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

iopsies after 6 and 12 months treatment in 24 patients. Summary. Our
study reveals beneficial effects of PegIntron in PMF or post-PV-MF
patients. The most stricking effect of IFN was observed on lowering of
platelet counts and on a decrease of the JAK2 expression in bone marrow
cells. Pegylated IFN may be reconsidered as treatment alternative in the
early stage of PMF associated to thrombocytosis.
Figure 1. Platelet counts and JAK2-V617F allelic ratios.
0649
JAK2 (V617F) MUTATION BURDEN, PHENOTYPE, AND CLINICAL COURSE OF CHRONIC
MYELOPROLIFERATIVE DISORDERS
F. Passamonti, E. Rumi, D. Pietra, M.G. Della Porta, E. Boveri, C. Elena,
S. Boggi, L. Arcaini, C. Pascutto, M. Lazzarino, M. Cazzola
Fondazione IRCCS Policlinico San Matteo, PAVIA, Italy
Background. An identical mutation (V617F) of JAK2 is found in most
patients with polycythemia vera (PV) and in about half of those with
essential thrombocythemia (ET) and primary myelofibrosis (PM). Clonal
cells can be either heterozygous or homozygous for the mutation,
and the JAK2 (V617F) burden can vary considerably in myeloid cells.
Previous reports suggested that this variable burden might influence
both phenotype and disease severity. Aims. To define the relationship
between granulocyte JAK2 (V617F) mutation burden, phenotype, and
clinical course of chronic myeloproliferative disorders (CMD). Methods.
We studied 608 patients with CMD classified according to the diagnostic
criteria of the World Health Organization (WHO). The JAK2 (V617F)
mutation burden was assessed through a quantitative evaluation of granulocyte
mutant alleles by real-time polymerase chain reaction. Results.
Overall, 423 out of 608 (69.5%) patients carried JAK2 (V617F) and
showed variable proportions of mutant alleles in circulating granulocytes
(1-100%). Relationships were observed between JAK2 (V617F)
mutation burden and hematologic parameters. In particular, the higher
the percentage of granulocyte mutant alleles, the higher the hemoglobin
level and the lower the platelet count. The majority of patients with
high mutation burden (granulocyte mutant alleles in excess of 50%) had
splenomegaly, increased LDH levels, leukocytosis and elevated circulating
CD34-positive cell counts. The JAK2 (V617F) mutation burden was
found to increase in untreated patients and phenotypic conversions (from
essential thrombocythemia to polycythemia vera, and from this latter to
myelofibrosis) were observed. Patients with more than 50% mutant
alleles had worse event-free survival (p=0.039) and overall survival
(p=0.042) as compared with those with lower mutation burden (1-50%
mutant alleles). Conclusions. The JAK2 (V617F) mutation burden, as
assessed by the proportion of granulocyte mutant alleles, influences the
clinical phenotype of myeloproliferative disorders and contributes to
determining their severity. Patients with high mutation burden tend to
have more advanced disease with abnormal stem cell trafficking. They
also have worse prognosis both in terms of disease-related complications
and overall survival.
