Haematologica 2003 - Supplements

364
Prophylaxis of deep vein thrombosis with fixed lowdose
warfarin in patients with multiple myeloma
receiving first-line combined thalidomidedexamethasone
Elena Zamagni, Michele Cavo, Patrizia Tosi, Claudia
Cellini, *Lelia Valdrè, Delia Cangini, Paola Tacchetti,
*Gualtiero Palareti, Sante Tura and Michele Baccarani
Institute of Hematology and Medical Oncology “Seràgnoli”,
*Department of Angiology, University of Bologna, Italy
In patients with advanced and refractory multiple myeloma (MM)
treated with thalidomide ± glucocorticoids, the risk of deep vein
thrombosis (DVT) didn’t exceed 5%. Recently, an increase in the
frequency of DVT, up to the range of 21-28%, was reported with
the use of thalidomide and doxorubicin-contaning regimens as
primary therapy for newly diagnosed disease. In 2002, we started
a phase II study with thalidomide and dexamethasone as first-line
induction of remission for patients with de novo MM (Cavo et al,
IX International Workshop on MM). The starting dose of
thalidomide was 100 mg/d, with a subsequent increase to 200
mg/d after 14 days; the monthly dose of dexamethasone was 40
mg/d on days 1 to 4, with courses repeated on days 9 to 12 and 17
to 20 on odd cycles. Among the first 19 patients who entered the
study (group A) and received a median of 4 months of
thalidomide-dexamethasone, 5 (26%) had symptomatic DVT, of
whom 1 with associated non-fatal pulmonary embolism. DVT
was documented by doppler ultrasonography and developed in
the lower extremities at the first month of therapy in 2 patients, at
the second month in 1 patient, at the third month in 1 patient and
at the end of the fourth month of therapy in the last patient. Based
on this unexpectedly high frequency of DVT, treatment protocol
was amended and the use of fixed low-dose warfarin (1.25
mg/day) as prophylaxis against DVT was instituted. Forty-three
consecutive patients entered the amended study and received a
median of 4 months of thalidomide-dexamethasone along with
prophylaxis against DVT (group B). Comparison between
patients in groups A and B revealed that they were well balanced
with respect to risk factors for both thrombosis and MM,
including abnormalities of chromosome 11 and 13. Among the 43
patients included in group B, DVT in the lower extremities was
documented by doppler ultrasonography in 4 patients (9%). It is
worthy of note that in 2 of these 4 patients DVT occurred 10 and
30 days after low-dose warfarin therapy was discontinued.
Baseline laboratory evaluation for inherited risk factors for
thrombosis – including antithrombin III deficiency, protein C and
protein S deficiencies, resistance to activated protein C, lupus
anticoagulant and antiphospholipid antibodies, prothrombin gene
abnormalities (G20210A) – were performed in all patients.
Results of the analysis excluded primary hypercoagulable states
in all the 5 patients who had DVT in group A, whereas 1 patient
out of the 4 who had DVT in group B was found to be
heterozygous for factor V Leiden. It is concluded that in patients
with de novo MM receiving first-line combined thalidomidedexamethasone
1) therapy carries an increased risk of DVT; 2)
the hypercoagulable state is generally not related to identifiable
prothrombotic abnormalities; 3) fixed low-dose warfarin may
provide an effective and well manageable prophylactic measure
to reduce the risk of thrombosis.
Supported in part by MIUR, progetto FIRB RBAU012E9A_001
(M. Cavo), Università di Bologna, Progetti di Ricerca ex-60%
(M. Cavo) and Fondazione Carisbo.
365
Elevated levels of Factor VIII and von Willebrand Factor
after thalidomide treatment for malignancy:
relationship to thromboembolic events.
Ward CM1,2, Yen T1, Harvie R3, Pavlakis N3.
1Northern Blood Research Centre, University of Sydney;
2Department of Haematology and Transfusion Medicine,
3Department of Medical Oncology, Royal North Shore Hospital,
Sydney, Australia
Thalidomide exhibits potent anti-tumour activity in myeloma, but
in combination with chemotherapy leads to venous or arterial
thromboembolism in up to 20% of patients. Other anti-angiogenic
therapies under investigation have been similarly prothrombotic,
through unknown mechanisms. Elevations of FVIII coagulant
activity (FVIII:c), von Willebrand factor antigen (vWF:Ag), or
acquired resistance to activated protein C (aPC-R) have been
implicated in this process. We performed a pilot study to
investigate these parameters in patients on thalidomide plus
chemotherapy during the first 4 months when thromboembolic
events are known to occur with the highest frequency. Eleven
patients with mesothelioma, currently enrolled in a parallel nonrandomised
phase-II study were studied. Six received thalidomide
alone, and five received thalidomide, cisplatin and gemcitabine
(combination therapy). Four patients on combination therapy
developed thromboembolic events in the first 3 weeks (2 with
pulmonary emboli, one DVT/ pulmonary embolus, and one upper
limb DVT), with no thrombotic events in the thalidomide arm.
All patients in this study showed increased levels of vWF:Ag,
with marked elevations in the 4 patients with thromboembolic
events (193-205%, normal range 50-150%). Pretreatment
vWF:Ag levels were high in three patients (195–196%), and
baseline FVIII:c was markedly elevated in two patients (2.10–
2.96 IU/mL; RR 0.50–1.50 IU/mL), suggesting a pre-existing
prothrombotic state. Only one patient with thrombosis had
normal pre-treatment vWF:Ag (143%), and levels reached 194%
during treatment. coinciding with the thrombotic event. To
determine the effect of thalidomide therapy on procoagulant
parameters, patients with high baseline vWF:Ag and FVIII:c (5
and 2 cases respectively) were omitted from the following
analysis.
Patients with normal pre-treatment procoagulant levels
demonstrated significantly increased vWF:Ag levels after starting
thalidomide (mean vWF:Ag, 113% pre-treatment; 155% at one
month, p < 0.02; 170% at two months, p < 0.001) with high levels
still apparent at 4 months (mean 144%). Thalidomide also
increased FVIII:c (mean pre-treatment FVIII:c, 0.92 IU/mL, 1.16,
1.24, 1.46 and 1.43 IU/ mL at 1, 2, 4 and 8 months respectively),
which was statistically significant at 4 months (p < 0.05).
Elevated FVIII:c is a known cause of acquired activated protein C
resistance (aPC-R), so aPC-R was assessed by two methods
(APTT and DRVVT-based). One patient with thrombosis had a
clearly abnormal aPC-R associated with heterozygosity for Factor
V Leiden. Two additional patients (one with thrombosis) showed
aPC-R not associated with Factor V Leiden; however, this
preceded treatment and was not linked to an elevated FVIII:c.
These preliminary data suggest that many patients who develop
thrombosis on thalidomide/combination therapy have pre-existing
prothrombotic risks, including elevated coagulation factors and
acquired aPC-R. In addition, patients with normal coagulation
parameters appear to develop high FVIII:c and vWF on
thalidomide, typically within 4 weeks of therapy. Further studies
are urgently needed to define the mechanisms of thalidomideinduced
thrombosis, both to identify those patients at high risk,
and to develop safer therapeutic approaches.
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