Transcript Document

Prophylaxis in hemophilia
Peyman Eshghi
Prof. of Pediatric Hematology &Oncology
Pediatric Congenital Hematologic Disorders Research Center
Mofid Children Hospital
S.B.M.U
Shiraz-3-93
Main topics
• Definitions and types of prophylaxis
• Cost-effectiveness ; Availablity & Affordability
• Early prophylaxis & Toleration to inhibitor development
• Protocols:
• When to start; Dosage & Intervals ; When to stop;
• Adverse events & barriers in the prophylaxis
• Prophylaxis is the treatment by intravenous injection of factor
concentrate to prevent anticipated bleeding and should be the goal
of therapy to preserve normal musculoskeletal function. (Level 2)
• In patients with repeated bleeding, particularly into target joints,
short-term prophylaxis for 4– 8 weeks can be used to interrupt the
bleeding cycle. This may be combined with intensive physiotherapy or
synoviorthesis. (Level 3)
• Prophylactic replacement of clotting factor has been shown to be
useful even when factor levels are not maintained above 1 IU/ dL at
all times
WFH Guidelines for management of hemophilia, 2013
WFH Guidelines for management of hemophilia, 2013
Main topics
• Definitions and types of prophylaxis
• Cost-effectiveness ; Availablity & Affordability
• Early prophylaxis & Toleration to inhibitor development
• Protocols:
• When to start; Dosage & Intervals ; When to stop;
• Adverse events & barriers in the prophylaxis
Individual PK curve - FVIII Levels over Time
single infusion of 50 + 5 IU/kg bodyweight FVIII at time zero
F V III L e v e l (% )
100
80
Goal of
prophylaxis:
60
keep FVIII levels
>1% all the time
40
20
0
0
6
12 18 24 30 36 42 48
Time (hours)
Administration and dosing schedules
• There are two prophylaxis protocols currently in use for which there are
long-term data:
The Malmo¨ protocol:
o 25–40 IU kg1 per dose administered three times a week for those with hemophilia A,
and twice a week for those with hemophilia B.
The Utrecht protocol:
o 15–30 IU kg1 per dose administered three times a week for those with hemophilia
A, and twice a week for those with hemophilia B.
• Prophylaxis is best given in the morning to cover periods of activity.
• The protocol should be individualized as much as possible based on age,
venous access, bleeding phenotype, activity, and availability of clotting
factor concentrates.
WFH Guidelines for management of hemophilia, 2013
Antonio Coppola et al., Blood transfuse 2008; 6 (supp2)
ON-DEMAND VS. PROPHYLACTIC THERAPY
OUTCOME AT DIFFERENT DOSES
France
(on demand)
Dose adjustment
Numbers
Age at study analysis
Age at start of hometreatment
Age at start of prophylaxis
Annual number of Joint
bleeds
Pettersson score
Orthopaedic joint score
Clotting consumption
(IU kg-¹ year-¹)
Netherlands
Sweden
(Intermediate- (High dose
dose
prophylaxis)
prophylaxis)
clinical
preinfusion
factor level
116
23
21
21
19
16-22
8.9
NA
9.1
4.6
NA
2.6
16.3
18.8
7.7
1634
5.3
6.0
2.0
1828
3
6.5
2.4
3713
Haemophilia 2003; 9 (Suppl.1): 27-31
intermediate dose prophylaxis would be equally or even
less costly after two decades.
Individualizing the regimen
• Pharmacokinetic considerations: 3-fold variation in
clearnce and half life of factors
• Clinical outcome
• Other factors on coaguability of patients
Canadian tailored prophylaxis
Feldman et al. JTH 2006;4:1228-36
• Starting at 1 to 2 years old
• Tailored (escalating-dose) prophylaxis (EscDose):
 Low-dose prophylaxis regimen (step 1): Children begin prophylaxis with 50
FVIII units/kg, once a week [40%*]
Medium-dose prophylaxis (step 2) : The dose is escalated to 30 FVIII units/kg,
twice a week [44%*]
Equivalent of Standard prophylaxis (step 3) :This Dose is further escalated to
25 FVIII units/kg, on alternate days [16%*]
• The dose escalation criteria :
 developing Three bleeds into any one joint in a 3-month period OR
 Four clinically significant soft tissue or joint-bleeds while on
prophylaxis.
• Need to CVA : 40% vs 90% in JOS (joint outcome study with SP)
• 191 severe/moderate HA children with arthropathy from 15 centers
were enrolled to undergo :
an 8-week on-demand treatment: ‘optimal-dose’ therapy: 20 IU kg1 for the
first infusion and 10 IU kg1 once or twice a day until recovery
followed by
6 to 12-week low dose secondary prophylaxis:10 IU kg1 twice a week
• significantly decreased bleeding (78.8% haemarthrosis and 68.9%
severe bleedings) and improved daily activities with no increase in
factor consumption
• 12-week low dose secondary
prophylaxis-study period (for
haemophilia A, factor VIII
concentrate 10 IU kg)1 twice
weekly; for haemophilia B, factor
IX concentrate 20 IU kg)1 weekly
THE FIRST STEP IN PRIMARY PROPHYLAXIS , IN ALGERIA.
