PNH –izkušnje zdravljenja z ekulizumabom pri slovenskih bolnikih

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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