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

open-label, multi-centre study enrolled 35 patients (all provided informed
consent) who were either naïve or currently receiving anagrelide therapy.
For those on anagrelide prior to the study, the dosing regimen was
maintained at the same pre-study level. For naïve patients, anagrelide
was initiated at 0.5 mg daily. Patients were treated with anagrelide for
3 months. Safety parameters and a range of PK and PD endpoints were
assessed. Results. A total of 35 patients were enrolled in the study; 8 paediatric
(″11 years) patients with essential thrombocythaemia (ET), 9 adolescents
(age 12-15 years) with ET and 18 adolescents/adults (age ≥16
years) with ET (12), polycythemia vera (5) or another MPD (1). The
majority of the patients had experienced anagrelide prior to the study
(94% in ≤15 years group, 72% in ≥16 years group) and exposure prior
to the study was similar in the two groups. The median starting total daily
dose was 1.0 mg in both groups, increasing to median final total daily
doses of 1.5 mg and 2.0mg in the older and younger groups, respectively.
The incidence of on-study AEs and related AEs in those aged ″15
years (53% and 18%, respectively) was lower than for those in the ≥16
years group (67% and 34%). There were no apparent differences in the
types of AEs observed in the two groups and no patients discontinued
the study due to AEs. The three most frequent AEs were palpitations,
fatigue and headache. The majority of events were considered drugrelated.
There were no clinically significant abnormalities in terms of
24-hour ECGs, 12-lead ECGs or cardiovascular function (as assessed by
echocardiogram). A comparison of PK data (normalised to 1mg dose and
70kg bodyweight) showed that exposure to anagrelide (maximum
observed plasma concentration [Cmax] and area under the plasma concentration-time
curve during the dosing interval [AUCt]) was substantially
lower (48% and 55%, respectively) in those ≤15 years than in those
?16 years. No differences in the exposure to the active metabolite
BCH24426 were observed. A number of correlations were analysed, and
for example, when the age groups were analysed together, there was a
good correlation between anagrelide and BCH24426 daily plasma exposure
(Cmax and AUCt) and decreases in platelet count. Conclusions. The
safety findings were as expected and were consistent with the pharmacological
profile of anagrelide and underlying diseases. Acceptable differences
in PK profiles were observed and from this study current dosing
regimens for anagrelide appear appropriate for use in children.
0644
PROGNOSTIC FACTORS IN IDIOPATHIC MYELOFIBROSIS: SINGLE CENTER ANALYSIS AND
PROPOSAL FOR A NEW SCORING SYSTEM
C.G. Gabutti, E.M. Pungolino, M.G. Draisci, M. Nichelatti, A. Nosari,
S. Cantoni, G. Nador, M. Riva, E. Morra
Ospedale Niguarda Ca'Granda, MILANO, Italy
The survival of patients with IM is known to be extremely variable,
ranging from a few months to more than 20 years. Such variability
requires some prognostic factors, in order to orientate the therapy choice
in this cohort of patients. The Lille scoring system, proposed for patient
risk stratification, seems unable to clearly discriminate between intermediate
and high risk patients.
Figure 1. Risk stratification in 65 patients with IM.
The aim of our study was to evaluate risk factors in our population of
IM patients and to stratify patients into risk groups. Therefore we carried
out a retrospective study of 65 patients (43 males and 22 females;
12 th Congress of the European Hematology Association
median age 62 years, range 35-80) diagnosed between 1990 and 2000.
Fifty-three cases were de novo IM, while twelve were secondary disease
(policytemia vera, 6; essential thrombocytemia, 6). Statistical analysis
was performed with Logrank test, Cox test and Roc analysis. At univariate
analysis the following parameters were considered as prognostic factors:
age, hemoglobin level (Hb), white blood cell count, platelet count,
spleen size and percentage of circulating blasts. The parameters having
relevant adverse prognostic significance were Hb < 10 g/dL and circulating
blasts > 1%. The multivariate analysis considering only these two
adverse prognostic factors permitted us to divide patients into 3 risk
groups: low risk (0 factor), intermediate risk (1 factor) and high risk (2
factors), as shown in Figure 1. The median survival for each group was
respectively 145, 62 and 50 months, with a very significant p value
( 1% were also able
to predict the progression to acute leukemia. Obviously a wider population
is needed to validate the results of this study.
