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

Immune Tolerance and the Treatment of Hemophilacs with an Inhibitor 71
were high-responders, with historical peaks of
above 300 and 90 BU, respectively. In the first
patient (Figure 2), the FIX concentration could
be kept at around 1 IU/mL during the first 6
days, with a continuous infusion rate of 8 units
per kg per hour. IX:C dropped to zero on day 7,
and the continuous infusion was increased to
25 units per kg per hour. The inhibitor reappeared,
peaked on day 12 at more than 350 BU,
and levelled out at around 250-300 BU. The
treatment was considered a failure and stopped
on day 23.
The second patient was pre-treated with protein
A adsorption, after which FIX:C in plasma
could be kept at a high level of around 1 IU/mL.
However, the level dropped to zero on day 8 and
the inhibitor reappeared, peaking at 450 BU.
The treatment was stopped on day 21 because
of failure. No side-effects of the treatment were
seen.
Discussion
We have thus treated 3 patients with hemophilia
A and 2 patients with hemophilia B using
the Malmö protocol, but with continuous infusion
of FVIII/IX instead of intermittent injection.
In 2 episodes, cyclophosphamide was replaced
by prednisone in order to avoid potential longterm
side-effects of chemotherapy. In one
patient with hemophilia A 2 courses of treatment
were given. Immune tolerance induction
had already been tried unsuccessfully in 3 of the
patients. A brisk inhibitor response was seen in
all cases, with levels rising to the historical peak
or beyond. There are only scarce reports in the
literature regarding continuous infusion during
IT. Kucharski and co-workers 7 treated 15 high
responders (7-1,400 BU) with the modified
Malmö protocol, in which continuous infusion
was given for 1-6 weeks. For 5 patients the
authors report a very good result, meaning that
they considered successfully induced tolerance;
in 5 patients a fairly good result was obtained,
i.e. partial tolerance and 5 patients did not
respond. Thus from currently available data it
does not seem that continuous infusion during
IT using treatment schedules based on the original
Malmö protocol improves the success rate.
However, as previously explained, continuous
infusion is an attractive mode of delivery for clotting
factor concentrates and if technically feasible
the role of continuous infusion during IT
should be further explored. The study material
used was highly selected and probably more
resistant to treatment than the average inhibitor
patient. Attempts in a more non-selected patient
group seem reasonable.
REFERENCES
1. Freiburghaus C, Berntorp E, Ekman M, Gunnarsson
M, Kjellberg BM, Nilsson IM. Tolerance induction
using the Malmö treatment model 1982-1995.
Haemophilia 1998; 5:32-9.
2. Ghirardini A, Puopolo M, Chiarotti F, Mariani G. Participants
of the International Immune Tolerance Study
Group (ITSG). The international registry of immune
tolerance; 1994 update. Vox Sang 1996; 70 (Suppl
1): 42-6.
3. Martinowitz U, Schulman S, Gitel S, Horozowski H,
Heim M, Varon D. Adjusted dose continuous infusion
of factor VIII in patients with haemophilia. Br J
Haematol 1992; 82:729-34.
4. Carlsson M, Björkman S, Berntorp E. Multidose pharmacokinetics
of factor IX: implications for dosing in
prophylaxis. Haemophilia 1998; 4:83-8.
5. Nilsson IM, Berntorp E, Zettervall O. Induction of
immune tolerance in patients with hemophilia and
antibodies to factor VIII by combined treatment with
intravenous IgG, cyclophosphamide, and factor VIII.
N Engl J Med 1988; 318:947-50.
6. Tengborn L, Berntorp E. Continuous infusion of factor
IX concentrate to induce immune tolerance in two
patients with haemophilia B. Haemophilia 1998; 4:
56-9.
7. Kucharski W, Scharf R, Nowak T. Immune tolerance
induction in haemophiliacs with inhibitor to FVIII:
high- or low-dose programme. Haemophilia 1996; 2:
224-8.
DISCUSSION 8
Regimes of factor VIII administration-continuous
infusion vs.
bolus
Berntorp E, (Malmö, Sweden)
OLDENBURG: My comment may not be
directly related to continuous infusion therapy
but yesterday you showed some risk factors for
the success of immune tolerance which were that
the success rate is correlated with inhibitor titer
at the start of therapy and with the dosage. One
could speculate that it’s free factor VIII antigen
that induces the active immune response and one
can also speculate that a bolus of factor VIII and
the circulation time of free factor VIII may be
higher than when it’s given continuously; in fact,
factor VIII is bound directly by an antibody and
so it could be less effective to induce an immune
response than factor VIII that is given by bolus
and may circulate longer and hence can produce
an active immune response in the sense of anti
idiotypic antibody creation.
BERNTORP: On the other hand when we give
intermediate injections they are given very frequently
and so we never go below 40% of factor
Haematologica vol. 85(supplement to n. 10):October 2000