Haematologica 2000;85:supplement to no. 10 - Supplements ...

Haematologica 2000; 85(suppl. to n.10)
p. 83-85
Clinical and Organizational Aspects
Related to Immunotolerance Protocols
Immune tolerance induction: treatment duration analysis and
economic considerations
L.M. ALEDORT,* B. KRONER,° G. MARIANI^
*Department of Medicine, Mount Sinai Medical School, NY, NY, USA; °Research Triangle Institute, Rockville
MD, USA; ^Hematology, University of Palermo Medical School, Italy
Since the introduction of the concept of
immune tolerance induction (ITI) for the
eradication of inhibitors in hemophilic
patients, 1 there has been growing interest in its
application. Many regimens have been used
with varying results. Retrospective international
2 as well as U.S. registries 3 have been compiled.
Although there are differences, both concluded
that we do not as yet have enough data
to predict successful outcome consistently, and
that the procedure is very expensive. There are
no data in the literature as of yet, other than
theoretical modeling 4 which, in addition,
addresses the last benefit or health outcomes
of patients with inhibitors compared to those
without, and the costs of immune tolerance.
A recent letter 5 only evaluated the use of the
product for seven young patients undergoing
ITI, and only achieving true success using 7x10 6
units of recombinant factor VIII. In comparison,
4.7x10 6 units of the same material treated all
bleeding episodes and surgical intervention for
73 previously untreated patients (PUPs) for five
years. It is becoming clearer therefore, especially
in our more health-care-cost-conscious environment,
that we need to be able to predict successful
outcome for our patients. This is particularly
true as costs of factor are not the sole
costs. Many children require venous access
devices. These require professional support,
hospitalization, and are fraught with complications.
All of these have a cost associated with
them.
In the International Immune Tolerance Registry,
there were a substantial number of cases
(n=128) in which patients achieved success by
a definition now accepted by treaters. The
inhibitor titer has to disappear, the recovery and
half-life normalize, and when challenged, there
is no anamnesis.
Figure 1 demonstrates that for those patients
who achieved a loss of their inhibitor and developed
normal kinetics, 85% did so in two years,
but 60% became tolerant in one year. There is,
Correspondence: L.M. Aledort, The Mount Sinai Medical Center, New
York, NY 10029, USA. E-mail: louis.aledort@mssm.edu
hence, a marked degree of heterogeneity concerning
the precocity of the response which we
must analyze in order to identify prognostic factors
associated with early success.
Reviewing the data of these patients, they fell
into two categories: a) those with a favorable
prognosis who had a titer prior to institution of
ITI of 100/kg/day, and the time from initial
inhibitor detection to institution of ITI was
less than five years and b) those with opposite
features and a poor prognosis. We analyzed,
then, their time to success (Figure 2). Those
patients with favorable predictors had a 65%
chance of becoming tolerant within one year,
in contrast to those with poor indicators, who
had a 35% chance of becoming tolerant during
that time.
Using these data, to determine product costs
for ITI, we made the following assumptions:
a) a children weighing 25 Kg;
b) an adult weighing 75 Kg;
c) a factor VIII dose of 200 IU/kg/day;
d) a factor VIII plasma derived cost of 0.50
US$/IU;
e) a factor VIII recombinant cost of 1.00
US$/IU.
If one then determines factor consumption
and costs for the two extreme settings (a child
and an adult), the former belonging to the
favorable prognosis group and the latter to the
poor prognosis group, and choosing as the end
point a 50% success rate, we see the difference
in factor consumption and costs is very pronounced
(Table 1).
Some of the additional costs that may be
applicable to all involved in ITI are the use of
products to manage bleeding episodes. These
include APCC and rVIIa, and in some programs,
the adjuvant use of APCC and/or rVIIa while ITI
is in progress, medical and paramedical personnel,
and venous access since installation,
and its attendant infections and thrombotic
complications.
Despite these cost-modeling data, which are
retrospective in nature, many unresolved issues
Haematologica vol. 85(supplement to n. 10):October 2000