Berkouk. X Int hemophilia forum-Dubai-2013
• 14 Hemophilia A patients
primary Low dose prophylaxis =
15 IU / kg 2x/week FVIII.
• Started at the age of 3 years
• mean consumption of CFC:
• 1751 IU / kg / patient / year (LDP)
• 1611 IU / kg / patient / year (OD)
hemarthrosis
Target joint
PAGE-431
When to start?
Astermark,Haemohilia2003,9,(suppl.1),32-37
When should it be stopped, if at all?
• some data suggest that a proportion of young adults can do
well off prophylaxis
Fischer K, Van Der Bom JG, Prejs R et al.Discontinuation of prophylactic therapy ins evere haemophilia:
incidence and effects onoutcome. Haemophilia 2001; 7: 544–50.
1-Cost-benefit issue
2-scarcity of factor concentrates worldwide
3-mature joints may not vulnerable to bleed as growing joints
Rooendaal et al.J of Rheumatol 200;27;1740-4
4-adults are less active and more cautious
• In the adults with arthropathy : flexible prophylaxis with
lower doses and longer intervals vs on-demand therapy?
Main topics
• Definitions and types of prophylaxis
• Cost-effectiveness ; Availablity & Affordability
• Early prophylaxis & Toleration to inhibitor development
• Protocols:
• When to start; Dosage & Intervals ; When to stop; etc
• Adverse events & barriers in the prophylaxis
Inhibitors develop at an early age
• Typically, inhibitors develop in
early childhood within 10–20
exposure days to FVIII or FIX1
• •Rarely, treated adults can
develop inhibitors (<3%)
Günter Auerswald ;Prof.-Hess-Kinderklinik ;Klinikum Bremen-Mitte
Factors influencing inhibitors
• Patient genetics :
•
•
•
•
•
Type of mutation
MHC class I/II genotype
Race
FHx
Polymorphic genes of cytokines
• Patient environment :
• Intensive FVIII exposure, -immunologic challenge –immunisation; –infection; –
surgery; –major bleeding events -age of first infusion -immune system challenges;peak treatment moment(<or>3-5days)
• Treatmen :
• Type of factor
• Therapeutic regimen
• Continuous infusion
EMEA/CHMP/BPWP/123835/2006. Report on expert meeting on FVIII products and inhibitor development. Feb 28-Mar 2, 2006
AstermarkJ. Haemophilia 2006;12:52–60
Different influence of factors
CTLA4-318
TNFα A2
Continuous infusion
IL10 134
CANAL-study: treatment on demand
• Longer treatment / higher dose increase the risk of inhibitor
development
Günter Auerswald ;Prof.-Hess-Kinderklinik ;Klinikum Bremen-Mitte
Danger model
Antigen-Presenting Cells
(APCs) are activated by
endogenous danger signals
from distressed or injured
cells (e.g. exposure to
pathogens, toxins,
mechanical damage):
E.g. if we give FVIII at the
time that something else is
causing damage (surgery, …),
the immune system will
associate that new molecule
with the (unassociated)
damage and respond to it.
Matzinger P. Expert,Rev.Clin.Immunol.2012; 8(4),
311-317; 3Mathinger P. Science 2001; 296,301
Günter Auerswald ;Prof.-Hess-Kinderklinik ;Klinikum Bremen-Mitte
Antibody response
Tolerance
Danger signals is everything that brings the immune system into an alarm position
Günter Auerswald ;Prof.-Hess-Kinderklinik ;Klinikum Bremen-Mitte
Inhibitor Development is caused by a Complex Interaction
between Genetic and Environmental Factors
While inherited genetic risk factors cannot be changed, it is thought that
on a given genetic background, defined by the type of F8 gene mutations
and polymorphisms of immune response genes, the environmental
factors may allow to move a “high risk” patient to a “low risk” patient by
choosing treatment regimens less prone to inhibitor development, such
as early prophylaxis in the absence of hemorrhage
Oldenburg J. Genetic basis for inhibitor development. In: Rodriguez-Merchan et al (eds). Current and Future Issues
in Hemophilia Care. 1st ed. Wiley-Blackwell; Oxford, 2011
WHAT SHOULD WE DO FOR PUP?
 LESS INTENSIVE & LESS FREQUENT FACTOR EXPOSURE
 NO BLEEDING DANGER SIGNAL
 AS POSSIBLE AS LATE EXPOSURE
Treatment scheme for PUPs receiving the new
prophylaxis regimen Treatments
Comparison of standard prophylaxis with a new regimen
RODIN
(Research Of Determinants of INhibitor
Development among pups with haemophilia) register)
Gouw SC, van der Bom JG, Ljung R et al. Factor VIII products and inhibitor development
in severe hemophilia A. N Engl J Med 2013; 368: 231–9.