0645
PROGNOSTIC RELEVANCE OF JAK2 V617F MUTATION IN PRIMARY MYELOFIBROSIS
G. Barosi, 1 G. Bergamaschi, 1 M. Marchetti, 1 M. Massa, 1 V. Rosti, 1
E. Bonetti, 1 A.M. Vannucchi, 2 P. Guglielmelli, 2 E. Antonioli, 3
R. Campanelli, 1 L. Villani, 1 G.L. Viarengo, 1 T. Barbui4 1 Fondazione IRCCS Policlinico S. Matteo, PAVIA; 2 Azienda Osped. Universit.
Careggi, FIRENZE; 3 Azienda Ospedal. Universit. Careggi, FIRENZE;
4 Ospedali Riuniti, BERGAMO, Italy
Background. An acquired point mutation in JAK2 V617F is reported in
about half of patients with primary myelofibrosis (PMF). However,
whether the presence of the mutation is associated with distinct prognosis
is still a matter of debate. Aims. To study the onset of the relevant
outcomes of the disease. To exclude time and selection biases, i.e. the
effect of different time periods before genotyping and the effect of
patients who died before genotyping, we analyzed only patients who
had the JAK2 genotype determined at their diagnosis. Methods. A cohort
of patients with a diagnosis of PMF who had received the JAK2 V617F
mutational study at the time of diagnosis or no later than 3 months from
the diagnosis were analyzed in a longitudinal study. The primary outcome
events analyzed were total mortality, development of severe anemia
(Hb less than 10 g/dL), development of large splenomegaly (spleen
larger than 10 cm from the left costal margin), development of thrombocytopenia
(platelet count lower than 150×10 9 /L), development of
leukopenia (WBC lower than 4 ×10 9 /L), major thrombosis (i.e. non-fatal
myocardial infarction, stroke, deep vein thrombosis, including splanchnic
vein thrombosis, pulmonary embolism or cardiovascular death), and
development of blast transformation (peripheral blood blasts greater
than 20% of WBC and/or blasts in the bone marrow greater than 40%).
The censoring for the development of severe anemia, large
splenomegaly, thrombocytopenia and leukopenia was considered at the
beginning of cytostatic, thalidomide, steroid, or androgen treatment.
The distribution for overall and progression-free survival was estimated
using the method of Kaplan and Meier. The log-rank test was used to test
for differences in survival between groups. Results. These were 111
patients (66 males, 45 females), aged 52 years (median, range 11 to 89
years). In 14 of them, a diagnosis of prefibrotic myelofibrosis was done.
The mean follow up was 111 months (range, 1-266 months). Over the
course of follow-up, 39 patients (35.1%) developed severe anemia, 40
(36%) large splenomegaly, 25 (22.5%) thrombocytopenia, 23 (21%)
leukopenia, 25 (22.5%) thrombosis. Only 3 patients develop blast transformation
and only 5 died, so these events were not used as major analyzable
outcomes. Baseline V617F mutated status was not significantly
associated with increase rate of development of anemia, splenomegaly,
thrombocytopenia and leukopenia (log-rank test = NS). The thrombosis-free
survival was longer in non-mutated patients, but the difference
did not reach a statistical significance. Conclusions. We conclude that the
influence of having V617F JAK2 mutation on the natural history of the
disease is not visible at a median follow-up of 111 months.
0646
JAK2 MUTATIONS IN EXON 12 AND EXON 14 IN POLYCYTHEMIA VERA PATIENTS
B. Bellosillo, L. Martínez-Avilés, C. Besses, A. Álvarez-Larrán,
B. Espinet, F. Solé, L. Florensa, S. Serrano, B. Bellosillo
Hospital del Mar, BARCELONA, Spain
Background. The JAK2 V617F mutation, which is located in exon 14,
is found in 90-97% of polycythemia vera (PV) patients, being a small pro-
haematologica/the hematology journal | 2007; 92(s1) | 241