Transcript Meeting the Challenges of Managing Hemophilia

Meeting the Challenges of
Managing Hemophilia:
Prophylactic vs Episodic Therapy
Duc Q. Tran, MD
Winship Cancer Institute, Emory University, Atlanta, Georgia
A REPORT FROM THE 65TH ANNUAL MEETING OF THE NATIONAL HEMOPHILIA FOUNDATION (NHF 2013)
AND THE 55TH ANNUAL MEETING OF THE AMERICAN SOCIETY OF HEMATOLOGY (ASH 2013)
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Disease Characteristics

Hemophilia is an X-linked recessive bleeding disorder
caused by a deficiency of:
»
»

Hemophilia A: coagulation factor VIII
Hemophilia B: coagulation factor IX
Severity depends on coagulation factor activity levels:
» Mild disease: greater than 5 IU/dL but less than 40 IU/dL
» Moderate disease: between 1 and 5 IU/dL
» Severe disease: less than 1 IU/dL

Prevalence:
»
Hemophilia A: 1 in 5,000 male live births
» Hemophilia B: 1 in 30,000 male live births
Tuddenham EGD, Cooper DN. The Molecular Genetics of Haemostasis and Its Inherited Disorders; 1994
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Disease Characteristics

The most common morbidity of patients with severe
hemophilia A or B is spontaneous joint bleeding
(hemarthrosis), which primarily affects the ankles,
knees, and elbows.

Patients also are at risk for spontaneous soft-tissue,
gastrointestinal, and central nervous system (CNS)
bleeding.

Recurrent hemarthroses can lead to debilitating joint
disease (hemophilic arthropathy).

Treatment revolves around coagulation factor
replacement
Srivastava A et al. Hemophilia. 2013;19: e1
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Prophylaxis in Children
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Prophylaxis in Children

Current treatment goal is to prevent bleeds to allow
patients to have more active and fuller lifestyles.

Prophylactic factor replacement therapy was first
pioneered in Sweden in 1958, when patients with
moderate hemophilia were found to be less likely to
have chronic debilitating joint disease than those
with severe hemophilia.

The Joint Outcome Study in the United States and
the Evaluation Study on Prophylaxis: a Randomized
Italian Trial (ESPRIT), which compared prophylactic
therapy with episodic treatment, showed definitive
benefits with early prophylaxis.
Nillson IM et al. J Intern Med. 1992;232:25
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Prophylaxis in Children
Both the Joint Outcome Study and ESPRIT evaluated
the use of prophylactic factor replacement in young
boys who had either no or few joint bleeds.
Manco-Johnson MJ et al. N Engl J Med. 2007;357:535; Gringeri A et al. J Thromb Haemost. 2011;9:700
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Prophylaxis in Children:
Joint Outcome Study Results
Bleeding was significantly less with prophylactic
therapy compared to episodic treatment, even as the
children grew older and became more active.
Manco-Johnson MJ et al. N Engl J Med. 2007;357:535
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Prophylaxis in Children:
Joint Outcome Study Results
Final evaluation of 56 patients at 6 years old by MRI
showed that 93% of patients on the prophylactic
treatment arm did not have joint damage, compared to
55% of patients on the episodic treatment arm.
Manco-Johnson MJ et al. N Engl J Med. 2007;357:535
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Prophylaxis in Children:
ESPRIT Results
Fewer bleeding episodes with less radiographic
evidence of arthropathy were observed among patients
on the prophylactic treatment arm, compared with
those on the episodic treatment arm.
Gringeri A et al. J Thromb Haemost. 2011;9:700
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Prophylaxis in Children:
Joint Outcome Study and ESPRIT Data

Both the Joint Outcome Study and ESPRIT showed
significantly more use of coagulation replacement
factor on the prophylactic treatment arm than on the
episodic treatment arm.

In addition to greater cost due to higher factor
consumption, complications related to the placement
of indwelling catheters to maintain the prescribed
prophylactic regimen were more frequent on the
prophylactic therapy arm in both studies.
Manco-Johnson MJ et al. N Engl J Med. 2007;357:535; Gringeri A et al. J Thromb Haemost. 2011;9:700
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Prophylaxis in Children:
Canadian Tailored Prophylaxis Study

Altogether, 25 boys began primary prophylaxis with
50 IU/kg of recombinant factor VIII (rFVIII) once
weekly, followed by stepwise increases to 30 IU/kg
twice weekly and then 25 IU/kg every other day,
depending on the frequency of bleeding episodes.

After 5 years, 10 of the 25 children were receiving
weekly infusions, 8 were being treated twice weekly,
and 7 were being treated every other day.

At the end of the study, all of the children had
normal joints by physical examination and minimal
radiographic changes.
Feldman BM et al. J Thromb Haemost. 2006;4:1228
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Prophylaxis in Children:
Canadian Tailored Prophylaxis Study

Only 10 of the 25 children (40%) required indwelling
IV catheters, compared with 29 of the 32 children
(91%) who were on the prophylactic treatment arm
of the Joint Outcome Study.

All of the children in the Canadian study had followup MRI examinations at age 9 years, and about 50%
of them showed evidence of changes in target joints.

