Leukemia (2008) 22, 414­423
& 2008 Nature Publishing Group All rights reserved 0887-6924/08 $30.00
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ORIGINAL ARTICLE
Prevention of thalidomide- and lenalidomide-associated thrombosis in myeloma
A Palumbo1, SV Rajkumar2, MA Dimopoulos3, PG Richardson4, J San Miguel5, B Barlogie6, J Harousseau7, JA Zonder8,
M Cavo9, M Zangari6, M Attal10, A Belch11, S Knop12, D Joshua13, O Sezer30, H Ludwig14, D Vesole15, J Blade´16, R Kyle17,
J Westin18, D Weber19, S Bringhen1, R Niesvizky20, A Waage21, M von Lilienfeld-Toal22, S Lonial23, GJ Morgan24, RZ Orlowski25,
K Shimizu26, KC Anderson4, M Boccadoro1, BG Durie27, P Sonneveld28 and MA Hussein29 on behalf of the International
Myeloma Working Group
1Division of Hematology, University of Turin, Azienda Ospedaliera S. Giovanni Battista, Torino, Italy; 2Division of Hematology,
Mayo Clinic College of Medicine, Rochester, MN, USA; 3Department of Clinical Therapeutics, University of Athens School of
Medicine, Athens, Greece; 4Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA; 5Department of Hematology,
Hospital Clinico Universitario de Salamanca, Servicio de Hematologia, Salamanca, Spain; 6Division of Hematology/Oncology,
Myeloma Institute for Research and Therapy, University of Arkansas for Medical Sciences, Little Rock, AK, USA; 7Service
d'He´matologie, Ho^pital Hotel-Dieu, Nantes, France; 8Division of Hematology-Oncology, Karmanos Cancer Center, Wayne State
University School of Medicine, Detroit, MI, USA; 9Institute of Hematology and Medical Oncology [Sera`gnoli], University of
Bologna, Bologna, Italy; 10Service d'He´matologie, Ho^pital Purpan, Toulouse, France; 11Department of Medical Oncology, Cross
Cancer Institute, Edmonton, Alberta, Canada; 12Tuebingen University Hospital, Department of Hematology/Oncology,
Tuebingen, Germany; 13Institute of Hematology, Royal Prince Alfred Hospital, Sydney, Australia; 141st Department of Medicine,
Center for Oncology and Hematology, Wilhelminenspital, Vienna, Austria; 15Department of Medicine, St Vincent's
Comprehensive Cancer Center, New York, NY, USA; 16Hematology Department, Institute of Hematology and Oncology, Hospital
Clinic, IDIBAPS, University of Barcelona, Barcelona, Spain; 17Division of Hematology, Laboratory Medicine, Mayo Medical
School, Rochester, MN, USA; 18Division of Hematology, Department of Medicine, University of Lund, Lund, Sweden;
19Department of Lymphoma/Myeloma, The University of Texas M.D. Anderson Cancer Center, Houston, TX, USA;
20Center of Excellence for Lymphoma and Myeloma, Division of Hematology and Medical Oncology, Weill Medical College of
Cornell University, New York Presbytarian Hospital-Cornell Medical Center, New York, NY, USA; 21Department of Hematology,
University Hospital Trondheim, Trondheim, Norway; 22Bone Marrow Transplant Unit, St James's University Hospital, Leeds,
UK; 23Division of Hematology-Oncology, Winship Cancer Institute, Emory University, Atlanta, GA, USA; 24Section of
Haemato-Oncology, Royal Marsden Hospital and Institute of Cancer Research, London, UK; 25Division of Hematology/Oncology,
University of North Carolina at Chapel Hill, Chapel Hill, NC, USA; 26Department of Medicine, Nagoya City Midori General
Hospital, Nagoya, Japan; 27Aptium Oncology, Cedars-Sinai Comprehensive Cancer Center, Los Angeles, CA, USA; 28Department
of Hematology, Erasmus Medical Center Rotterdam, Rotterdam, The Netherlands; 29Department of Interdisciplinary Oncology,
Multiple Myeloma Multidisciplinary Clinical Research Program, Cleveland Clinic Taussig Cancer Center, Ohio,
OH, USA and 30Department of Hematology and Oncology, Charite´ - Universitaetsmedizin Berlin, Berlin 10117, Germany
The incidence of venous thromboembolism (VTE) is more than
or doxorubicin. Full-dose warfarin targeting a therapeutic INR
1% annually in the general population and increases further in
of 2­3 is an alternative to LMWH, although there are limited data
cancer patients. The risk of VTE is higher in multiple myeloma
in the literature with this strategy. In the absence of clear data
(MM) patients who receive thalidomide or lenalidomide, espe-
from randomized studies as a foundation for recommendations,
cially in combination with dexamethasone or chemotherapy.
many of the following proposed strategies are the results of
Various VTE prophylaxis strategies, such as low-molecular-
common sense or derive from the extrapolation of data from
weight heparin (LMWH), warfarin or aspirin, have been
many studies not specifically designed to answer these
investigated in small, uncontrolled clinical studies. This manu-
questions. Further investigation is needed to define the best
script summarizes the available evidence and recommends a
VTE prophylaxis.
prophylaxis strategy according to a risk-assessment model.
