L’INIBITORE IN EMOFILIA: QUALITÀ DELLA VITA, ASPETTI ... · L’INIBITORE IN EMOFILIA: QUALITÀ...
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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
Group A Group B Group C
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
Group A Group B Group C
13
4,12,8
2
4,93,65
1,5 2,02,2*
5,3
0
5
2,6
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
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
Group A Group B Group C
14
3,9 3,7 3,85
6,2* 6,4*6,2*
2,7* 1,1* 1,9
8
0
5
10
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
•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.
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