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L’INIBITORE IN EMOFILIA: QUALITÀ DELLAVITA, ASPETTI SOCIALI E CLINICI

Bari, 14 novembre 2015

Aula Magna “G. De Benedictis”

Policlinico di Bari

Massimo Morfini – Past President AICE

Le line guida AICE sull’inibitore

Italian guidelines for the diagnosis and treatment of patients with haemophilia and inhibitors.Gringeri A, Mannucci PM; Italian Association of Haemophilia Centres. Haemophilia. 2005 Nov;11(6):611-9.

Management of bleeding in inhibitor patientsHigh Responders

<5 BU/ml

>5 BU/ml

Severe bleeding or major surgery

Low Responders

Human FVIII/FIX

Severe bleeding or major surgery

Mild/moderate bleeding

actual

Inh titer

or major surgery

Immunoabsorption

+FVIII/FIX

or major surgeryMild/moderate bleeding

or minor surgery

PCCAPCC or

rFVIIa

Human FVIII/FIX rFVIIa or APCC APCC

or rFVIIa

Gringeri & Mannucci, AICE guidelines,

Haemophilia 2005

Principles of treatment and update of recommendation s for the management of haemophilia and congenital bleeding disorders in Ita ly.Rocino A, Coppola A, Franchini M, Castaman G, Santoro C, Zanon E, Santagostino E, Morfini M; Italian Association of Haemophilia Centres (AICE) Working Party.Blood Transfus. 2014 Oct;12(4):575-98.• L’approccio terapeutico al paziente con inibitore richiede notevoli competenze specialistiche

• Si raccomanda la presa in carico esclusivamente da parte di Centri emofilia

• L’obiettivo primario del trattamento è rappresentato è rappresentato dall’eradicazione

dell’inibitoredell’inibitore

• L’induzione della immunotolleranza con la somministrazione di FVIII ad alte dosi e per

lunghi periodi rappresenta l’unica modalità terapeutica in grado di arggiungere tale

obiettivo.

• I bambini con inibitore di recente insorgenza e high responder rappresentano I principali

candidate al trattamento di ITI

• Negli adulti con inibitori di vecchia data, l’opportunità di ricorrere a regimi di ITI deriva dal

riscontro di gravi e frequenti episodi emorragici.

Principles of treatment and update of recommendation s for the management of haemophilia and congenital bleeding disorders in Ita ly.Rocino A, Coppola A, Franchini M, Castaman G, Santoro C, Zanon E, Santagostino E, Morfini M; Italian Association of Haemophilia Centres (AICE) Working Party.Blood Transfus. 2014 Oct;12(4):575-98.

• Nei pazienti con inibitore ad alto titolo (>5 UB/ml) l’unica possibilità di trattamento degli

episodi emorragici acuti è data dall’uso di agenti bypassanti (aPCC o rFVIIa).

• L’efficacia emostatica degli agenti bypassanti è dimostrata in ampi studi clinici, anche se la

risposta emostatica è meno prevedibile e monitorabile rispetto alla terapia sostitutivarisposta emostatica è meno prevedibile e monitorabile rispetto alla terapia sostitutiva

• In casi clinici particolarmente gravi, I due agenti bypassanti sono stati impiegati in

sequenza con discrete successo.

• Oltre all’impiego on demand, esistono studi clinici controllati sull’impiego in profilassi di

entrambi gli agenti bypassanti .

80

100

120

140

Andamento dell'inibitore nel tempo

U.B. La storia naturale degli inibitori, una volta sviluppati si, non è chiara e ben descritta -Paisley S et al.,Haemophilia 2003,9,405-417

2 4 6 8 10 12 14

20

40

60

80

High Responder per-manente

High Responder+ITI

High Responder transito-rio

Low Responder

MESI

The figure shows tests for inhibitors (upper curve) and surgical synovectomy performed at Castelfranco Veneto

Haemophilia Centre, 1973–2010. The majority of the tests were performed during the period 1973–1990 when most of the

surgical synovectomy programme was developed. The curve shows two peaks, the first during the 70s when the

synovectomy programme was more intensive and the second during the mid-80s when patients undergoing synovectomy

were overlapped by patients regularly followed up for inhibitor. The last two decades represent the follow up of the

patients (right upper curve) and more recent years when surgical synovectomy was completely abandoned and substituted

by synoviorthesis (data not reported).