Leukemia (2008) 22, 414­423; doi:10.1038/sj.leu.2405062;
Individual risk factors for thrombosis associated with thalido-
published online 20 December 2007
mide/lenalidomide-based therapy include age, history of VTE,
Keywords: thrombosis; prophylaxis; risk factors; thalidomide;
central venous catheter, comorbidities (infections, diabetes,
lenalidomide
cardiac disease), immobilization, surgery and inherited throm-
bophilia. Myeloma-related risk factors include diagnosis and
hyperviscosity. VTE is very high in patients who receive high-
Introduction
dose dexamethasone, doxorubicin or multiagent chemotherapy
in combination with thalidomide or lenalidomide, but not with
Deep vein thrombosis (DVT) and its potentially lethal complica-
bortezomib. The panel recommends aspirin for patients with
p1 risk factor for VTE. LMWH (equivalent to enoxaparin 40 mg
tion, pulmonary embolism (PE), are manifestations of venous
per day) is recommended for those with two or more individual/
thromboembolism (VTE). The age- and sex-adjusted incidence of
myeloma-related risk factors. LMWH is also recommended
VTEismore than1% annually, including 0.5% for DVT and 0.7%
for all patients receiving concurrent high-dose dexamethasone
for PE.1 In cancer patients, the incidence of VTE is more than 7%.2
Hematological neoplasia patients, in particular those with multiple
myeloma (MM), have the highest risk of thrombosis.3 The oral
Correspondence: Dr A Palumbo, Azienda Ospidaliera San Giovanni
immunomodulatory drugs, thalidomide and lenalidomide, further
Battista `Le Molinette', Divisione di Ematologia, Via Genova 3, 10126
increase the risk of VTE. Various VTE prophylaxis strategies have
Torino, Italy.
been investigated in clinical studies. This review summarizes the
E-mail: appalumbo@yahoo.com
Received 9 October 2007; accepted 13 November 2007; published
results of these trials and recommends a prophylaxis strategy
online 20 December 2007
according to a risk-assessment model.
Thalidomide- and lenalidomide-associated thrombosis
A Palumbo et al
415
Incidence and risk factors in general population
much as 28-fold.3 The pathophysiology of thrombosis in cancer
is a complex process. The interaction between malignant cells
VTE is a disease of older age, the incidence of which rises
and monocyte/macrophage cells stimulates the release of tumor
markedly from less than 2% in individuals younger than 55 years
necrosis factor, interleukin-1 and -6, all causing endothelial
to more than 5% in those older than 65 years.1 VTE may be a
damage. The interaction between tumor cells and macrophages
lethal disease, mostly due to PE: the 1-week survival rate after PE is
also activates platelets, factor XII and X. Cysteine protease
71%, and one-fourth of all cases of PE present as sudden death.4
and tissue factor are highly expressed in cancer cells, have
Patients at risk must be identified and must receive the appropriate
procoagulant activity, and can directly activate factor X and
prophylaxis to reduce the incidence of this serious adverse event.
VII.10,11 The risk of VTE is increased 4.1-fold in malignant
The most important risk factors can be categorized into individual
neoplasms without chemotherapy, and 6.5-fold with chemo-
and disease-related risk factors.5­9 Individual factors include
therapy. Patients are most likely to develop VTE in the first few
patients' general characteristics (such as age and body mass
months after diagnosis. In a recent study, the adjusted odds ratio
index), inherited thrombophilic abnormalities, central venous
within the first 3 months was found to be as high as 58.2, to
catheter (CVC), previous superficial vein thrombosis, pregnancy/
decrease from the third month to the first year to 13.4 and to
puerperium and drug use. Major inherited prothrombotic condi-
continue to decrease thereafter.6 The conditions that increase
tions are antithrombin III deficiencies, protein C and protein S
the risk of VTE in cancer patients are active therapy,
deficiencies, activated protein C resistance, factor V Leiden
immobilization, surgery, CVC and erythropoiesis-stimulating
mutation, prothrombin gene (G20210A) mutation and high levels
agents. In two large clinical trials of women with node-negative
of homocysteine.9 The presence of inherited thrombophilia should
breast cancer, the 5-year incidence of VTE was 0.2% in those
be evaluated, especially in patients with previous history of VTE.
who received placebo, 0.9% in those who received tamoxifen
The disease-related factors include recent (generally less than 3
and 4.2% in those who received tamoxifen plus chemo-
months) clinical conditions such as surgery, trauma or hospital
therapy.12,13 Cancer patients undergoing surgery have at least twice
admission, and chronic clinical conditions such as nursing home
the risk of postoperative DVT and more than three times the risk
confinement, malignant neoplasm with or without chemotherapy
of fatal PE than noncancer patients who are undergoing similar
and neurologic disease with extremity paresis6 (Table 1). As shown
procedures.14 In the general population, the presence of CVC is
in Table 1, the increased relative risk of these conditions is quite
an independent risk factor for thrombosis in axillary/subclavian
heterogeneous, varying from 2 to 40. The simultaneous presence of
veins.6 In cancer patients with indwelling CVC, the rate
more than one risk factor exponentially increases the risk of
of thrombosis varied between 5 and 40%.15­18 Recently, the
thromboembolic complications.
