12th Congress of the European Hematology ... - Haematologica

12 th Congress of the European Hematology Association
ual, yet steady reductions in percentage of PCR product with the V617F
mutation. Conclusions. MK-0457 is worthy of further exploration at lower
doses (20 mg/m 2 /hr) which are more suitable for chronic administration
in patients with less aggressive disease, in contrast to patients with
AML transformation of JAK2-mutated MPD in which higher, more
myelosuppressive doses may be warranted.
0652
THE JAK2-V617F MUTATION IS A RISK FACTOR FOR VENOUS BUT NOT FOR ARTERIAL
THROMBOSIS IN ESSENTIAL THROMBOCYTHEMIA
H. Gisslinger, H. Esterbauer, R. Kralovics, B. Gisslinger, M. Kees,
T. Wörl, L. Muellauer, F. Wiesbauer
Medical University of Vienna, VIENNA, Austria
Background. Essential thrombocythemia (ET), the most benign disorder
of the group of chronic myeloproliferative disorders (MPDs) is considered
as a prothrombotic state without any significant reduction of life
expectancy. The morbidity in this disorder is characterized by the occurrence
of thromboembolic events or bleeding. Previous thrombotic events,
older age or high platelet counts (>1000G/L) are associated with an
increased risk for thrombosis or bleeding. An additional occurrence of
thrombophilic parameters in ET like a factor V Leiden mutation or the prothrombin
mutation may potentiate the risk for thrombosis. The pathophysiology
of thrombophilia and bleeding in ET is not elucidated. A major
step towards understanding the ethiology of MPDs was the discovery of
a somatic mutation in the Janus kinase 2 (JAK2-V617F) gene that can be
found in about 50% of ET patients. Recent studies have postulated that
JAK2-V617F might be considered as a risk factor for thromboembolic
events. The aim of this study was to evaluate the influence of the JAK2-
V617F mutation on different types of thrombotic events (venous versus
arterial thrombotic events) in a well characterized cohort of ET patients.
Figure 1. Association of JAK2-V617F mutation with thrombosis.
Patients and Methods. We investigated a cohort of 97 ET patients (55
female, 42 male; median age 66 years, range 25-93 years) and analyzed
the influence of the JAK2-V617F mutation on arterial thrombosis, venous
thrombosis and bleeding complications. The statistical analysis was
done using Kaplan-Meier survival estimates. Results. The presence of
the JAK2-V617F mutation shows a trend towards higher mortality in
patients with the mutation (p=0.098), however, the relatively small number
of patients might diminish a statistically significant difference
between the two groups. Considering all venous thrombotic events
244 | haematologica/the hematology journal | 2007; 92(s1)
from the time from birth, there was a statistically highly significant difference
between those patients who had the JAK2-V617F mutation compared
to the wild-type patients (p=0.0008). This highly significant statistical
difference was diminished when the patients were observed only
during the time from diagnosis (p=0.1). There was no statistical significant
difference for arterial thrombosis taking the observation time from
birth as well as from diagnosis (p=0.52 and 0.57 respectively). The same
was true for the bleeding events as there was no difference between the
frequency of bleeding in patients with the JAK2-V617F mutation compared
to the wild-type patients. The combined analysis of arterial and
venous thrombosis diminished the statistically highly significant difference
and did only show a trend (p=0.07) towards more thrombotic
events in the patient group who had the mutation.
0653
DIFFERENCES IN TOLERABILITY OF TWO COMMERCIAL ANAGRELIDE FORMULATIONS
MAY BE CAUSED BY DIFFERENCES IN BIOAVAILABILITY
P.E. Petrides, 1 H. Gisslinger, 2 M. Steurer, 3 H. Linkesch, 4 G. Krumpl, 5
A. Schüller, 6 R. Widmann6 1 2 Hematology Oncology Center, MÜNCHEN, Germany; Dep of Hematology,
Univ of Vienna, VIENNA, Austria; 3Dep.of Hematology, Univ.of Innsbruck,
INNSBRUCK, Austria; 4Dep.of Hematology, Univ.of Graz, GRAZ, Austria;
5Medical Res.Network GmbH, VIENNA, Austria; 6AOP Orphan Pharmaceuticals,
VIENNA, Austria
Background. Anagrelide is an important drug for the reduction of
platelets in patients with thrombocythemia. It is commercially available
from two manufacturers (Xagrid/Agrylin ® , Shire, England and
Thromboreductin ® , AOP, Austria). Although most clinical studies investigating
the platelet-reducing efficacy of anagrelide have revealed similar
results, there is a striking divergence concerning adverse effects with
discontinuation rates from 8 to about 28% This may be explained by the
different experience of hematologists handling the drug, patient selection
and study conduct. Alternatively, the difference in tolerability may
be due to the fact that either Xagrid/Agrylin ® or Thromboreductin ® were
used in these studies (e.g. PT-1 and ANAHYDRET). Adverse effects of
anagrelide are mediated through the phosphodiesterase 3 (PDE 3) system
which is present in platelets and in the cardiovascular and cerebral
system. Whereas anagrelide and its active metabolite 3-hydroxyanagrelide
are equipotent with regard to their action on the megakaryocyte, 3hydroxyanagrelide
is 40 times more potent as an inhibitor of PDE 3.
Aims. 1. to analyze the pharmacokinetic parameters of anagrelide and its
metabolites in healthy volunteers on Xagrid/Agrylin ® or Thromboreductin?
and relate these to the adverse event profiles and 2. to compare
the platelet reducing activity of both anagrelide formulations in the same
patient cohort. Methods. In a bioequivalence study with 42 healthy volunteers
on either Agrylin/Xagrid ® or Thromboreductin ® anagrelide and
metabolites (3-hydroxyanagrelide and FL603) were determined by a
combined HPLC-MS procedure. In addition to the pharmacokinetic
parameters adverse events were recorded. We also compared in vitro dissolution
profiles of Agrylin/Xagrid ® and Thromboreductin ® in an assay
mimicking the intragastric milieu. The platelet reducing efficacy of
Xagrid/Agrylin ® and Thromboreductin ® was studied in 33 patients with
thrombocythemia which were switched from one formulation to the
other. Results. The raise and fall of the major metabolite 3-hydroxyanagrelide
is delayed by about 45 minutes when compared to anagrelide.
The cmax and AUC values of 3-hydroxyanagrelide represent about 50
and 65% of the corresponding values for anagrelide. When the anagrelide
plasma levels after the ingestion of either Xagrid/Agrylin ® or Thromboreductin
® are compared in healthy volunteers different profiles
become evident: Cmax and AUC are significantly lower for Thromboreductin
® when compared to Xagrid/Agrylin ® . In the group taking
Xagrid/Agrylin ® there was an increased rate of adverse events (particularly
headache and dizziness). In the in vitro dissolution assay anagrelide
from the Xagrid/Agrylin ® capsule is released within 5 minutes to reach
the 90% level whereas it takes over 30 minutes for anagrelide in the
Thromboreductin ® capsule to reach this level. Both anagrelide formulations
showed equal efficacy in maintaining platelet counts in patients
with thrombocythemia within the predefined margin of clinical equivalence.
Conclusions. Xagrid/Agrylin ® and Thromboreductin ® show different
pharmacokinetics which are caused by different intragastric dissolution
profiles and hence intestinal absorption rates. In particular, the different
pharmacokinetics of 3-hydroxyanagrelide may explain why they
have an equal platelet reducing activity but differ in tolerability in various
clinical trials.