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

PCH97-19) were studied. Conventional cytogenetic analyses were done
on bone marrow samples prior to therapy and during treatment
(response evaluation prior course three and later). In selected cases,
monosomy 7 was monitored by fluorescence in situ hybridization (FISH)
during treatment. Results. Of 115 karyotyped pts, 51 (44%) had a normal
karyotype and 64 (56%) had chromosomal aberrations. 34 (30%) pts
showed single aberrations, including 6 pts with loss of chromosome 7
or del(7)(q22q34). In 20 (17%) pts, complex karyotypes were detected,
11 of these contained chromosome 7 abnormality. 4/6 (67%) pts with
isolated chromosome 7 abnormality achieved complete (n=3) or major
(n=1) cytogenetic responses. Median number of courses until best cytogenetic
response was 2 (range 2-3), median time to (cytogenetic) relapse
was 13.5 months (range 9-15). Median cytogenetic response duration in
the 15 pts with other cytogenetic abnormalities was 8 months (range 3-
12), this difference was statistically significant by t-test. 4/11 pts with
complex karyotype including aberrations of chromosome 7 showed
cytogenetic responses (median response duration 8 months, range 7-9)
compared to 2 responders out of 9 pts with complex karyotype not containing
chromosome 7 abnormality. Conclusions. A high cytogenetic
response rate to low-dose DAC was seen in pts with sole chromosome
7 abnormalities, with a significantly longer response duration than for
responding pts with aberrations of chromosome 7 in the context of a
complex karyotype, or cytogenetic responders without initial chromosome
7 abnomalities. The reason for this preferential response is presently
unclear, but might be associated with the more frequent methylated
phenotype of these patients
References
Daskalakis et al., Blood 2002;100:2957-64.
Christiansen et al., Leukemia 2003;17:1813-9.
0234
DISEASE PROGRESSION IN DEL(5Q) MDS PATIENTS TREATED WITH LENALIDOMIDE:
ANALYSIS OF RISK FACTORS AND LONG TERM OUTCOME IN 45 PATIENTS
A. Giagounidis, 1 S. Haase, 2 V. Lohrbacher, 2 B. Schuran, 2 M. Heinsch, 2
C. Aul1 1 2 St. Johannes Hospital, DUISBURG; Medizinische Klinik II, DUISBURG,
Germany
Lenalidomide is a novel immunomodulatory drug (IMiD?) that has
successfully been used in patients with transfusion-dependent MDS
with del(5q.31) chromosomal abnormality. The recently published
Lenalidomide-MDS-003 study reported a 76% erythroid response rate
with 67% transfusion independency in an intent-to-treat analysis of 148
patients. This result was unaffected by cytogenetic complexity or bone
marrow blast percentage in the study population. During the first year
of study, a number of disease progressions to higher FAB subtypes or to
AML occurred that raised the question whether lenalidomide might promote
disease progression in some patients. Patients and Methods. We retrospectively
analysed data on 45 patients that were treated with lenalidomide
at our institution to identify risk profiles that might account for progression.
28 female patients and 17 male patients (median age 71 years)
were treated with initial lenalidomide doses of 10 mg po daily. Additional
therapy used was G-CSF in case of neutropenia grade >2 and antibiotics.
Results. 13 out of 45 patients (29%) experienced progression of disease
to either higher FAB subtype or AML. Analysis of contributing factors
showed that 7 of the 13 patients had RAEB at the point of first drug
intake. 3 of those 7 patients had additional chromosomal aberrations (2,
trisomy 21; 1, complex karyotype). Of the remaining 6 patients, 2 had a
complex karyotype at time of lenalidomide therapy commencement,
and 1 an additional inv(9)(p11q12). Of the remaining 3 patients, 1 patient
had a hypocellular bone marrow at the start of lenalidomide therapy so
that no FAB subtype could be assigned. Conclusions. Within the subgroup
of del(5q) MDS, the best survival has been identified in patients with an
isolated del(5q) chromosomal aberration and a bone marrow blast count
of 5%
bone marrow blasts or additional chromosomal anomalies. Only 2 out
of 45 patients (4.4%) with 5q-syndrome progressed to AML. Interestingly,
both those patients developed acute erythroid leukaemia (FAB M6).
Lenalidomide does not seem to increase the risk of transition of del(5q)
MDS to higher stages of disease.