Food and Drug Administration discussed concerns about risks
of thromboembolic disease, promotion of tumor growth and
decreased survival associated with the erythropoiesis-stimulat-
Thrombosis and cancer
ing agents used to treat anemia caused by chemotherapy.19
In two phase 3 clinical trials, an increased risk of sudden
The overall risk of VTE is increased 7- to 10-fold in patients with
death or a cardiovascular or thromboembolic event was
malignancy. In hematological cancer, the risk is increased as
reported in patients with chronic renal failure who received
Table 1
The most important noninherited risk factors for deep vein thrombosis and pulmonary embolism6
Risk factors
Univariate analyses
Multivariate analyses
OR
95% CI
OR
95% CI
Individual
Age (years)
1.38
1.09­1.74
NA
NA
Body mass index, kgmÀ2
0.98
0.96­1.00
NA
NA
Previous superficial vein thrombosis
2.5
1.40­4.46
4.32
1.76­10.61
Previous central venous catheter or pacemaker
11.83
5.14­27.23
5.55
1.57­19.58
Disease-related
All cardiac disease
1.57
1.18­2.08
NA
NA
Chronic renal disease
3
1.19­7.56
NA
NA
Neurologic disease with extremity paresis
5.17
2.78­9.59
3.04
1.25­7.38
Institutionalization within previous 90 days
18.44
11.48­29.64
NA
NA
Institutionalization without recent surgery
NA
NA
7.98
4.49­14.18
Institutionalization with recent surgery
NA
NA
21.72
9.44­49.93
Malignant neoplasm
7.67
4.69­12.53
NA
NA
Malignant neoplasm with chemotherapy
9.9
3.89­25.18
6.53
2.11­20.23
Malignant neoplasm without chemotherapy
6.9
3.92­12.17
4.05
1.93­8.52
General surgery
15
6.07­37.09
NA
NA
Orthopedic surgery
11.67
5.07­26.86
NA
NA
Neurosurgery
41
2.48­677.92
NA
NA
Any anesthesia
17.5
9.25­33.10
NA
NA
Trauma
20.5
7.51­55.93
12.69
4.06­39.66
Gynecologic surgery
11
1.42­85.20
NA
NA
Abbreviations: CI, confidence interval; NA, not applicable; OR, odds ratio.
Leukemia
Thalidomide- and lenalidomide-associated thrombosis
A Palumbo et al
416
erythropoiesis-stimulating agents to drive hemoglobin levels
thalidomide at diagnosis caused VTE in 12­20% of patients
into the normal range (13.5 g dlÀ1 or higher), but was not shown
who did not received any prophylaxis.25,26 Thalidomide plus
in those treated to achieve levels in a subnormal range
doxorubicin and dexamethasone further increased the risk of
(10.5­11.5 g dlÀ1).20,21 In summary, cancer patients are at
VTE to 10­27% at diagnosis41­43 and to 58% in a single study.44
increased risk for developing hypercoagulable events, and this
Table 2 summarizes the incidence of VTE as it relates to different
is confounded further by several factors, including therapy.
agents and regimens.24­26,30­53 No significant increase in
incidence of VTE was reported in patients who received
thalidomide alone, or in combination with prednisone as
Thrombosis and plasma cell dyscrasia
a maintenance therapy.54 Overall, the median time to onset of
a thrombotic event was around 3 months. The risk of VTE was
In 310 patients with monoclonal gammopathy of undetermined
higher in newly diagnosed patients.
significance (MGUS), the incidence of VTE was 6.1% after a
To further define the relative risk of VTE as it relates to the
median follow-up of 44 months.22 By univariate analysis, age
different therapeutic agents, Zangari et al.63 analyzed risk
X65 years, M protein X16 g lÀ1 and disease progression were
factors associated with the development of VTE in 535 patients
the significant risk factors for VTE. In another series of 174
treated either with thalidomide in combination with multiagent
MGUS patients, the incidence of VTE was 7.5%, and all events
chemotherapy or with dexamethasone only. Overall, the
occurred within the first 6 months of follow-up. The risk of VTE
incidence of VTE was 15%. By multivariate analysis, doxo-
was increased 8-fold if a personal history of VTE was present and
rubicin-containing regimens were associated with a 4.3-fold
27-fold in immobilized patients.23 However, it cannot be
increase in VTE, while newly diagnosed disease was associated
determined from these studies if there is a true increased risk
with a 2.5-fold increase of VTE in comparison with relapsed/
of VTE with MGUS, since the risk may be solely related to the
refractory disease. In a retrospective analysis, erythropoietin did
underlying medical problems that prompted laboratory testing
not increase the risk of VTE.64
for monoclonal proteins in the first place. The incidence of VTE
in MM patients is difficult to estimate and varies from 3%24 to
10%.23 However, based on the available data using standard
Thrombosis and lenalidomide
treatments for MM, the risk of VTE in the first 4 months following
diagnosis is approximately 3­4% in patients receiving either
Lenalidomide is an immunomodulatory drug that is structurally
dexamethasone alone24 or melphalan/prednisone therapy.25,26
similar to thalidomide yet functionally distinct. As a single
This risk could be as high as 10% with nonbiologic therapy.23
agent, lenalidomide did not significantly increase the risk of VTE
The exact mechanisms behind VTE in MM are not known. The
at relapse.55,56 By contrast, when lenalidomide was combined
type of drug therapy used to treat the disease is the dominant
with dexamethasone, the incidence of VTE was 75% in a small
factor determining the risk of VTE. Procoagulant antibody
group of newly diagnosed patients57 and 8­16% in relapsed/
formation, paraprotein interference with fibrin structure, acti-
refractory patients59,60 (Table 2). In two large randomized trials
vated protein C resistance and endothelial damage may play a
in which relapsed patients received lenalidomide­dexametha-
significant role.27 Furthermore, increased secretion of proin-
sone or dexamethasone alone without mandatory prophylaxis,
flammatory cytokines such as interleukin-6 and tumor necrosis
the incidence of VTE was 8­16 and 4%, respectively.59,60
factor can activate coagulation pathways.28 Elevated von
When lenalidomide was combined with cyclophosphamide
Willebrand and factor VIII, as well as decreased protein S and
in relapsed patients, the incidence of VTE was 14%.61 The
activated protein C resistance, have been described.29 Unfortu-
combination of lenalidomide­bortezomib did not increase the
nately, no single prothrombotic abnormality can be used to
risk of VTE in relapsed/refractory patients.62 The incidence of
predict which patients will develop VTE.
