 59-81 61-85
Retikulociti x109/L 140 230 70
NG x109/L 3.2 1.9 0.6
Trombociti x109/L 195 155 47
% GPI neg celic 21 38 10
LDH (IU/L) (n=120-270) 1550 3250 650
Bolečine v trebuhu-napad 1x/leto občasno Ne
Transfuzije nikoli 6enot/6 mes 10 enot/6m
Indikacija za
EKULIZUMAB
NE DA Verjetno NE
BJH, 2011, Luzatto L