Tagariello et al. Journal of Hematology & Oncology 2013 6:63 doi:10.1186/1756-8722-6-63

Table 1Distribution of patients with and without inhibitor development, high and low responders, transient, slowly resolving and permanent, dependen t on the severity of the disease

Severe Moderate Mild TotalHigh responders

Low responders

OR

n = 434 n = 60 n = 30 n = 524 n = 79 n = 101 (*)Withoutinhibitor

266 50 28 344

With inhibitor

168 10 2 180inhibitor

168 10 2 180

Transient 64 (38%) 5 (50%) 1 (50%) 70 (39%) 8 (10%) 62 (61%) -

Slowly resolving

44 (26%) 2 (20%) 1 (50%) 47 (26%) 15 (19%) 32 (32%) 3.6

Permanent 60 (36%) 3 (30%) 0 63 (35%) 56 (71%) 7 (7%) 62

The condition of HR at the onset confers the highest risk of persistent inhibitor (56 out of 79, 71%) while only a minority of

the patients become persistent when the onset is as LR (7 out of 101, 7%).

(*)The OR represents the risk of having a permanent or slow resolving inhibitor for those being HR as compared to those

being LR.

Tagariello et al. Journal of Hematology & Oncology 2013 6:63 doi:10.1186/1756-8722-6-63

30

40

50

60

70

n/1

00

0 p

az.

an

ni

Hay et al. Blood 2011; 117: 6367

1 2 3 4 5

63,4 9,4 5,3 5,2 10,5

0

10

20

n/1

00

0 p

az.

an

ni

0-4,9 5-9 10-49 50-59 >59

Incidenza dell'inibitori per fascie di età in anni

UKHCDO 1990-2009

Clinical evaluation of joints : number of bleeds within the last 12 months (ESOS, Morfini et al., Haemophilia. 2007 Sep;13(5):606-12)

11,412,3

0,7*6,2

10,5

10,5

68

101214

Num

ber

of b

leed

s pe

r jo

int

Group A Group B Group C

11

1,9 1,85 2

0,8* 0,5*0,6*

0,7*

1,62,4

0,9

0246

Num

ber

of b

leed

s pe

r jo

int

Clinical evaluation of joints : pain (ESOS, Morfini et al., Haemophilia. 2007 Sep;13(5):606-12)

3,9

5,8

2,73

4

5

6

7

mea

n nu

mbe

r of

pai

n pe

r jo

int


12

0,65 0,55 0,40,8 0,9

1*

0,2*0,1*

0,25

2,7

0

1

2

3

mea

n nu

mbe

r of

pai

n pe

r jo

int

Inclusion Criteria – Inhibitor Patients�Age between 14 years and 35 years defined as sub-group A�Age between 36 years and 65 years defined as sub-group B

Inclusion Criteria – Non-Inhibitor PatientsAge between 14 years and 35 years

�defined as group C

Clinical evaluation of joints : Gilbert score (ESOS, Morfini et al., Haemophilia. 2007 Sep;13(5):606-12)

14,6

20,2

10

15

20

25

Gilb

ert s

core

per

join

t


13

4,12,8

2

4,93,65

1,5 2,02,2*

5,3

0

5

2,6




Radiological evaluation of joints (Pettersson'sclassification)(ESOS, Morfini et al., Haemophilia. 2007 Sep;13(5):606-12)