VTE according to different agents and regimens is summarized
in Table 2. Risk factors associated with an increased risk of VTE
were the dexamethasone dose and erythropoietin administra-
Thrombosis and thalidomide
tion. In a recent report, lenalidomide was delivered at diagnosis
with high-dose dexamethasone (480 mg per month) or low-dose
As a single agent, thalidomide does not increase the risk of VTE
dexamethasone (160 mg per month); the incidence of VTE was
compared to dexamethasone alone or melphalan/prednisone.
23 and 8%, respectively.58 In patients receiving lenalidomide
The risk of VTE is highly variable, even within the same
and dexamethasone at relapse, the concomitant administration
combination. This difference is likely to be related to both
of erythropoietin significantly increased the risk of VTE
individual and therapy-related risk factors, including the dose of
(23 versus 5%) in one study,65 and though the risk was also
novel agents or, more importantly, the dose of dexamethasone.
elevated in a second study, the difference failed to reach
Thalidomide alone does not increase the risk of VTE: in newly
statistical significance (31 versus 14%).54
diagnosed MM the incidence of VTE was 3­4%30,31 and in
relapsed/refractory MM it was 2­4%.32­34 The combination of
thalidomide with dexamethasone significantly increased the
VTE prophylaxis in medical and surgical patients
incidence of VTE to 14­26% in newly diagnosed MM
patients24,35,36 and to 2­8% in relapsed/refractory patients.37,38
Models to estimate risk on the basis of number and type of risk
In a randomized trial comparing thalidomide/dexamethasone
factors present in an individual patient have been proposed,66,67
with placebo/dexamethasone, the incidence of VTE was 17% in
but none have been prospectively validated. Anticoagulant
the thalidomide arm versus 3% in the placebo arm. No specific
prophylaxis is generally considered reasonable for hospitalized
thromboprophylaxis was mandated in this trial.24 When
patients who are older than 40 years, are limited in their
thalidomide was combined with melphalan, the incidence of
mobility for more than 3 days, or have at least one risk factor.
VTE was 10­20% in newly diagnosed patients25,26,39 and 11%
A meta-analysis,68 including nine randomized studies comparing
in relapsed/refractory patients.40 In two independent phase
anticoagulant prophylaxis with no treatment in hospitalized
III trials, the combination of melphalan, prednisone and
medical patients, showed that anticoagulant prophylaxis is
Leukemia
Thalidomide- and lenalidomide-associated thrombosis
A Palumbo et al
417
Table 2
Venous thromboembolism incidence in trials of thalidomide or lenalidomide without thromboprophylaxis
Treatment regimen
Newly diagnosed patients
Relapsed/refractory patients
VTE incidence (%)
References
VTE incidence (%)
References
Thalidomide
Alone
3­4a
30,31
2­4
32­34
Plus dexamethasone
14­26
24,35,36
2­8
37,38
Plus melphalan
10­20
25,26,39
11
40
Plus doxorubicin
10­27
41­43
58b44
Plus cyclophosphamide
3b­11
45,46
4­8
47­50
Plus multiagent chemotherapies
16­34
51,52
15
53
Lenalidomide
Alone
FF
0­33
55,56
Plus dexamethasone
8­75
57,58
8­16
59,60
Plus cyclophosphamide
FF
14
61
Plus bortezomib
FF
0
62
Abbreviations: VTE, venous thromboembolism; F, data not available.
aAsymptomatic newly diagnosed multiple myeloma patients.
bBoth at diagnosis and relapse.
effective in preventing symptomatic VTE. All these trials included
VTE prophylaxis in cancer patients
only patients considered to be at high risk for VTE because they
had been hospitalized for such conditions as congestive heart
Very few randomized studies in cancer patients who received
failure, acute and chronic respiratory failure, acute infectious
anticoagulant prophylaxis or placebo are available. The
disease or rheumatologic disease. In the three largest randomized
previously described three studies on hospitalized patients
trials, the administration of anticoagulant prophylaxis in hospita-
included only a small number of cancer subjects, and they
lized patients decreased the risk of VTE 3-, 2- and two-fold,
were not balanced for the additional risk factors that occur in
respectively. In the first randomized study (MEDENOX), 1102
cancer patients.69­71 With these limitations, a subset analysis of
patients were randomly assigned to receive enoxaparin or
cancer patients in the MEDENOX study reported that enoxa-
placebo.69 Patients randomized to prophylaxis with 40 mg of
parin reduced by twofold the risk for VTE (relative risk 0.50,
enoxaparin daily had a significantly lower rate of VTE than the
95% CI 0.14­1.72) in the cancer cohort.77
placebo group (5.5 versus 14.9%, Po0.001). In the second study,
In one randomized trial,78 311 women with stage IV breast
3706 patients received deltaparin or placebo;70 deltaparin
cancer were randomized to receive low-dose warfarin or
significantly decreased the rates of VTE (2.8 versus 5.0%,
placebo for the duration of their multiagent chemotherapy.
