L`INIBITORE IN EMOFILIA: QUALITÀ DELLA VITA, ASPETTI

L’INIBITORE IN EMOFILIA: QUALITÀ DELLA
VITA, 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 patients
High Responders
Low Responders
Human FVIII/FIX
actual
Inh titer
<5 BU/ml
>5 BU/ml
Severe bleeding
or major surgery
Human FVIII/FIX
Mild/moderate bleeding
or minor surgery
rFVIIa or APCC
Severe bleeding
or major surgery
APCC
or rFVIIa
APCC or
rFVIIa
PCC
Immunoabsorption
+FVIII/FIX
Gringeri & Mannucci, AICE guidelines,
Haemophilia 2005
Principles of treatment and update of recommendations for the management
of haemophilia and congenital bleeding disorders in Italy.
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’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 recommendations for the management
of haemophilia and congenital bleeding disorders in Italy.
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 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 .
Andamento dell'inibitore nel tempo
U.B.
140
La storia naturale degli inibitori, una volta sviluppatisi, non
è chiara e ben descritta-Paisley S et al.,Haemophilia 2003,9,405-417
120
100
80
High Responder permanente
High Responder+ITI
High Responder transitorio
Low Responder
60
40
20
2
4
6
8
MESI
10
12
14
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 1
Distribution of patients with and without inhibitor development, high and low responders,
transient, slowly resolving and permanent, dependent on the severity of the disease
Low
High
responder responder OR
Severe
Moderate Mild
Total
s
s
n = 434
n = 60
n = 30
n = 524
n = 79
n = 101
(*)
Without
266
50
28
344
inhibitor
With
168
10
2
180
inhibitor
Transient
64 (38%)
5 (50%)
1 (50%)
70 (39%)
8 (10%)
62 (61%)
Slowly
44 (26%)
2 (20%)
1 (50%)
47 (26%)
15 (19%)
32 (32%)
3.6
resolving
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
70
Hay et al. Blood 2011; 117: 6367
60
n/1000 paz.anni
50
40
30
20
10
0
1
2
3
4
5
63,4
9,4
5,3
5,2
10,5
0-4,9
5-9
10-49
50-59
Incidenza dell'inibitori per fascie di età in anni
UKHCDO 1990-2009
>59
Clinical evaluation of joints : number of bleeds within
the last 12 months (ESOS, Morfini et al., Haemophilia. 2007 Sep;13(5):606-12)
Number of bleeds per joint
Group A
14
12
10
8
6
4
2
0
Group B
Group C
12,3
10,5
11,4
10,5
6,2
0,7*
1,9
1,6
0,8*
2,4
1,85
0,5*
2
0,6*
0,9
11
Clinical evaluation of joints : pain
(ESOS, Morfini et al.,
Haemophilia. 2007 Sep;13(5):606-12)
Group A
Group B
Group C
mean number of pain per joint
7
5,8
6
5
3,9
4
3
2,7
2
1
0,65
0,9
0,8
0,55
0,1*
0,2*
0,4
1*
0,25
0
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 Patients
Age between 14 years and 35 years
defined as group C
12
Clinical evaluation of joints : Gilbert score
(ESOS,
Morfini et al., Haemophilia. 2007 Sep;13(5):606-12)
Group A
Group B
Group C
Gilbert score per joint
25
20,2
20
14,6
15
10
5
4,1
5,3
4,9
2,8
1,5
3,65
2,0
2
2,6
2,2*
0
Inclusion Criteria – Inhibitor Patients
Age between 14 years and 35 years defined as subgroup A
Age between 36 years and 65 years defined as sub-group
B
Inclusion Criteria – Non-Inhibitor Patients
Age between 14 years and 35 years
defined as group C
13
Radiological evaluation of joints (Pettersson's
classification)
(ESOS, Morfini et al., Haemophilia. 2007 Sep;13(5):606-12)
Group A
Group B
Group C
35
31,8
pettersson's score
30
25
22,9
20
15
10
5
8
6,2*
6,2*
6,4*
3,9
3,85
3,7
2,7*
1,1*
1,9
0
Inclusion Criteria – Inhibitor Patients
Age between 14 years and 35 years defined as subgroup A
Age between 36 years and 65 years defined as sub-group
B
Inclusion Criteria – Non-Inhibitor Patients
Age between 14 years and 35 years
defined as group C
14
•The NEW ENGLAND JOURNAL of MEDICINE
365;18 NOVEMBER 3, 2011
•ORIGINAL ARTICLE
•Anti-Inhibitor Coagulant Complex
•Prophylaxis in Hemophilia with Inhibitors
•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
Wash-out
N=17
On- Demand
On-Demand
Prophylaxis
Prophylaxis
Randomization
N=17
6 mesi
3 mesi
6 mesi
Profilassi: APCC 85 U/Kg + 15% 3 giorni non consecutivi per settimana
On-demand: APCC 85U/Kg + 15%
PROOF Risultati: Mediana ABR
3/17 (17.6%) pazienti
non manifestavano
episodi emorragici
n = 19
n = 17
Median ABR for all bleeds was 72.5% less in the prophylaxis arm as compared to
the on-demand arm (P=0.0003)
Antunes SV et al. Haemophilia 2013; Aug 1. doi: 10.1111/hae.12246.