22,9

31,8

15

20

25

30

35

pette

rsso

n's

scor

e


14

3,9 3,7 3,85

6,2* 6,4*6,2*

2,7* 1,1* 1,9

8

0

5

10




•The NEW ENGLAND JOURNAL of MEDICINE

•ORIGINAL ARTICLE

•Anti-Inhibitor Coagulant Complex•Prophylaxis in Hemophilia with Inhibitors•Cindy Leissinger, Alessandro Gringeri, Bülent Antmen,

365;18 NOVEMBER 3, 2011

•Cindy Leissinger, Alessandro Gringeri, Bülent Antmen, Erik Berntorp, Chiara Biasoli, , Shannon Carpenter, Paolo Cortesi, Hyejin Jo, Kaan Kavakli, Riitta Lassila, Massimo Morfini, Claude Négrier, Angiola Rocino, Wolfgang Schramm, Margit Serban, Marusia Valentina Uscatescu, Jerzy Windyga, Bülent Zülfikar, and Lorenzo Mantovani

•1

Pro-FEIBA Study

N Engl J Med 2011; 365: 1684-92

Disegno dello studio Pro-FEIBA

Randomization

On- Demand On-DemandN=17

Wash-out

On- Demand

Prophylaxis Prophylaxis

6 mesi 3 mesi 6 mesi

N=17

Profilassi: APCC 85 U/Kg + 15% 3 giorni non consecutivi per settimanaOn-demand: APCC 85U/Kg + 15%

PROOF Risultati: Mediana ABR

3/17 (17.6%) pazientinon manifestavanoepisodi emorragici

Median ABR for all bleeds was 72.5% less in the prophylaxis arm as compared to the on-demand arm (P=0.0003)

n = 19 n = 17

Antunes SV et al. Haemophilia 2013; Aug 1. doi: 10.1111/hae.12246.

6

7

8

9

Ble

eds/

mon

th

Be fore prophylaxis During prophylaxis

Bleeds/month before and during prophylaxis with rFV IIa

Slide No. 21 • Massimo Morfini •

0

1

2

3

4

5

Cases

Ble

eds/

mon

th

A retrospective patient case collection

on prophylactic treatment with rFVIIaPRO-PACT case series

30

78,9

40

50

60

70

80

90

BLEU = N

ROSSO = %

30

8

21,1

0

10

20

30

sicurezza virale immunogen.

Quale è l'elemento più importante nella scelta del concentrato?

32

86,5

40

50

60

70

80

90

100

BLEU = N

ROSSO = %

5

32

0

13,5

00

10

20

30

Prima possibile Titolo inib.<5UB/ml solo se sintomatico

Quando inizi la ITI in un bambino emofilico che ha sviluppato l'inibitor?

ROSSO = %

30,3

69,7

40

50

60

70

80

BLEU = N

ROSSO = %

10

23

30,3

0

10

20

30

SI NO

Sei solito iniziare la ITI in un emofilico adulto con inibitore?

92,6

40

50

60

70

80

90

100

BLEU = N

ROSSO = %

25

0 20

7,4

0

10

20

30

Lo stesso verso cui si è

sviluppato l'inibitore

Un diverso concentrato rFVIII Un concentrato pdFVIII

Nel caso che iniziate una ITI per la prima volta in un PUP trattato con rFVIII, quale

concentrato usate?

48,6 48,6

30

40

50

60

BLEU = N

ROSSO = %

1

18 18

2,7

0

10

20

50U/kg/die alterni 100U/kg/die 200U/kg/die

Quale dosaggio usi nell ITI del bambino

ROSSO = %

82,9

40

50

60

70

80

90

BLEU = N

0

29

6

17,1

0

10

20

30

50U/kg/die alterni 100U/kg/die 200U/kg/die

Quale dosaggio usi nell ITI dell'adulto?

BLEU = N

ROSSO = %

25

32,4

67,6

30

40

50

60

70

80

BLEU = N

ROSSO = %

12

25

0

10

20

30

Fenotipo clinico grave In tutti i gravi, indipendentemente dal

fenotipo clinico

In quale situazione clinica ricorri alla profilassi nei bambini?