P ¼ 0.002). In the third study, 849 hospitalized patients received
Warfarin was given at 1 mg daily for the first 6 weeks and then
fondaparinux or placebo.71 Once again, fondaparinux significantly
the dose was adjusted to maintain the international normalized
reduced the incidence of VTE (5.6 versus 10.5%, P ¼ 0.03).
ratio (INR) at 1.3­1.9. VTE was observed in 4% of patients
No study has directly compared different commonly used
receiving placebo and in 0.6% of those taking low-dose
anticoagulant regimens. A meta-analysis of eight trials compar-
warfarin. The VTE risk was reduced by sixfold in warfarin
ing unfractionated heparin with low-molecular-weight heparin
patients (P ¼ 0.03). No difference in any major bleeding was
(LMWH) for prophylaxis in high-risk hospitalized patients72
found. Despite these results, the use of low-dose warfarin is not
showed no significant differences between the two treatment
frequently used in cancer patients for a number of reasons. First,
groups in the rates of VTE, but patients receiving LMWH had a
low-dose warfarin is poorly tolerated in some patients and the
twofold decrease in the risk of major bleeding (relative risk,
use of low-dose warfarin with INR monitoring is a laborious task
0.48; 95% CI, 0.23­1.00).
often unattractive to both patients and physicians. Second, the
Recent recommendations73 are based on the above-summar-
relatively low risk of VTE of 4% in the control patients in this
ized results and are consistent with the guidelines of the
study raises the question of whether routine prophylaxis is
American College of Chest Physicians.74 They strongly recom-
warranted. Third, the influence of cytochrome P-450 CYP2C9
mend the use of either unfractionated or LMWH in acutely ill
polymorphisms and warfarin-drug interactions may increase
hospitalized patients with heart failure, severe respiratory
warfarin sensitivity and lead to over anticoagulation with higher
disease, acute stroke, immobility or multiple risk factors.
risk of hemorrhage.79 Finally, there has been no other study that
Like medical patients, surgical patients also derive significant
confirms these findings.
benefit from thromboprophylaxis with LMWH.74 Individual
trials of antiplatelet therapy, usually used to prevent arterial
thromboembolism, revealed discrepant results, but a meta-
VTE prophylaxis in myeloma patients receiving thalidomide
analysis indicated a reduction of about one quarter in the risk of
or lenalidomide
VTE in surgical and high-risk medical patients who received
antiplatelet therapy.75 In a large randomized study, 17 444
Given the high risk of VTE with combination regimens including
patients undergoing orthopedic surgery were randomized to
either thalidomide or lenalidomide, at least all newly diagnosed
receive 160 mg per day of aspirin or placebo. VTE occurred in
patients should receive thromboprophylaxis. To address this
1.6% of patients assigned aspirin compared with 2.5% of those
issue several studies have added anticoagulant prophylaxis to
assigned placebo, with an absolute reduction of the risks of VTE
induction therapies (Table 3). In one study, the thalidomide­
of about one third.76
dexamethasone combination was delivered at diagnosis without
Leukemia
Thalidomide- and lenalidomide-associated thrombosis
A Palumbo et al
418
any prophylaxis and the incidence of VTE was 26%.
lenalidomide plus aspirin (100 mg per day), and VTE was
The protocol was then amended, low-fixed-dose prophy-
5%.85 In a combination study of lenalidomide, doxorubicin
lactic warfarin (1.25 mg daily) was introduced and the
and dexamethasone, 85% of patients received erythropoietin
incidence of VTE dropped to 13%.35 In another study
therapy; the incidence of VTE was 9% with the use of aspirin
thalidomide, dexamethasone and low-fixed-dose warfarin were
(81 mg per day).86 Numbers are limited and only a few trials
administered; the incidence of VTE, at 25%, did not appear to
have addressed the question of VTE prophylaxis with lenalido-
be impacted.31 In a rather small series of 26 patients who
mide-containing regimens. The dose of aspirin is still an open
received thalidomide­dexamethasone at diagnosis, either ther-
issue: on the one hand, the full dose (325 mg) inhibits both
apeutic LMWH or warfarin (INR 2.0-3.0) was used, and VTE was
prostaglandins and prostacyclines, and on the other hand, the
seen in 8%.80
81­162 mg dose inhibits only the prostaglandins, leaving the
In a randomized trial, melphalan, prednisone and thalido-
antiplatelet protective prostacycline levels intact.87 With these
mide were administered as induction therapy. In the first 65
limitations, aspirin nevertheless seems an effective anticoagulant
patients who did not receive anticoagulant prophylaxis, the
prophylaxis for lenalidomide treatment.
incidence of VTE was 20%, but dropped to 3% when
A black box warning was recently added to the package
enoxaparin was introduced at 40 mg per day for the first 4
inserts for thalidomide and lenalidomide, indicating that
months of therapy. All thromboembolic events occurred within
patients treated with these drugs and dexamethasone may
2 months after the discontinuation of enoxaparin.25 In a
benefit from VTE prophylaxis.88,89 The American College of
randomized study, 412 newly diagnosed patients received
Chest Physicians recommends the use of LMWH for VTE
vincristine­doxorubicin­dexamethasone or thalidomide­doxor-
prophylaxis in high-risk cancer patients and strongly recom-
ubicin­dexamethasone. Patients who received thalidomide
mends against the use of aspirin.74 Randomized trials are
were treated with nadroparin. The incidence of VTE was 5%
urgently needed to define the best anticoagulant prophylaxis.
in the control group and 9% in the thalidomide group, with all
On the one hand, full-dose warfarin with a target INR of 2.0­3.0
events occurring in the first 6 months of therapy.81 In a smaller
and LMWH are both highly effective, but are cumbersome and
study, 50 patients received thalidomide, pegylated liposomal
require close monitoring, in the case of warfarin, or subcuta-
doxorubicin, dexamethasone and low-fixed-dose warfarin
neous injections, in the case of LMWH. Moreover, elderly
(1.25 mg per day), and the incidence of DVT was 14%.82 In
patients may have difficulty complying with and following these
another study, 105 patients received a combination of pegylated
strategies. On the other hand, aspirin as well as low-fixed-dose
doxorubicin, vincristine, thalidomide and dexamethasone at
warfarin are quite simple options, but their efficacy must be
diagnosis without any prophylaxis; VTE incidence was
validated.
