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

12 th Congress of the European Hematology Association
tors Colony Forming Unit-Fibroblast (CFU-F) and late ones Colony Forming
Bone nodules (CFU-OB). On the other hand we found that Bortezomib
significantly induced osteoblast phenotype in human mesenchymal
cells incubated in presence of osteogenic factors. A stimulatory effect
on osteoblast markers was observed after 24 hours of Bortezomib treatment.
Consistently we found that Bortezomib significantly increased the
activity of the transcription factor Runx2/Cbfa1 in human osteoblast progenitors
without affecting the canonical WNT signaling pathway checked
by the evaluation of nuclear and cytoplasmatic active β-catenin levels.
Consistently we found that Bortezomib at low dose induces bone nodule
formation in human mesenchymal cells after 21 days of exposition.
Similar results were obtained using specific proteasome inhibitors as
MG-132 and MG-262 suggesting that the pro-osteogenic effect of Bortezomib
was due to its capacity to block proteasome activity. To extent our
in vitro observation we have evaluated the potential effect of Bortezomib
in vivo in MM patients. Bone histomorphometry as well as immunostainig
for Runx2/Cbfa1 was performed on BM biopsies obtained from 21 MM
patients before and after 6-8 cycles of Bortezomib administrated in monotherapy.
A significant increase in the number of osteoblastic cells X mm 2
of bone tissue and in the number of Runx2/Cbfa1 positive osteoblastic
cells was observed only in responder patients showing an early increase
of the serum alkaline phosphatase. In conclusion our data indicate that
Bortezomib may increase osteoblast differentiation in human mesenchymal
cells without affecting the proliferation, survival and function of
mature osteoblasts. in vivo and in vitro observations support the hypothesis
that both direct and indirect effects on bone formation process could
occur during Bortezomib treatment.
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ANGIOPOIETIN1/ANGIOPOIETIN2 RATIO IS REDUCED AND CORRELATES WITH DISEASE
SEVERITY IN RELAPSED/REFRACTORY MYELOMA PATIENTS. NORMALIZATION OF THE
RATIO POST BORTEZOMIB THERAPY
K. Anargyrou, 1 E. Terpos, 1 S. Sachanas, 2 T. Tzenou, 2 S. Masouridis, 2
T. Christoulas, 1 M.K. Angelopoulou, 2 S.I. Kokoris, 2
T.P. Vassilakopoulos, 2 M.P. Siakantaris, 2 C. Kalpadakis, 2 P. Panayiotidis, 2
K. Tsionos, 1 G.A. Pangalis, 2 M.C. Kyrtsonis2 1 2 251 General Air force Hospital, ATHENS; National and Kapodistrian University,
ATHENS, Greece
Background. Angiogenin, angiopoietin-1 (ang1), angiopoietin-2 (ang2),
vascular endothelial growth factor (VEGF) and VEGF-A (the main angiogenic
VEGF fraction) are cytokines involved in the process of neoangiogenesis
and possibly in multiple myeloma (MM) pathophysiology. Ang1
and ang2 are competitive ligands for the same receptor, Tie-2. There is
very limited information concerning the effect of bortezomib on angiogenic
cytokines. Aim. to evaluate pre- and post-bortezomib serum levels
of angiogenin, ang1, ang2, VEGF and VEGF-A in refractory/relapsed MM.
Patients and Methods. Thirty-five patients (24M/11F, median age:68 years)
were studied. Twenty-four patients had IgG, 8 IgA, and 3 light-chain
MM. According to ISS, 10 patients had stage 1, 7 stage 2 and 18 stage 3
disease, while according to Durie-Salmon (DS) staging, 3 patients had
stage I, 20 stage II and 12 stage III MM. Seventeen patients received bortezomib
as 2nd line treatment, while 18 patients were in ≥2nd relapse.
Median time from diagnosis to bortezomib was 30 months. Bortezomib
was given at the standard dose, while dexamethasone was added to 15
patients who did not respond after 2 cycles of therapy. Serum cytokines’
levels were measured pre-bortezomib (baseline) and on day 21 of the 4th
cycle, using ELISA methodology (R&D Systems, Minneapolis, USA, for
all, except VEGF-A: Diaclone, Bensancon, France). Results. The objective
response (OR) rate was 71%. Baseline levels of all studied angiogenic
cytokines, except of ang1, were elevated in patients, while the ratio of
ang1/ang2 was reduced compared to healthy individuals (HI) (Table 1).
Baseline ang2 levels were higher in patients with ISS 3 or DS III compared
to lower stages (p=0.04), and correlated with β2M (0.008). Baseline ang1
levels correlated negatively with DS stage and time from diagnosis to
bortezomib (p=0.05 and 0.01, respectively). More importantly, the ratio
of ang1/ang2 at baseline correlated negatively with β2M, DS stage and
PS (p