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

12 th Congress of the European Hematology Association
portion of cases negative for this mutation. Recently, it has been
described that JAK2V617F negative PV patients have mutations in exon
12 of the JAK2 gene. Aims. To determine the JAK2 mutational status
analysing both exon 12 and exon 14 in a series of PV patients. Patients
and Methods. In 86 patients (44M/42F) from a single institution diagnosed
with PV, at a median age of 62 years (range 25-87), analysis of
JAK2 exons 12 and 14 was performed by direct sequencing using granulocyte
RNA. At the time the JAK2 analysis was performed, 24/86 PV
patients were receiving therapy with platelet-lowering agents: hydroxyurea±ASA
(n=23); anagrelide±ASA (n=1). Twenty-eight patients only
received ASA and 34 patients did not receive any specific treatment.
Results. The JAK2 mutational status of our cohort is summarized in the
Table. The V617F JAK2 mutation was detected by direct sequencing in
77 cases. In two of these cases, additional mutations to the V617F in the
same exon 14 were found: a C616C silent mutation in one patient and
a C618R exchange in the second one. In this latter patient, V617F was
a consequence of two heterozygous nucleotide substitutions at positions
1849 and 1851 resulting in a GTC>TTT exchange at codon 617.
Exon 12 mutations were detected in 3 out of 8 patients negative for the
JAK2 V617F mutation (37%). These three mutations in exon 12 were different
from each other (Table 1). Moreover, exon 12 was analyzed in the
whole cohort, but no mutations were detected among JAK2V617F positive
patients. In 5 patients no mutations were found in either exon 12
or exon 14. Conclusions. Mutations in exon 12 are detected in a percentage
of JAK2V617F negative patients, but not in all cases. Exon 12 and
exon 14 mutations are mutually exclusive, but the V617F mutation may
coexist with other mutations in exon 14.
Table 1.
0647
THE NATURAL HISTORY OF FAMILIAL CHRONIC MYELOPROLIFERATIVE DISORDERS:
CLINICAL PRESENTATION, OUTCOME, AND ANTICIPATION
E. Rumi, F. Passamonti, C. Elena, L. Arcaini, C. Del Curto, M.G. Della
Porta, D. Pietra, E. Boveri, C. Pascutto, M. Cazzola, M. Lazzarino
Fondazione IRCCS Policlinico San Matteo, PAVIA, Italy
Background. Chronic myeloproliferative disorders (CMD) appear to
have a sporadic occurrence in most instances. However, familial clustering
of CMD has been recently reported. Our group has demonstrated
that JAK2 (V617F) represents an acquired somatic mutation in familial
CMD and that the mutation occurs as a secondary genetic event in the
background of a pre-existing clonal hematopoiesis. To date, no definite
data are available on the clinical presentation and disease progression in
patients with familial CMD. Aims. The aim of this study was to assess
the clinical presentation and outcome of patients with familial CMD and
to provide a comparison with sporadic cases. In addition, we studied the
phenomenon of anticipation in two-generation pairs. Patients and Methods.
We interviewed on family history for CMD 348 patients with apparently
sporadic CMD followed at our Department. Patients were grouped
in two categories: familial cases, and sporadic cases as controls. Results.