58%. The protocol was then amended and the remaining 58
In the absence of clear data from randomized studies as a
patients received aspirin (81 mg per day), resulting in a VTE
foundation for recommendations, many of the following
incidence of 18%.44
proposed strategies are the results of common sense or derive
In one study, 256 newly diagnosed myeloma patients
from the extrapolation of data from many studies not specifically
received multiagent chemotherapy (including doxorubicin,
designed to answer these questions. The treatment decision
dexamethasone, etoposide, cyclophosphamide, cisplatin) with
needs to be individualized based on the type of therapy and
or without thalidomide. Without anticoagulant prophylaxis, VTE
patients' individual risk factors.
was 14% in patients who received chemotherapy only and 34%
in those who received chemotherapy plus thalidomide. VTE was
31% in patients who received chemotherapy, thalidomide and
Recommendations in myeloma patients receiving
low-fixed-dose warfarin (1 mg per day), but 15% in those who
thalidomide or lenalidomide
received chemotherapy, thalidomide and enoxaparin (40 mg per
day).83 In another study, the incidence of VTE among 162
The choice of thromboprophylaxis needs to be modified
patients randomly assigned to multiagent chemotherapy plus
depending on the baseline risk of VTE associated with a given
thalidomide versus no thalidomide was 34 versus 18%,
regimen. The goal should be to use the safest and least
respectively. The protocol was subsequently amended and
cumbersome form of thromboprophylaxis that reduces the risk
LMWH was introduced, but VTE remained at 24% among the
of VTE to at least below 10%.
patients enrolled in the multiagent chemotherapy plus thalido-
mide group, and at 15% in the patients enrolled in the
multiagent chemotherapy control group.51 These data clearly
Thalidomide
show that the combination of multiagent chemotherapy with
In published articles, thalidomide alone as induction therapy or
thalidomide causes the highest risk of VTE, and that LMWH at a
maintenance after chemotherapy has consistently shown an
prophylactic dose may not effectively prevent this adverse
incidence of VTE below 5%.30,31,54 In accordance with these
event.
data, anticoagulant prophylaxis is not recommended for patients
Among 34 patients who received lenalidomide, dexametha-
receiving single-agent thalidomide. In newly diagnosed patients,
sone and aspirin (80­325 mg per day) at diagnosis, VTE was as
who received the combination of thalidomide and dexametha-
low as 3%.84 In a larger randomized study, newly diagnosed
sone, the risk of VTE was effectively reduced by full-dose
patients received lenalidomide with high-dose dexamethasone
warfarin, while low-fixed-dose warfarin was ineffective31,35,80
(480 mg per month) or low-dose dexamethasone (160 mg per
and no report is available for either LMWH or aspirin. For newly
month); the incidence of VTE was 23 and 8%, respectively,
diagnosed patients treated with combinations including mel-
without any prophylaxis, but dropped to 14 and 5%, respec-
phalan, LMWH was quite effective, but no other anticoagulant
tively, after the introduction of aspirin.58 This study clearly
prophylaxis has been studied.25 Low-fixed-dose warfarin and
suggests both that high-dose dexamethasone by itself represents
full-dose aspirin were ineffective in patients who received
a major risk factor for VTE, and that aspirin prophylaxis seems
thalidomide plus doxorubicin or multiagent chemothera-
appropriate in patients treated with low-dose dexamethasone. In
pies.44,83 LMWH was equally ineffective for the combination
another trial, patients received melphalan, prednisone and
of thalidomide and doxorubicin, except when used in a regimen
Leukemia
Thalidomide- and lenalidomide-associated thrombosis
A Palumbo et al
419
Table 3
Venous thromboembolism incidence in trials of thalidomide or lenalidomide with thromboprophylaxis in newly diagnosed patients
Treatment regimen
VTE incidence (%)
References
LMWH
Low-fixed-dose warfarin
Full-dose warfarin
Aspirin
Thalidomide
Plus dexamethasone
F
13­25
8
F
31,35,80
Plus melphalan
3
FF
F
25
Plus doxorubicin
9
14
F
18
44,81,82
Plus multiagent chemotherapies
15­24
31
F
51,83
Lenalidomide
Alone
FF
F
F
F
Plus dexamethasone
FF
F
3­14
58,84
Plus melphalan
FF
F
5
85
Plus doxorubicin
FF
F
9
86
Abbreviations: LMWH, low-molecular-weight heparin; VTE, venous thromboembolism; F, data not available.
containing bortezomib.90 LMWH with the combination of
Table 4
Risk assessment model for the management of
thalidomide and multiagent chemotherapies was not effective,
venous thromboembolism in multiple myeloma patients treated with
with a 24% incidence of VTE.51 The heterogeneity of data
thalidomide or lenalidomide
reported in the literature does not allow a precise recommenda-
tion. In the majority of studies, both LMWH and full-dose
Actions
warfarin were effective, while results with aspirin were negative
Individual risk factors
or not available. In relapsed/refractory patients, very limited
Obesitya
If no risk factor or any one risk factor is
data are available on the efficacy of thromboprophylaxis. The
present:
risk of VTE (2­15%) at relapse is much lower than at the time of
Previous venous
Aspirin 81­325 mg once daily
diagnosis (3­34%). For these reasons, anticoagulant prophylaxis
thromboembolism
in relapsed patients may be suggested only in those with a high
Central venous catheter
risk of VTE.
