Haematologica 2003 - Supplements

untreated patients with high tumor mass (Hgb 11.5 mg/dl), a disease stage for which similar patients
had previously received a VAD-based regimen. Treatment
consisted of thalidomide 150-200 mg q hs and dexamethasone 20
mg/m2 on days 1-4, 9-12, 17-20. Anticoagulation was provided
by warfarin (INR 2.0-3.0) or, preferably, low molecular weight
heparin. Results were compared with those observed in 50
matched patients with high tumor mass who received high-dose
fractionated cyclophosphamide (2.4 gms/m2) with VAD
(HCVAD) by continuous infusion through a central venous
catheter (1996-2001); this program included prophylactic
neupogen and oral antibiotics. For both TD and HCVAD,
clinical features were similar (Hgb 11.5 mg/dl in 41 vs 62%, median β2M
7.1 vs 8.9 mg/L). With either program, early deaths occurred in
6%, but HCVAD induced grade 4 neutropenia in all patients of
whom 20% were hospitalized for serious infection; grades 3 or 4
thrombocytopenia also occurred in 70% of patients. None treated
with TD developed similar reduction of blood counts, but
nonneutropenic infections required hospitalization in 3 patients
(17%); whether prophylactic antibiotics may reduce the
frequency of such infection is not clear. Other serious
complications included one patient with DVT and PE and one
patient with dehydration. Response rates were similar with either
program (71% with TD vs 67% with HCVAD), the median time
to remission was similarly rapid (0.6 month), and CR occurred in
2 patients in each group (p=0.18). One-half of patients received
intensive therapy with autologous blood stem cell support after
TD or HCVAD, exclusions based on medical and/or
socioeconomic factors. The median survival was 26 months with
HCVAD and is projected at a similar duration with TD. While
similarly effective against myeloma, TD was superior to HCVAD
for patients with advanced disease because a central venous
catheter was not required and severe neutropenia and
thrombocytopenia were avoided.
353
EFFECT OF THALIDOMIDE TREATMENT ON VEGF,
bFGF AND HGF SECRETION IN MULTIPLE MYELOMA
PATIENTS
J. Maäko1, A. Dmoszyäska1, I. Hus1, A. Bojarska-Junak2,
D. Jawniak1, M. Soroka-Wojtaszko1, M. Hus1
1 Department of Hematooncology and Bone Marrow
Transplantation Center; 2 Clinical Immunology Department
University Medical School, 20-954 Lublin, Jaczewskiego 8, Poland,
Tel: 48 81 7425203, Fax: 48 81 7425102; email:
hematologia@o2.pl
Introduction: Increased angiogenesis has recently been
recognized in active multiple myeloma (MM). Vascular
endothelial growth factor (VEGF), basic fibroblast growth factor
(bFGF) and hepatocyte growth factor (HGF) are key mediators of
angiogenesis. Thalidomide (Thal) is a drug with well established
antitumor activity in relapsed and refractory to chemotherapy
MM patients. One of postulated mechanisms of action is based on
its antiangiogenic properties
Methods:.To test the hypothesis that the antiangiogenic potential
of thal is caused by reduction of angiogenic cytokines secretion,
serial measurements (0, 3, 6 months of thal therapy) of serum and
bone marrow levels of VEGF, bFGF and HGF were performed in
group of 20 patients with resistant or relapsed MM. by ELISA
method.
Results:We found no statistical differences in angiogenic
cytokines levels during observation period, though in the whole
group increase of VEGF and bFGF levels, and decrease of HGF
level was observed. In patients responding to Thal pretreatment
serum level of bFGF was significantly lower then in nonresponding
group. After 3 months of ,Thal treatment bFGF and
HGF serum levels were significantly lower in responding patients
than in non-responding group.
Conclusions: We conclude, that the mechanism of Thal action in
MM is not caused by a specific inhibition of studied cytokines
secretion (VEGF, bFGF, HGF). However lower serum levels of
bFGF and HGF in responding patients may indicate an influence
of thal on these cytokines production in MM patients.
354
INFLUENCE OF THALIDOMIDE ON ANGIOGENESIS IN
BONE MARROW IN MULTIPLE MYELOMA PATIENTS
I. Hus1, A. Dmoszyäska1, J. Maäko1, D. Skomra2, D.
Jawniak1, M. Soroka-Wojtaszko1, M. Hus1, W. Legie†1
1 Department of Hematooncology and Bone Marrow
Transplantation Center; 2 Department of Pathology University
Medical School, 20-954 Lublin, Jaczewskiego 8, Poland, Tel: 48
81 7425203, Fax: 48 81 7425102; email: hematologia@o2.pl
Introduction: The importance of neoangiogenesis for the
progressive growth and viability of solid tumors is well
established. Recently, there has been growing evidence, that
angiogenesis might also be important in haematological
malignancies. Among the hematologic malignancies, myeloma
has been the most studied in this respect. Recently it has been
reported, that bone marrow angiogenesis is correlated with
clinical stage of disease and the plasma cell labeling index and
often predicts the response to treatment in MM. Thalidomide
(Thal), a drug with postulated antiangiogenic properties was
showed in the last years to be effective in MM treatment.
Methods of angiogenesis research involve determination of
microvessel density in bone marrow and concentration of
angiogenic cytokines in peripheral blood and bone marrow. So
far, only few in vitro data confirming inhibiting influence of
thalidomide on microvessel density are available. The purpose of
the current study was to investigate microvessel density (MVD)
in bone marrow in MM patients treated with thalidomide.
Materials and methods: We evaluated MVD from bone marrow
(BM) samples obtained before and after 6 months of thalidomide
treatment in patients with refractory to chemotherapy or relapsed
patients. BM MVD was examined using immunohistochemical
staining for vonWillebrand factor (vWF) and anti-CD34
monoclonal antibodies. MVD was estimated by determining the
averege number of vessels in three hot spots examined at x 400
magnification.
Results: In immunohistochemical vWF stained paraffin
embedded bone marrow biopsies of 20 patients with multiple
myeloma median MVD was 34,7 vessels/mm2 with a range of 3-
85 vessels/mm2 before thalidomide treatment and after thal
therapy median bone marrow MVD was 19.4 vessels/mm2 with a
range of 5-48 vesels/mm2. Median bone marrow MVD measured
in immunohistochemical CD34 stained bone marrow biopsies
was 35,5 vessels/mm2 (range 2 - 90) before thalidomide
treatment and after therapy median bone marrow MVD was 21,2
vessels/mm2 (range 5 - 45).
Before Thal treatment, in responding patients group median
MVD measured in immunohistochemical vWF stained bone
marrow biopsies was 31.1 vessels/mm2 (range 3-59
vessels/mm2) and in non-responding group 38.8 (12- 85
vessels/mm2). After Thal treatment in responding group median
MVD was 19.3 (range 5-42), and in non-responding group was
19.4 vessels/mm2 (range 5-48).
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