• The RODIN study supports the view
that starting prophylaxis at an early
age with a minimum number of on
demand exposure days can reduce
inhibitor risk
• Prophylaxis was started too late
(after median of 15 on demand
EDs (IQR 7-25) and at a median age
of 16.7 months (IQR 12.4-24.4) .
• When started earlier after 0 EDs
only 12% developed an inhibitor
Main topics
• Definitions and types of prophylaxis
• Cost-effectiveness ; Availablity & Affordability
• Early prophylaxis & Toleration to inhibitor development
• Protocols:
• When to start; Dosage & Intervals ; When to stop; etc
• Adverse events & barriers in the prophylaxis
Adverse events in the prophylaxis:
• Transmission of pathogens
• Inhibitor development : early treatment(especially < 6 months
age) with FVIII may be associated with an increased risk of
Inhibitor development
• Allergic reactions : mainly with intermediate purity concentrate
• Immunologic abnormality
• Catheter related complications (infection, pneumothorax,
thrombosis…)
• Sports-related injuries
Centeral venous line?
R.LJUNG , Haemophilia(2003),9,suppl.,88-93
Textbook of Haemophilia 2011,pp-128-129
• Most of the HTCs.(7/19 of centers in Europe) don`t use it for their patients at all
• Main indications :
• HOME THERAPY
• ITI
• LONG TERM PROPHYLAXIS
• Infection is the most important complications(#0.2-1.6/1000days )especially in
inhibitor patients.
• In the best of hands, a patient without inhibitors who has a Port - A - Cath and is
on regular prophylaxis will have catheter - related infection at most
• Non-inhibitor:one every 5 – 10 years
• Inhibitor: one infection per 1 – 2 years of use
• Catheter related thrombosis:
• in most instances “ clinically silent, ”
• related to the site of the catheter (jugular or subclavianvein), the type of concentrate used,
or some genetic thrombophilicfactor
• Some centers have successfully used arteriovenous fistulae in children as an
alternative to a central venous line
Prophylaxis in Inhibitor Patients: Definitions
Primary (Early) prophylaxis* (long-term):
Starts during ITI or after ITI failure
Aims: (1) to prevent target joint development
(2) to avoid haemorrhages altogether
Secondary prophylaxis (intermittent or long-term)
 During ITI preventing breakthrough bleeds
 Perisurgical coverage
 Risk behavior, ICH risk, severe phenotype
 proregressive target joint
Aims: (1) to stop progression of joint disease
(2) to prevent life threatening haemorrhages
Escuriola,-Ettingshausen personal communication Budapest symposium 2008
• We recommend to do synoverthesis ASAP if Target Joint developed:it
should not be postponed after secondary prophylaxis in Inhibitor
cases
• Intra-articular injections (e.g, steroids, hylan )may relieve persistent
inflammation prior to a synovectomy
• a prospective, randomized, crossover study on 34
patients
• Dosage : 85 U/kg ± 15% TIW
• Results:
• 62% reduction in all bleeding episodes (P<0.001),
• 61% reduction in hemarthroses (P<0.001),
• 72%reduction in target-joint bleeding
rFVIIa prophylaxis dosage:
90 mcg/kg/day
Case discussion
case1
• 6 month old sever HA
• FH of HA with inhibitor
• He has not have any
joint bleeding yet
• He comes with a large
hematoma on buttock
What do you do for him
30U/kg FVIII daily until recovery
20-25 U/kg FVIII once and
clinically follow him
nothing
case1
• He improved
How do you mange him then?
A.
25 u/kg once weekly
B.
10-15 u/kg 1-2 times weekly (LD P.)
C.
20 u/kg 2-3 times per week (intermediate
dose P.)
D.
30-40 u/kg 3 times per week (high dose P.)
E.
50 u/kg once weekly (escalated dose
prophylaxis)
F.
Wait till first Joint bleed then :A/B/C/D/E
case1
• He was on regimen A
for 2 months
• Then after he has had
one episode of
hemarthrosis in his
right knee and left
ankle and left elbow
How do you mange him then?
A. 50 u/kg once weekly (2nd
escalated dose prophylaxis)
B. 25 u/kg 2 times weekly
C. 25 u/kg 3 times weekly
D. 30-40 u/kg 3 times per week
(2nd high dose P.)
E. 10-15 u/kg 2 times weekly
(2nd LD P.)
case2
• 3 years old sever HA
• He has already received
just on demand regimen
• He had 3 times
spontaneous Joint
bleeding in R ankle in
last 3 months ,which
improved completely
and now he has no sign
and symptom
How do you mange him then?
A. 25 u/kg 3 times weekly for 8
weeks
B. Synoverthesis
C. Continuous secondary
prophylaxis with :
A. 50 u/kg once weekly (escalated
dose prophylaxis)
B. Intermediate dose P.(15-30u/kg
2-3 times per week)
C. LD P. (10-15u/kg2 times per
week)
D. A & B
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