or pacemaker
Associated disease
If two or more risk factors are present:
Lenalidomide
Cardiac disease
LMWH (equivalent of enoxaparin
Chronic renal disease
40 mg once daily)
Lenalidomide alone does not induce a high risk of VTE and
Diabetes
Full-dose warfarin (target INR 2­3)
thromboprophylaxis is not suggested when lenalidomide is used
Acute infection
as a single agent. In the reported studies, aspirin has been
Immobilization
appropriate prophylaxis in patients who received lenalidomide
in combination with low-dose dexamethasone, melphalan or
Surgery
General surgery
doxorubicin, reducing the incidence of VTE to less than
Any anesthesia
10%.59,84­86 High-dose dexamethasone is an additional risk
Trauma
factor and may mandate the delivery of more aggressive
prophylaxis, such as LMWH or full-dose warfarin.
Medications
Erythropoietin
Choice of thromboprophylaxis
Blood clotting disorders
Thromboprophylaxis should be tailored to the presence of risk
Myeloma-related risk factors
factors that may increase the risk of VTE, as shown in Table 4.
Diagnosis
The relative risk of these factors is quite heterogeneous, varying
Hyperviscosity
from 2 to 40. Accordingly, the hazard ratio of a specific risk
should be taken in account in the choice of the appropriate
Myeloma therapy
anticoagulant prophylaxis.
High-dose
LMWH (equivalent of enoxaparin
dexamethasoneb
40 mg once daily)
Doxorubicin
Full-dose warfarin (target INR 2­3)
Risk factors
Multiagent chemotherapy
Individual risk factors, such as, age, obesity, history of VTE,
Abbreviations: INR, international normalized ratio; LMWH, low-molecular-
central-venous catheter, comorbidities (diabetes, infections,
weight heparin.
a
cardiac diseases), surgical procedures (including vertebro-
Obesity was defined as body mass index X30 kgmÀ2.
b
plasty and kyophoplasty) and inherited thrombophilia;
X480 mg per month.
myeloma-related risk factors such as diagnosis per se as well
as hyperviscosity;
therapy-related risks such as high-dose dexamethasone,
doxorubicin or multiagent chemotherapies.
Thromboprophylaxis
Both individual and myeloma-related risks of VTE should be
taken into account in determining the type of thrombopro-
Although aspirin is more appealing because of its conve-
phylaxis. Therapy-related risk factors should be considered,
nience and ease of administration, the rate of thrombosis,
per se, high-risk factors.
especially in patients treated with thalidomide-based
Leukemia
Thalidomide- and lenalidomide-associated thrombosis
A Palumbo et al
420
combinations is relatively high when full-dose is used. Until
usually in response to trauma or surgery. Approximately 25%
further evidence becomes available, aspirin should only be
of untreated distal thromboses extend into the proximal
recommended for low-risk patients, such as those with no risk
veins, usually within a week after presentation.95 Proximal-vein
factor or one individual/myeloma-related risk factor;
thrombosis is complicated by PE, either symptomatic or
LMWH or full-dose warfarin should be recommended in the
asymptomatic, in approximately 50% of patients.96 In the case
presence of at least two individual/myeloma-related risk
of suspect VTE, the diagnostic test of choice is compression
factors;
ultrasonography, which has sensitivity and specificity of more
LMWH or full-dose warfarin should be considered in all
than 95%. When PE is suspected, imaging remains the mainstay
patients who receive high-dose dexamethasone or doxorubi-
for diagnosis. Computed tomography pulmonary angiography is
cin or multiagent chemotherapy, independent of the presence
now the most widely used diagnostic test. Nuclear medicine
of additional risk factors.
techniques are used much less frequently. Magnetic resonance
pulmonary angiography may be considered an alternative to
Given the limitations of the data upon which these recommen-
computed tomography pulmonary angiography in patients who
dations are made, they should not be considered firm guide-
have contraindications to iodinated contrast media.97
lines. The specific form of thromboprophylaxis recommended
for a given patient ultimately should be based on the treating
physician's best clinical judgment.