The NEW ENGLAND JOURNAL of MEDICINE

ORIGINAL ARTICLE

Factor VIII Products and InhibitorDevelopment in Severe Hemophilia A

Samantha C. Gouw, Johanna G. van der Bom, Rolf Ljung, Carmen Escuriola, Ana R. Cid, Ségolène Claeyssens-

2013 Jan 17;368(3):231-9

Rolf Ljung, Carmen Escuriola, Ana R. Cid, Ségolène Claeyssens-Donadel, Christel van Geet,

Gili Kenet, Anne Mäkipernaa, Angelo Claudio Molinari,Wolfgang Muntean, Rainer Kobelt, George Rivard,

Elena Santagostino, Angela Thomas, and H. Marijke van den Berg, for the PedNet and RODIN Study Group*

Intensity of factor VIII treatment and inhibitor de velopment in children with severe hemophilia A: the RODINstudy. Gouw SC1, et al. PedNet and Research of Determinants of INhibitor development (RODIN) Study Group. Blood. 2013 May 16;121(20):4046-55

adjusted hazard ratio [aHR] 2.0 for surgery and major bleedings; aHR for Prophylaxis 0.61-0.85

EMA starts risk-benefit review of second generation factor VIII

products (octocog alfa) Kogenate Bayer/Helixate NexGen

Source: European Medicines Agency

Date published: 11/03/2013 16:23A

dju

ste

d r

ela

tiv

e r

isk

(9

5%

CI)

1

2

0

3

The NEW ENGLAND JOURNAL of MEDICINE JANUARY 17, 2013

Factor VIII Products and Inhibitor Development in Seve re Hemophilia ASamantha C. Gouw et al. For the RODIN Study Group

N=486

INH= 31.7%

N=88

INH =33.1%ALL Products Types

N=574 INH 32.4%

Recombinant factor VIII products and inhibitor development in previously untreated

boys with severe hemophilia A.

Calvez T, Chambost H, Claeyssens-Donadel S, d'Oiron R, Goulet V, Guillet B, Héritier V,

Milien V, Rothschild C, Roussel-Robert V, Vinciguerra C, Goudemand J.

Blood. 2014 Sep 24. [Epub ahead of print]

HTCs n=33

Product A Product B Product C Product D Product E Product F All Products

Eds No/I Eds No/I Eds No/I Eds No/I Eds No/I Eds No/I Eds No/I

2074 48/10 331 11/4 1412 29/8 4749 122/56 4995 108/33 483 12/3 14044 303/1142074 48/10 331 11/4 1412 29/8 4749 122/56 4995 108/33 483 12/3 14044 303/114

In January 2013 the Research of Determinants of Inhibitor Development (RODIN) study group reported an

unexpectedly high risk of inhibitor development with a so-called second-generation full-length rFVIII (Product "D") in

previously untreated patients (PUPs) with severe hemophilia A (HA). A prospective cohort was established by French

public health authorities in 1994 to monitor hemophilia treatment safety. …….. After excluding 50 patients who also

participated in the RODIN study, the primary analysis focused on 303 severe HA boys first treated with a rFVIII product.

A clinically significant inhibitor was detected in 114 boys (37.6%). The inhibitor incidence was higher with Product D

versus the most widely used rFVIII product (adjusted-HR 1.55, 95%CI 0.97-2.49). …… No heterogeneity was observed

between RODIN and FranceCoag results. … Our results confirm the higher immunogenicity of Product D versus other

rFVIII products in PUPs with severe HA.

• BHK � Gal-α1,3-Gal

turoctocog alfa master slide deck 18 November, 2015Slide no

34

• BHK � Gal-α1,3-Gal

• CHO � Neu5Gc

(ac. Neuraminico)

Presentation title Date 35

Adapted from Hironaka et al J Biol Chem 1992; 267:8012-8020 and Valentino LA et al Haemophilia 2014;20 (suppl. 1):1-9.

Grazie per l’attenzione! Saluti da Firenze!

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