12 th Congress of the European Hematology Association
0650
PREGNANCY IN THROMBOCYTHEMIA: 118 CASES FROM THE REGISTRO ITALIANO
TROMBOCITEMIA
L. Melillo, 1 A. Tieghi, 2 G. Comitini, 3 D. Valente, 1 A. Candoni, 2
R. Ciancia, 4 V. Martinelli, 5 F. Radaelli, 2 G. Specchia, 2 R. Latagliata, 6
F. Palmieri, 2 M. Antonio, 2 E. Usala, 2 N. Cascavilla, 2 G. Luigi2 1 Casa Sollievo della Sofferenza, S. GIOVANNI ROTONDO, FOGGIA;
2 Hematology Unit, REGGIO EMILIA; 3 Obstetric Unit, REGGIO EMILIA;
4 Hematology, University Federico II, NAPOLI; 5 Hematology University Federico
II, NAPOLI; 6 Hematology, University La Sapienza, ROMA, Italy
Essential Thrombocythaemia (ET) is diagnosed in the childbearing
age in about 20% of patients. Fertility reduction and adverse outcome
of pregnancy due to thrombotic or haemorrhagic complications are a
matter of concern. The pregnancies observed in ET patients in 17 Italian
Hematological Centres from 1998 to 2006 and registered in the RIT are
object of this retrospective study. One hundred-eighteen pregnancies
occurring in 91 women with ET, diagnosed according to the PVSG or
WHO criteria, are considered. The median age at the conception was 31
yr (21-45). Median platelet count was at diagnosis 996 (range 489-2140)
and at delivery 520 (232-1530). Beside 81 (69%) live births, 24 (20%)
spontaneous abortions (17 in the first trimester, 7 in the second
trimester), 4 (3%) still births, and 5 (4%) voluntary abortions were
described. Four pregnancies are ongoing. Of the 81 live births 12 (15%)
were premature births and 67 of the remaining 69 pregnancies were
associated with a normal foetal growth. Three pregnancies in patients
with antiphospholipid antibodies resulted no complicated. Two cases of
pre-eclampsia were also observed. The delivery was by caesarean section
in 42% of cases. In 85 (72%) pregnancies aspirin treatment (mainly
100 mg/day) was reported, associated in 18 cases to prophylactic
LMWH one week before delivery and for six weeks post-partum. A
cytoreductive treatment at conception was registered in 36 pregnancies
(Interferon α 20, Anagrelide 9, Hydroxyurea 6, and Busulphan 1). The
Interferon α, associated or not to aspirin, was administered during 18
pregnancies considered at high thrombotic risk. Fifteen of these pregnancies
were valuable (2 ongoing and 1 elective abortion) and, interestingly,
all cases ended in live births. These data confirm that fetal morbidity
and mortality rate is not negligible in ET. Cytoreductive therapy with
interferon α seems able to protect against fetal loss. The epidemiological,
clinical and biological data on pregnancy in ET are now object of a
prospective study by the RIT (GIMEMA project).
0651
MK-0457 IS A NOVEL AURORA KINASE AND JANUS KINASE 2 INHIBITOR WITH ACTIVITY
IN TRANSFORMED JAK2-POSITIVE MYELOPROLIFERATIVE DISEASE
J. Giles,V D.A. Bergstrom, 2 G. Garcia-Manero, 1 S. Kornblau, 1
M. Andreeff, 1 D. Jones, 1 S.J. Freedman, 2 S. Verstovsek, 1 H. Kantarjian, 1
D. Rizzieri3 1 M.D. Anderson Cancer Center, HOUSTON; 2 Merck & Co., Inc., UPPER
GWYNEDD; 3 Duke University, DURHAM, USA
Background. MK-0457 (VX-680) was developed as a small-molecule
inhibitor of Aurora kinases A, B, and C (Ki,app = 0.66-18 nM). Recent
screening for additional kinase activity shows that MK-0457 inhibits
JAK-2 with an IC50 of 123 nM for wild type JAK2 and 295 nM for the
JAK2 V617F activating mutation. Aims. The aim of this study was to
determine the tolerability of MK-0457 in patients with hematological
malignancies, including patients with myeloproliferative disorders
(MPD). Methods. After IRB approval, eleven consenting patients with
documented JAK2-mutated MPD, including 2 patients with prior MPD
progressing to AML, were treated with MK-0457 at either 20, 24 or 28
mg/m 2 /hr administered by a continuous 5-day intravenous infusion
every 3 weeks. The age range was 37- 83 (median 64); 5 (45%) patients
were male and performance status was 0 or 1 in 10 (91%) patients. Five
(45%) patients were previously splenectomized and 2 (33%) of the nonsplenectomized
patients had splenomegaly present at baseline. Two
(18%) patients had diploid cytogenetics, eight (73%) were pseudodiploid
with varying abnormalities and one (9%) had a -17 abnormality. Results.
One patient with hepatosplenomegaly at enrollment experienced complete
resolution of hepatomegaly and >50% reduction in splenomegaly
with a single cycle of therapy. Of the 10 (91%) patients starting therapy
with a normal or increased absolute neutrophil count, all experienced
grade 3 or 4 neutropenia during the study period. Transient reductions
in platelet counts of patients with normal or elevated baseline platelets
were also seen. Six of 7 (86%) patients with serial JAK2 testing had grad-
haematologica/the hematology journal | 2007; 92(s1) | 243