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

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D. DiMichele et al.
Discussion
The North American Immune Tolerance Registry
represents the second retrospective characterization
of a large cohort of hemophilia A
inhibitor patients who underwent immune tolerance
through August 1997. 2 It was performed
in an effort to further understand both the outcome
and outcome predictors of ITT as practised
in North America. The study differs from its
predecessor, the International Immune Tolerance
Registry previously reported by Mariani et
al. in 1994 3 in that 1) hemophilia B inhibitor
patients were included; 2) potential outcome
predictors such as race and peak inhibitor titer
on ITT were also studied; 3) inhibitor patients
still undergoing tolerance were also characterized
in an effort to study trends in ITT over time;
4) complications related to clotting factor
administration and frequent venous access were
recorded and 5) the maintenance of tolerance
after successful therapy was documented.
In this paper, the maintenance of tolerance in
successfully induced hemophilia A and B
patients was reviewed. The results suggest that
over a significant period of observation, tolerance,
once achieved, was maintained in the
majority of both hemophilia A and B patients
studied. However, the weekly doses of clotting
factor received by successfully tolerized patients
with hemophilia A and B varied widely. In the
small hemophilia B cohort, all four patients were
maintained on regular (prophylactic) factor IX
infusions following tolerance achievement. This
was not the case, however, in the hemophilia A
cohort. In these patients, it was therefore possible
to study the maintenance of tolerance both
on and off regular FVIII infusions. Interestingly,
tolerance was maintained equally well over similar
median observation periods, whether or not
a prophylactic FVIII regimen was continued after
its initiation. However, the important question
of whether or not tolerance is maintained when
patients are immediately switched to an “on
demand” factor regimen after successful induction,
could not be answered by this study.
The small number of hemophilia A patients
with inhibitor recurrence upon either the reduction
of regular FVIII dosing or complete cessation
of the prophylactic regimen, presented an
opportunity to examine the impact of the definition
of successful ITT on long-term tolerance.
The most stringent definition of success (normal
recovery and survival) was underrepresented
(11% vs. 31%) and conversion to low responder
status was overrepresented (11 vs. 4%) in
the relapse cohort when compared to the entire
group of hemophilia A and B patients undergoing
ITT (Table 1). However, given the small number
of patients who relapsed, no significant
inverse correlation between the definition of success
and the maintenance of successful tolerance
could be definitively ascertained.
Although useful, the retrospective study of
maintenance of tolerance in cohorts of immune
tolerance patients is confounded by the limited
ability to ensure adequate reporting and conduct
ongoing long-term follow-up. However,
this important question will be further
addressed prospectively in the hemophilia A
inhibitor population undergoing ITT through
the International Immune Tolerance Study due
to begin early in the year 2000.
Acknowledgments
The authors would like to acknowledge the assistance
of Ms. Valisha McFarlane in the preparation of this
manuscript.
REFERENCES
1. Information from the National (US) and the Canadian
Hemophilia Foundations.
2. DiMichele DM, Kroner B, and Members of the Factor
VIII and IX Subcommittee. Analysis of the North American
Immune Tolerance Registry (NAITR) 1993-1997:
current practice implications. ISTH Factor VIII/IX Subcommittee
Members. Vox Sang 1999; 77 (Suppl
1):31-2.
3. Mariani G, Ghirardini A, Bellocco R. Immune tolerance
in hemophilia. Principal results from the International
Registry. Thromb Haemost 1994; 72:155-8.
DISCUSSION 5
The maintenance of tolerance
after successful ITT induction
in hemophilia A and B: the
North American Registry
D. Di Michele, B. Kroner and
the Factor VIII/IX Subcommitee
of the International Society
for Thrombosis and
Haemostasis (New York, NY
and Rockville, MD, USA)
ALEDORT: Dr. Di Michele my first comment is
with respect to your definition of success. Does
it really compare to the data shown by Dr.Mariani
or the German registry because you used a
very different definition, in that success in the
other two registries was defined unequivocally
as a normal recovery and a normal half life My
second comment relates to your showing that
although you didn’t reach significance in the difference
between the recombinant and mono-
Haematologica vol. 85(supplement to n. 10):October 2000