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

Immune Tolerance and the Treatment of Hemophilacs with an Inhibitor 41
used for maintenance of tolerance following successful
ITT, as well as the access and therapeutic
complications incurred while on ITT.
Definition of variables
ITT outcome was categorized as a success, a
failure, or indeterminate because of ongoing
therapy. The NAITR permitted the criteria for
success and failure to be determined by the individual
respondents, but these criteria were all
recorded to document the current standards of
ITT practices in North America. The ITT was categorized
as ongoing if the enrollee had not yet
achieved the criteria of success established by
the individual center and was continuing to
receive ITT doses of clotting factor. Maintenance
therapy was defined as any clotting factor regimen
administered subsequent to the patient
achieving the treating physician's criteria for successful
immune tolerance.
Results
Inhibitor demographics/frequency of ITT
A total of 68 centers, 40% of those polled, submitted
data to the NAITR. The data represented
5,000 (43%) of the known North American
individuals with hemophilia A and 1,325 (39%)
with hemophilia B followed at the recognized
HTCs. Included were 2,489 (43%) of the estimated
severe hemophilia A patients and 473
(35%) of the estimated severe hemophilia B population.
1
Outcome data
Of the 130 registry subjects with hemophilia A
who completed ITT, 93 (72%) successfully
achieved tolerance. Of the 11 completed ITT
courses in individuals with hemophilia B, only 4
(36%) were successful.
Success was defined by criteria established at
each participating center. The definition of success
included a negative inhibitor titer (≤ 1 BU)
in 90/97 (93%) of hemophilia A and B cases.
Success was further defined by a normal recovery
of ≥ 70% of predicted in 59/97 (61%) of individuals.
Only 29/97 (30%) of the registry subjects
had a successful immune tolerance determination
that included a negative inhibitor titer
as well as both a normal recovery, and factor
survival (≥ 12 hours). The criterion for successful
ITT in four patients was conversion from high
to low responding inhibitor status.
Maintenance of tolerance
Hemophilia A
Seventy-five (81%) of the 93 individuals in the
hemophilia A cohort who successfully achieved
immune tolerance were maintained on a regular
(prophylactic) regimen of factor VIII (FVIII) infusion
for a variable period of time post-IT induction.
The median dose used for maintenance
therapy was 150 units/kg/week (range: 17-700)
administered in variable dosing regimens. At the
time of the last data analysis, 48 (64%) subjects
remained tolerant while continuing to receive
regular doses of FVIII for a median observation
period of 13 months (range 0-129 months). Of
the 27 patients whose maintenance therapy had
been stopped, the status of 1 patient was
unknown, 17 (68%) remained tolerant over a
median observation period of 19 months (range
1-54 months), and 9 had relapsed. Among the
relapses, 3 occurred at between 1 and 8 months
after maintenance therapy was stopped, and 6
were noted during maintenance therapy at a
median time of 11 months (range 2-61
months). Due to the questionnaire design, no
outcome data were obtained on the 18/93
patients who were never maintained on a FVIII
regimen after successful tolerance was induced.
The definition of tolerance was reviewed for
those 9 subjects who relapsed on maintenance
treatment. Tolerance had been defined by a normal
recovery and survival in only 1/9 patients and
by a normal recovery alone in 4/9 patients. Three
relapses had a negative Bethesda titer as the sole
determinant of successful tolerance, and one success
had been initially defined as a conversion
from high to low responder status (Table 1).
Hemophilia B
Among the 11 hemophilia B subjects in the
cohort who completed the tolerance induction
protocol, 4 had a successful outcome using factor
IX therapeutic dosing regimens of between
43 and 200 units/kg/day. This included one
patient with an inhibitor – associated allergic
phenotype. Once tolerance was induced, all 4
individuals were placed on maintenance regimens
of 25-100 units/kg/day of factor IX. At the
time of the last data analysis in 1997, maintenance
was ongoing for all subjects and 4/4
remained tolerant.
Table 1. NAITR maintenance of tolerance. Comparison
of total/relapse cohorts.
Definition HA/HB ITT Successes* HA/Relapse
(n = 94) (n = 9)
≤ 1 BU alone 31 (33%) 3 (33%)
≤ 1 BU / Rec ≥ 70% expected 30 (32%) 4 (44%)
≤ 1 BU / Normal Rec / T 1 /2 29 (31%) 1 (11%)
Conversion to LR 4 (4%) 1 (11%)
*Information not available for 3/97 patients.
Haematologica vol. 85(supplement to n. 10):October 2000