Bleeds/month before and during prophylaxis with rFVIIa
Be fore prophylaxis
During prophylaxis
9
8
B l e e d s / m o n th
7
6
5
4
3
2
1
0
Cases
Slide No. 21 • Massimo Morfini •
PRO-PACT case series
A retrospective patient case collection
on prophylactic treatment with rFVIIa
90
78,9
80
70
BLEU = N
ROSSO = %
60
50
40
30
30
21,1
20
8
10
0
sicurezza virale
immunogen.
Quale è l'elemento più importante nella scelta del concentrato?
100
86,5
90
80
70
60
50
40
BLEU = N
ROSSO = %
32
30
20
10
13,5
5
0
0
Prima possibile
Titolo inib.<5UB/ml
0
solo se sintomatico
Quando inizi la ITI in un bambino emofilico che ha sviluppato l'inibitor?
80
69,7
70
60
BLEU = N
ROSSO = %
50
40
30,3
30
23
20
10
10
0
SI
NO
Sei solito iniziare la ITI in un emofilico adulto con inibitore?
100
92,6
90
80
BLEU = N
ROSSO = %
70
60
50
40
30
25
20
7,4
10
0
0
Lo stesso verso cui si è
sviluppato l'inibitore
0
Un diverso concentrato rFVIII
2
Un concentrato pdFVIII
Nel caso che iniziate una ITI per la prima volta in un PUP trattato con rFVIII, quale
concentrato usate?
60
48,6
50
48,6
40
30
BLEU = N
ROSSO = %
18
20
18
10
1
2,7
0
50U/kg/die alterni
100U/kg/die
Quale dosaggio usi nell ITI del bambino
200U/kg/die
90
82,9
80
70
60
50
40
BLEU = N
ROSSO = %
30
29
17,1
20
10
0
6
0
50U/kg/die alterni
100U/kg/die
Quale dosaggio usi nell ITI dell'adulto?
200U/kg/die
80
67,6
70
60
BLEU = N
ROSSO = %
50
40
32,4
30
25
20
12
10
0
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
2013 Jan 17;368(3):231-9
ORIGINAL ARTICLE
Factor VIII Products and Inhibitor
Development in Severe Hemophilia A
Samantha C. Gouw, Johanna G. van der Bom,
Rolf Ljung, Carmen Escuriola, Ana R. Cid, Ségolène ClaeyssensDonadel, 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 development 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
Adjusted relative risk (95% CI)
3
2
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 16:23
1
0
N=486
INH= 31.7%
N=88
INH =33.1%
ALL Products Types
N=574 INH 32.4%
The NEW ENGLAND JOURNAL of MEDICINE JANUARY 17, 2013
Factor VIII Products and Inhibitor Development in Severe Hemophilia A
Samantha C. Gouw et al. For the RODIN Study Group
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
303/114
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.
turoctocog alfa master slide deck
• BHK
18 November, 2015
Gal-α1,3-Gal
• CHO Neu5Gc
(ac. Neuraminico)
Slide no
34
Presentation title
Adapted from Hironaka et al J Biol Chem 1992; 267:8012-8020 and Valentino LA et al Haemophilia 2014;20 (suppl. 1):1-9.
Date
35
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