Among 348 patients, 30 pedigrees (8.6%) have been identified with one
or more relatives affected with CMD. In familial cases, the diagnosis of
CMD in a member of the family did not prompt specific investigations
within relatives. Pedigrees included 64 patients: 31 with polycythemia
vera (PV; 253 person-years of follow-up), 19 with essential thrombocythemia
(ET; 144 person-years of follow-up), and 14 with primary
myelofibrosis (PM; 84 person-years of follow-up). Nineteen families had
242 | haematologica/the hematology journal | 2007; 92(s1)
an homogeneous clinical phenotype (12 families with PV, 5 with ET, 2
with PM), while 11 families had a mixed CMD phenotype. Kolmogorov-
Smirnov test did not reveal statistically significant differences in clinical
presentation between patients with familial CMD and those with sporadic
CMD. During follow-up of familial CMD, the incidence of thrombosis
was 26.8×1000 person-years (95% CI 12-60) in PV and 14.6×1000
person-years (95% CI 3.7-58.7) in ET; the incidence of leukemia was 7.9
×1000 person-years (95% CI 1.9-31.7) in PV and 48.6×1000 person-years
(95% CI 18.2-129.5) in PM; the incidence of secondary myelofibrosis
was 4×1000 person-years (95% CI 0.5-28.4) in PV and 10.1×1000 person-years
(95% CI 3.5-56.3) in ET. In familial cases, 10-year survival
was 91.5% for patients with PV, 100% for those with ET and 30% for
those with PM. Finally, we studied the anticipation of disease onset in
15 families with two generation pairs. At diagnosis, the median age was
61 years (range, 43-78) for the first generation and 37 years (range 23-
57) for the second generation. Wilcoxon matched pair test showed a
significant difference between these values (p=0.0004). Applying Nelson
Aalen estimator, we compared the cumulative hazard of CMD onset
between patients of the first and the second generation adopting age as
a time scale: a significantly different hazard was obtained (p=0.00001).
Conclusions. This study provides evidence that patients with familial
CMD have a clinical phenotype at diagnosis similar to that of sporadic
CMD. Similarly to sporadic cases, patients with familial CMD may
develop thrombosis or may progress to myelofibrosis or leukemia. Our
data are in favour of the anticipation of disease onset in familial CMD.
0648
CLINICAL AND MOLECULAR RESPONSE DURING PEGYLATED INTERFERON ALPHA
THERAPY IN PRIMARY AND POST-POLYCYTHEMIC MYELOFIBROSIS
H. Gisslinger, 1 B. Gisslinger, 1 M. Griesshammer, 2 C. Langer, 2 M. Fiegl, 3
J. Thaler, 4 R. Schoder, 1 S. Schauer, 2 L. Muellauer, 1 I. Simonitsch-Klupp, 1
R. Kralovics1 1 Medical University of Vienna, VIENNA; 2 Department of Medicine III, ULM,
Germany; 3 Medical Unviversity of Innsbruck, INNSBRUCK, Austria;
4 Klinikum Kreuzschwestern Wels, WELS, Austria
Background. Based on the absence of specific treatment in primary
myelofibrosis (PMF) or postpolycythemic myelofibrosis (post-PV-MF)
myelosuppressive therapy with hydroxyurea is considered as standard
therapy in order to delay a further deterioration of splenomegaly and to
prevent progression of bone marrow fibrosis. An increased release of
platelet derived growth factor (PDGF) and transforming growth factor β
(TGF-β) seem to play an importatant pathogenetic role. Aims.Interferon
α (IFN) has been shown to suppress the proliferation of megakaryocyte
cell lines and in vivo studies have shown that IFN inhibits the production
and release of PDGF and TGF-β from megakaryocytes. An early therapeutic
intervention with IFN may therefore prevent disease progression
to myeloid metaplasia in these patients. Patients/Methods. Twenty-seven
patients (10 female, 17 male; median age 58 years, 34-81 years) with PMF
(n=25) or post-PV-MF (n=2) were assigned to be included in a phase II
study with PegIntron.One patient had to be excluded after screening
phase. Results. The treatment was initiated in 25 patients with 50 µg and
in one with 80 µg PegIntron/week. In 7 patients the dose was increased
to 80 µg/week. In all patients this dosage had to be decreased at least to
50 µg/week due to intolerance during long-term treatment. The treatment
had to be withdrawn in 6 patients after a median treatment duration of
24 weeks. The reason for withdrawal was treatment failure or disease
progression in three patients, severe abdominal pain after dose increase
to 100µg/week in one patient, heart failure in one patient, psychosis in
one patient, and one patient did decide to stop treatment. The most frequent
side effects were fatigue, fever, arthralgia, nausea, anemia, mild
thrombopenia and leukopenia and psychological alterations. After a
median treatment follow-up of 12 months platelet counts dropped significantly
(p