Treatment of venous thromboembolism
Without a published direct comparison of different antic-
All patients should be instructed to promptly inform the
oagulants in this setting, the choice may be based on specific
physician if clinical symptoms of VTE, such as, redness of the
clinical factors. For example, the initiation of anticoagulant
skin, pain in the extremities and/or chest, shortness of breath or
prophylaxis and, more importantly, of antiplatelet agents,
rapid heartbeat occur. When deep-vein thrombosis is diag-
warrants exclusion of acquired von Willebrand disease, a rare
nosed, the goals of treatment are relief of symptoms and
but typical complication of lymphoproliferative diseases. Full-
prevention of embolization and recurrence. The appropriate
dose warfarin might best be avoided in patients in whom severe
initial therapy for outpatients is LMWH. The optimal doses of
thrombocytopenia is likely to develop, such as with thalidomide
the most commonly used LMWH are 100 U kgÀ1 every 12 h
or lenalidomide combined with chemotherapy. Note, though,
or 200 U kgÀ1 daily for deltaparin; 1 mg kgÀ1 every 12 h or
that since such combinations are associated with a relatively
1.5 mg kgÀ1 daily for enoxaparin; 86 U kgÀ1 every 12 h or
high risk of VTE, LMWH (with its lower risk of secondary
171 U kgÀ1 daily for nadroparin. If the risk of concomitant
bleeding and a short half-life) is a more suitable option than
thrombocytopenia is low, oral anticoagulation should generally
either warfarin or aspirin. The most widely used schema of
be started on the first day of treatment. Heparin should be given
LMWH prophylaxis employ enoxaparin 40 mg once daily or
for a minimum of 5 days and not stopped until the patient's INR
deltaparin 5000 U once daily. Renal failure may limit the use of
has been from 2.0 to 3.0 for 2 consecutive days. The optimal
LMWH since renal clearance is the primary mode of elimination
duration of therapy remains controversial. However, in cancer
for this drug. In patients with reduced creatinine clearance
patients who have had a VTE, the risk of recurrence in the year
(o30 ml minÀ1), LMWH is not an optimal choice because it may
after discontinuation of anticoagulant therapy is more than
accumulate and increase the risk of bleeding. The best choice in
10%.98 A randomized trial showed that long-term maintenance
this situation could therefore be full-dose warfarin.91,92
therapy with LMWH resulted in halving the recurrence risk as
The duration of prophylaxis may vary according to length of
compared to maintenance with coumarin derivatives.99 On the
treatment. In cancer patients, the majority of VTE appear within
basis of these results, extended therapy with LMWH should be
12 months from diagnosis.6 In myeloma, the vast majority of
considered in cancer patients balancing its advantages with
VTE has been reported in the first 6 months of treatment and all
such possible disadvantages as cost, the need for daily injections
episodes occurred within the first 12 months.25,52,83 It may be
and the risk of osteoporosis.
reasonable to deliver anticoagulant prophylaxis for 4­6 months,
In myeloma patients treated with thalidomide or lenalidomide
while longer periods may be considered in the presence of
who develop VTE, it is reasonable to briefly discontinue
additional patient- or treatment-specific risk factors.
thalidomide or lenalidomide and resume the treatment when
The major adverse event of thromboprophylaxis is bleeding.
full anticoagulation has been established.81 As with other cancer
Prophylactic doses of LMWH or aspirin confer very little risk of
patients, long-term therapy with LMWH, or with warfarin if
major bleeding. The vitamin K antagonist warfarin may slightly
heparin is not practical, should be continued for the total
increase the risk of bleeding, especially, in patients who develop
duration of thalidomide or lenalidomide therapy.
thrombocytopenia due to chemotherapy. Mechanical methods of
prophylaxis including graduated compression stockings, the use of
intermittent pneumatic compression devices and the venous foot
Conclusion
pump reduce stasis within the leg veins and reduce the frequency
of VTE. Unfortunately, no data from large studies are available. For
Myeloma patients treated with thalidomide or lenalidomide in
patients in whom anticoagulant prophylaxis may carry excessive
combination with steroids or chemotherapy have an increased
bleeding risk because of coexisting conditions such as active
risk of VTE and hence require routine thromboprophylaxis.
gastrointestinal or intracranial bleeding, the use of mechanical
LMWH, full-dose warfarin and aspirin (especially lower dose)
prophylaxis is a reasonable alternative.93,94
have all been shown to be effective in reducing the incidence of
VTE. Although attractive, low-fixed-dose warfarin needs more
extensive investigation. On the basis of available data, we
Management of thromboembolism
recommend specific thromboprophylaxis strategies according to
the type of therapy and the individual risk of patients (Table 4).
Diagnosis of venous thromboembolism
Aspirin alone is recommended for patients who have either no
DVT typically originates in the distal deep veins of the lower
risk factor or only one individual/myeloma-related risk factor.
extremities but occasionally originates in the proximal veins,
Patients who have at least two individual/myeloma-related risk
Leukemia
Thalidomide- and lenalidomide-associated thrombosis
A Palumbo et al
421
factors or therapy-related (high-dose dexamethasone, doxorubi-
19 FDA Alert. Information For Healthcare Professional: Eyrthropoiesis
cin or multiagent chemotherapy) should receive LMWH
Stimulating Agents (ESA) [Aranesp (Darbopoietin), Epogen
(equivalent to enoxaparin 40 mg once daily) or full-dose
(Epoietin Alfa), and Procrit (Epoietin Alfa)]. Food and Drug
warfarin (target INR 2­3) as thromboprophylaxis. All patients
Administration: Rockville, MD, March 9, 2007. Accessed May
25,
2007,
at
http://www.fda.gov/cder/drug/InfoSheets/HCP/
with therapy-related risks (high-dose dexamethasone, doxoru-
RHE2007HCP.htm..
bicin or multiagent chemotherapy) should receive LMWH or
20 Singh AK, Szczech L, Tang KL, Barnhart H, Sapp S, Wolfson M
full-dose warfarin. The ongoing randomized trials comparing
et al. Correction of anemia with epoietin alfa in chronic kidney
aspirin, warfarin and LMWH will soon determine the optimal
disease. N Engl J Med 2006; 355: 2085­2098.
prophylaxis strategy. The goal remains to define a strategy that
21 Drueke TB, Locatelli F, Clyne N, Eckardt KU, Macdougall IC,
will reduce the risk of VTE below 10% in patients receiving
Tsakiris D et al. Normalization of hemoglobin level in patients
with chronic kidney disease and anemia. N Engl J Med 2006; 355:
thalidomide or lenalidomide.
2071­2084.
22 Sallah S, Husain A, Wan J, Vos P, Nguyen NP. The risk of
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