12 th Congress of the European Hematology Association
Myeloproliferative disorders - Biology
0235
FUSION OF FIP1L1 AND RARA AS A RESULT OF A NOVEL T(4;17)(Q12;Q21) IN A CASE OF
JUVENILE MYELOMONOCYTIC LEUKEMIA
A. Buijs, M. Bruin
University Medical Center Utrecht, UTRECHT, Netherlands
Juvenile myelomonocytic leukemia (JMML) is a pediatric myeloproliferative
disease (MPD), characterized by proliferation of granulocytic
and monocytic lineages. 17q12 RARA rearrangements are the hallmark
of acute promyelocytic leukemia (APL), characterized by a differentiation
arrest of abnormal promyelocytes. Beside the frequent t(15;17)
resulting in PML/RARA fusion, variant rearrangements involving 17q21
RARA in APL are PLZF/RARA t(11;17)(q23;q21), NPM1/RARA?t(5;17)
(q35;q21), NUMA/RARA ?t(11;17)(q13;q21), STAT5b/RARA?der(17)
and t(3;17)(p25;q21). In chronic eosinophilic leukemia (CEL) a
FIP1L1/PDGFRA fusion gene has been identified due to a chromosome
4q12 interstitial deletion. FIP1L1 is an integral subunit of cleavage and
polyadenylation specificity factor (CPSF). By FISH and RT-PCR analyses
we identified FIP1L1/RARA fusions as a result of a t(4;17)(q12;q21) in a
case of JMML. Sequencing analysis demonstrated an in-frame
FIP1L1/RARA?fusion of exon 15 of FIP1L1, which is downstream of
FIP1L1/PDGFRA breakpoints that are distributed in introns 7-13. The
breakpoint fuses exon 3 of RARA, identical to all other RARA fusions.
All known chimeric RARA fusion proteins provide additional homodimerization
motifs, promoting formation of chimeric homodimers critical
for leukemic transformation. Recently, it was shown that
FIP1L1/PDGFRA mediated transformation, is FIP1L1 independent and
results from disruption of the autoinhibitory JM domain of PDGFRA.
Fusion of a strong homodimerization domain of ETV6 to PDGFRA could
overcome the inhibitory function of the PDGFRA JM domain. These
studies suggest that FIP1L1 does not seem to render direct homodimerization
ability to FIP1L1/PDGFRA. Observations using retroviral transduced
FIP1L1/PDGFRA?and FIP1L1/PDGFRA with an N-terminal deletion
of the FIP1L1 moiety showed differences with respect to cytokineindependent
colony formation and activation of multiple signaling pathways
in human primary hematopoietic precursor cells (personal communication,
Dr. Buitenhuis and Prof. Coffer, Dept. Immunology, University
Medical Center Utrecht). These observations indicate that FIP1L1
does contribute to FIP1L1/PDGFRA resulting in a myeloproliferative
phenotype. Therefore, our results, together with the data van Buitenhuis
and Coffer, suggest a functional role of FIP1L1 in both chimeric proteins
other than overt self-association. In conclusion, we report a
t(4;17)(q12;q21) resulting in reciprocal FIP1L1/RARA fusion transcripts
in a case of JMML. This is the second chromosomal aberration involving
4q12 FIP1L1 in MPD. Functional studies using FIP1L1/RARA and
FIP1L1/PDGFRA might give new insights in the mechanistic contributions
of chimeric FIP1L1 and RARA fusion proteins in MPD and APL. We
will discuss this remarkable observation in relation to disease phenotype
and molecular mechanism.
0236
BONE MARROW RENIN-ANGIOTENSIN SYSTEM EXPRESSION IN POLYCYTHAEMIA VERA
AND ESSENTIAL THROMBOCYTHAEMIA DEPENDS ON JAK2 MUTATIONAL STATUS
M. Marusic Vrsalovic, 1 V. Pejsa, 1 T. Stoos Vejic, 1 S. Ostojic Kolonic, 2
R. Ajdukovic, 1 V. Haris, 1 O. Jaksic, 1 R. Kusec1 1 2 Dubrava University Hospital, ZAGREB; Merkur University Hospital,
ZAGREB, Croatia
Background. Discovery of V617F mutation in JAK2 tyrosine kinase
gene in myeloid progenitors provided new insight into the pathogenesis
and clinical understanding of CMPD. There are several lines of evidence
suggesting the existence of local hematopoietic bone marrow
renin-angiotensin system (RAS) which contributes to the regulation of
normal and disturbed hematopoiesis. Recently, it was shown that Jak2
kinase is important upstream component in the regulation of the AGT
mRNA transcription: activated Jak2 kinase stimulates AGT gene transcription.
These observations suggest possibility for constitutively active,
mutated Jak2 to modulate transcriptional activation of AGT gene as well
as the expression of other RAS genes in CMPD. Aims. We analyzed the
expression of RAS genes (ACE, AGT, AT1R and REN) in normal BM
and that of PV and ET patients with the respect to the presence of activating
V617F JAK2 mutation. Methods. Fourteen PV-JAK2V617Fpos
haematologica/the hematology journal | 2007; 92(s1) | 85