Transcript Hemophilia A and B: Disease Difference

Hemophilia A and B:
Disease Differences and the
Use of Prophylactic Therapy
Anna Chalmers, MD
Rush University Medical Center, Chicago, Illinois
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)
© 2014 Direct One Communications, Inc. All rights reserved.
1
Similarities and Differences

Hemophilia A and B are X-linked, recessive
disorders caused by a deficiency or absence of
coagulation factors VIII (FVIII) and IX (FIX),
respectively.

They are clinically indistinguishable.

Not until 1952 was hemophilia B recognized as a
separate disease entity.

Hemophilia A and B have different causal mutations;
as a result, 35% of patients with hemophilia B have
severe disease, compared with 45% of patients with
hemophilia A.
Soucie JM et al. Blood. 2000;96:437
© 2014 Direct One Communications, Inc. All rights reserved.
2
Similarities and Differences

Hemophilia A and B have different pharmacokinetics.

The half-life of FIX if 18 hours, compared with 11
hours for FVIII.

As a result, post-infusion levels of FIX are sustained
longer than FVIII levels, thereby reducing the risk of
recurrent bleeding.

This difference in pharmacokinetics may explain why
patients with hemophilia B need joint arthroplasty at
one third the rate of those with hemophilia A.

Nevertheless, the treatment approach to hemophilia
A and B is similar.
Collins PW et al. Haemophilia. 2011;17:2; Björkman S. Haemophilia. 2003;9:101; Tagariello G et al. Blood.
2009;114:779
© 2014 Direct One Communications, Inc. All rights reserved.
3
Evolution of Current Treatment

Multiple factor replacements are available in the
United States to treat hemophilia B.

Prophylaxis with factor infusions two to three times
a week is the standard of care for children with
hemophilia B.

In March 2014, a new recombinant FIX product
(Alprolix) was approved that may be infused as
infrequently as once a week or every 10 days.
Shapiro A. Treatment update on hemophilia B. NHF 2013; Iorio A et al. Cochrane Database Syst Rev.
2011;(9):CD003429
© 2014 Direct One Communications, Inc. All rights reserved.
4
When to Start Prophylactic Therapy

Starting prophylaxis at an early age is important for
both hemophilia A and B, as it can lessen the risk of
degenerative joint disease.

The exact age to start is debated.

There are multiple treatment approaches:
Astermark J et al. Br J Haematol. 1999;105:1109; Donadel-Claeyssens S. Haemophilia. 2006;12:124
© 2014 Direct One Communications, Inc. All rights reserved.
5
When to Start Prophylactic Therapy
The approach to
primary prophylaxis
of hemophilia B used
at Malmö Hemophilia
Center in Sweden
Berntorp E. Prophylaxis for hemophilia B: best practices. NHF 2013
© 2014 Direct One Communications, Inc. All rights reserved.
6
Optimal Dosing

The optimal dosing strategy for long-term
prophylaxis is hotly debated.

Various prophylactic treatment strategies are used
throughout the world:
Berntorp E, Shapiro AD. Lancet. 2012;379:1447
© 2014 Direct One Communications, Inc. All rights reserved.
7
Optimal Dosing

A retrospective analysis of Dutch intermediate
dosing versus Swedish high-dosing found minimal
added benefit, with a large increase in cost. More
study is needed to compare these two options.

There is interest in the feasibility of low-dose
regimens, especially in resource-poor settings. In
China, using low-dose prophylaxis (10 IU/kg of
FVIII twice weekly for hemophilia A or 20 IU/kg of
FIX once weekly for hemophilia B) reduced the
number of bleeding episodes and improved joint
function over a 12-week period; however, patients
still experienced some joint bleeds on these doses.
Fischer K et al. Blood. 2013;122:1129; Wu R et al. Haemophilia. 2011;17:70
© 2014 Direct One Communications, Inc. All rights reserved.
8
Continue Prophylaxis Indefinitely?

Prophylaxis has dramatically improved the quality of
life and reduced the risk of arthropathy in children
with hemophilia; however, it is unknown if it should
be continued into adulthood.

At one hemophilia treatment center in the United
States, two thirds of the children and one half of the
adults with hemophilia B are on prophylaxis.

Early retrospective data have not shown a significant
difference in arthropathy scores when on-demand
and prophylactic treatment are compared in adults.

Prospective, randomized clinical trials are needed.
Koerper M. Burden of illness and quality of life in hemophilia B: HUGS VB study. NHF 2013; van Dijk K et al.
Br J Haematol. 2005;130:107
© 2014 Direct One Communications, Inc. All rights reserved.
9
Challenges in Implementing Prophylaxis

Cost of regular replacement factor infusions.

Poor adherence: patients with hemophilia B
receiving standard factor replacement products
require prophylaxis two to three times a week. Only
60% of hemophilia patients report infusing three
fourths or more of the recommended factor.

Missed doses: reasons include the complexity and
time commitment of treatment.

Prophylaxis also eliminates symptoms, paradoxically
decreasing adherence. Patients who have little
understanding of the importance of prophylactic
treatment are less likely to adhere to it.
Hacker MR et al. Haemophilia. 2001;7:392; De Moerloose P et al. Haemophilia. 2008;14:931;
Tang L et al. Haemophilia. 2013;19:27
© 2014 Direct One Communications, Inc. All rights reserved.
10
Improving Adherence

Patients who are treated at dedicated hemophilia
centers adhere better to their prophylcatic
replacement factor regimen than those who are
treated at home or an outpatient clinic.

Healthcare providers can improve patient adherence
to prophylactic therapy by:
» Maintaining a good relationship with their patients
» Reinforcing their patients’ positive belief in the importance
of prophylactic treatment
» Expanding their patients’ access to continuing health
education about hemophilia and its treatment
Hacker MR et al. Haemophilia. 2001;7:392; De Moerloose P et al. Haemophilia. 2008;14:931;
Tang L et al. Haemophilia. 2013;19:27; Schrijvers LH et al. Haemophilia. 2013;19:355
© 2014 Direct One Communications, Inc. All rights reserved.
11
Therapies on the Horizon

New replacement factors with longer half-lives may:
» Reduce the cost and inconvenience of frequent infusions
» Improve adherence to prophylactic therapy by allowing
significantly longer intervals between infusions
» Decrease complications related to frequent venous access

Gene therapy has the potential to cure hemophilia B,
as a small increase in factor level can drastically
improve bleeding rates.
» Six patients with severe hemophilia B were treated with a
virus vector that expressed factor IX; all of the patients had
a decrease in their need for factor replacement, with four
patients stopping prophylaxis completely.
Nathwani AC et al. N Engl J Med. 2011;365:2357
© 2014 Direct One Communications, Inc. All rights reserved.
12