This approach resulted in a cost reduction of about
20%–25% over the first 5 years, as compared with
the cost of a standard high-dose prophylactic
regimen over the same 5-year period.
Feldman BM et al. J Thromb Haemost. 2006;4:1228
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Prophylaxis in Children:
Netherlands Intermediate-Dose Study

In the Netherlands, children who started prophylaxis
at the onset of joint bleeding with intermediate doses
(15–25 IU/kg given 2–3 times/wk) of factor VIII
used less than 0.5 units/patient per year.

Outcomes were good but somewhat inferior to highdose prophylaxis, with some increase in bleeding and
greater clinical evidence of arthropathy.
Fischer et al. Haemophilia. 2002;8:753
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Prophylaxis in Adults
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Prophylaxis in Adults

About one third of patients on primary prophylaxis
choose to switch to episodic treatment as young
adults. An analysis of a self-reported cohort of
Danish and Dutch men with severe hemophilia A
compared outcomes of those who continued on
prophylaxis with those of men who switched to
episodic treatment (median follow-up, 3.6 years).

Although men who chose to switch to episodic
treatment experienced more joint bleeding, the
incidence was still less than that reported in other
cohorts of adults with severe hemophilia who
received episodic treatment their entire lives.
Makris M. Blood Transfus. 2012;10:165; van Dijk et al. Br J Haematol. 2005;130:107
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Prophylaxis in Adults
Three recent studies in adults evaluated the efficacy of
prophylaxis versus episodic treatment:

Those on episodic treatment who had a history of
very significant joint bleeding experienced no
bleeding episodes once switched to prophylaxis.

Annualized bleeding rates were reduced by 99% in a
second study after switching to prophylaxis, with
improvements in pain and physical function.

The third study (SPINART) showed a 93% decrease
in bleeding rate and less severe bleeding episodes in
patients on prophylaxis versus episodic therapy.
Collins P et al. J Thromb Haemost. 2010;8:83; Valentino LA et al. J Thromb Haemost. 2012;10:359;
Manco-Johnson MJ et al. J Thromb Haemost. 2013;11:1119.
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Prophylaxis in Adults

Based on pediatric evidence and the results of
pharmacokinetic studies, many adult patients with
hemophilia A can probably achieve bleeding control
with less than the standard 20–40 IU/kg rFVIII
three times per week, since the 48-hour trough levels
with this prophylactic dosing regimen are 3–6 IU/dL
in recent studies.

Individualizing dosing strategies will optimize the
costs of factor replacement to obtain the best
outcomes for these patients.
Collins P et al. J Thromb Haemost. 2010;8:83; Valentino LA et al. J Thromb Haemost. 2012;10:359
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Alloimmune Inhibitory Antibodies
and Current Management Options
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Alloimmune Inhibitory Antibodies

Alloimmune inhibitory antibodies (inhibitors) are
serious complications of treatment with factor VIII
concentrates and develop in about 25%–30% of
patients with severe hemophilia A after a median of
14–16 days of treatment.

The most significant risk factor are F8 gene mutations,
especially those with large multiexon gene deletions.

Black patients are more susceptible than white patients.

Other risk factors include early intensive exposure to
factors, polymorphisms in immune regulatory genes,
and association with specific HLA class II alleles.
Gouw SC et al. Blood. 2012;119:2922; Miller CH et al. Haemophilia. 2012;18:375; Gouw SC et al. Blood.
2013;121:4046; Gouw SC at al. J Thromb Haemost. 2007;5:1383; Astermark J et al. Haemophilia. 2010;16:747
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Alloimmune Inhibitory Antibodies

Prophylactic therapy may afford some protection
from inhibitor formation.

The prospective Research of Determinants of
Inhibitor Development (RODIN) study among 574
previously untreated patients with haemophilia:
» Found no immunogenic difference among patients treated
with plasma-derived coagulation factor products and those
treated with recombinant factors.
» A subgroup analysis suggested a second-generation fulllength recombinant factor might have a slight increase
relative risk for inhibitor formation, but there were no
definitive conclusions.
Gouw SC et al. Blood. 2012;119:2922; Miller CH et al. Haemophilia. 2012;18:375; Gouw SC et al. Blood.
2013;121:4046; Gouw SC at al. J Thromb Haemost. 2007;5:1383; Astermark J et al. Haemophilia. 2010;16:747
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Current Management Options

Eradicating inhibitors utilizing immune tolerance
induction (ITI) works in about 60%–80% of patients.

Median time to tolerance is about 9–12 months.

The International ITI Study randomized good-risk
patients to 50 or 200 IU/kg of rFVIII 3 times/wk:
» No difference between low- and high-dose regimen in time to
tolerance induction or the rate of tolerance induction.
» Time to negative inhibitor titer and time to normal recovery
were slower in the low-dose arm.
» Trial stopped early due to significantly more bleeds in the
low-dose arm and futility, since the enrollment was not
robust enough to determine equivalence between the arms.
Hay CR, DiMechele DM. Blood. 2012;119:1335
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Current Management Options

Patients who cannot have their inhibitor eradicated
and have a high inhibitor titer (> 5 BU/mL) are
treated with bypassing agents:
» Activated prothrombin complex concentrate (FEIBA)
» Recombinant factor VIIa

Prophylactic treatment with either bypassing agent
resulted in improved bleeding control when
compared with episodic treatment.
Konkle BA et al. J Thromb Haemost. 2007;5:1904; Leissinger C et al. N Engl J Med. 2011;365:1684
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