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Hematologic malignancies and thrombosis
Thrombosis Research 129 (2012) 360–366
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Thrombosis Research journal homepage: www.elsevier.com/locate/thromres
Review Article
Hematologic malignancies and thrombosis F. Elice, F. Rodeghiero ⁎ Department of Cell Therapy and Hematology, San Bortolo Hospital, Vicenza, Italy
a r t i c l e
i n f o
Article history: Received 22 September 2011 Received in revised form 17 November 2011 Accepted 20 November 2011 Available online 22 December 2011
a b s t r a c t Patients with hematologic malignancies have an increased risk of venous thromboembolism (VTE), particularly at diagnosis and during the treatment with chemotherapy, asparaginase or immunomodulatory drugs (IMiDs). A disease-dependent hypercoagulable condition associated with other risk factors like drugs, central venous catheter (CVC), immobility and infections are responsible for this high VTE rate. Thrombotic complications have a significant impact on morbidity and in some cases also on mortality of patients with oncohematologic diseases, therefore thromboprophylaxis to prevent VTE in this setting is needed. However, thrombocytopenia and hemorrhagic complications pone many difficulties in the management of an anticoagulant or antiaggregant treatment in these patients. Recommendations from current guidelines are limited to multiple myeloma patients treated with thalidomide or lenalidomide associated with dexamethasone or chemotherapy, but hematological clinical departments should implement a policy for prevention and treatment of thromboembolic complications in hematologic malignancies. © 2011 Elsevier Ltd. All rights reserved.
Contents Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Thrombosis in acute leukemia . . . . . . . . . . . . . . . . . . . . . . . . . Thrombosis in acute promyelocytic leukemia . . . . . . . . . . . . . . . . . . Pathogenesis of thrombosis in acute leukemia. . . . . . . . . . . . . . . . . . Thrombosis in lymphoma . . . . . . . . . . . . . . . . . . . . . . . . . . . Thrombosis in multiple myeloma and related disorders . . . . . . . . . . . . . Risk factors and pathogenetic mechanisms of thrombosis in plasma cell disorders . Thrombosis and survival . . . . . . . . . . . . . . . . . . . . . . . . . . . . Prophylaxis and therapy of thrombosis in hematologic malignancies . . . . . . . . Summary and conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . Conflict of interest statement . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Introduction Approximately 10-15% of patients with overt cancer will have a thrombotic complication during the course of the illness, but the rate of thrombosis in cancer varies greatly from 0.1% to 60% in relation to the tumor type, stage, and treatment (surgery, chemotherapy, radiotherapy or hormonal treatments) [1,2]. On the other side, in patients with a first episode of apparently idiopathic thrombosis, ⁎ Corresponding author at: Department of Cell Therapy and Hematology, San Bortolo Hospital, Viale Rodolfi, 37, 36100 Vicenza, Italy. Tel.: + 39 0444 753626; fax: + 39 0444 920708. E-mail address: [email protected] (F. Rodeghiero). 0049-3848/$ – see front matter © 2011 Elsevier Ltd. All rights reserved. doi:10.1016/j.thromres.2011.11.034
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20% are discovered to already have a malignancy and in up to 34% a new cancer will be diagnosed within one year [3]. Risk of venous thromboembolism (VTE) in hematologic diseases was considered lower than in solid tumors for long time and frequent fluctuations of platelet count have drawn most attention to the hemorrhagic complications as the major risk. However, recent reports suggest that the incidence of thromboembolic events in oncohematologic diseases may be similar to that found in solid tumors. In addition, the widespread use of central vein catheters (CVC) and the introduction of new immunomodulatory drugs (IMiDs: thalidomide, lenalidomide, pomalidomide) in the treatment of many hematologic neoplams have further enhanced the problem of thrombotic complications.
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In this review, we will discuss the incidence, risk factors and pathogenesis of thromboembolism in hematologic malingnancies. Philadelphia-negative myeloproliferative neoplasms have not been included because thrombotic events are intrinsic typical manifestations of the disease and require a completely different clinical approach. This report is not intended to be a comprehensive analysis of all works of this large field, so only the most relevant studies have been considered. Thrombosis in acute leukemia Incidence of VTE in acute leukemia ranges from 2.1% in the large retrospective analysis of Ziegler et al. [4] up to 12.1% in the retrospective study of Mohren et al. [5], as summarized in Table 1. However, the first study reported only VTE events observed at diagnosis or within the preceding 4 months. A prospective study including 379 leukemia patients [6] reported a 6.3% rate of thrombosis (80% venous and 20% arterial): about half of them (3.4%) were present at the time of diagnosis and all events occurred within 6 months from diagnosis. Pulmonary embolism was reported in 4 out of 24 patients (17%) and upper vein thrombosis in 4%, a very low rate in comparison with other series. A recurrent event occurred during remission in 5 patients. Fatalities for thrombosis accounted for 1% of all deaths. While no statistically significant differences were found in the incidence of thrombosis at the time of diagnosis between acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL) (1.4% vs. 3.2%, P = 0.1), a significant difference has been observed in the follow-up, with a cumulative 6-month rate of thrombosis of 10.6% in ALL and 1.7% in nonpromyelocytic AML. As in almost all series, acute promyelocytic leukemia (APL) had a higher incidence of thrombosis, both at diagnosis and during follow-up (9.6% and 8.4% respectively); VTE risk APL will be discussed later. The higher rate of thrombosis in ALL can be explained by iatrogenic events associated with the use of steroids and asparaginase in this disease. However this observation was not confirmed in other large series [4,7], in which AML and ALL had similar incidence of VTE. In studies including only children with ALL, incidence of VTE shows a broad range of variation (1-37%), mainly due to the different therapeutic protocols. In a recent meta-analysis, the rate of thrombosis in pediatric patients was 5.2% [8]. Children receiving asparaginase concomitant with prednisone have the highest risk of VTE and surprisingly the risk was higher for those receiving lower doses of asparaginase; Escherichia coli asparaginase seems associated with a higher risk of thrombosis in comparison with Erwinia asparaginase; as expected, prolonged use of asparaginase increases the
Table 1 Incidence of thromboembolic complications in hematologic malignancies. Disease
Overall incidence
Reference
MGUS
6% 3% 10% 10% 5-10% 11% 7,5% 6% 3% 7% 3% 6,5% 6% 2% 12%
Sallah et al. [27] Kristinsson et al. [29] Skralovic et al. [28] Barlogie et al. [31] Rickles et al. [2] Mohren et al. [22] Sgarabotto et al. [71] Mohren et al. [22] Sgarabotto et al. [71] Mohren et al. [22] Sgarabotto 2008 Sgarabotto et al. [71] De Stefano et al. [6] Ziegler et al. [4] Mohren et al. [5]
Myeloma Lymphoma High-grade non-Hodgkin lymphoma Low-grade non-hodgkin lymphoma Hodgkin lymphoma Myelodysplastic syndromes Acute leukemia
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VTE risk. Treatment with prednisone instead of dexamethasone, anthracyclines use, induction phase of treatment, presence of a CVC (strongly associated with upper vein thrombosis), and presence of at least one genetic prothrombotic defect (8-fold increased risk of VTE) were other risk factors for thrombosis in ALL children [8,9]. While deep vein thrombosis of lower limbs was the most common form of VTE in adults with ALL [10], the majority of symptomatic complications in children are localized in the central nervous system and in upper veins; thrombosis involving the cerebral venous sinuses is a unique feature of asparaginase-related thrombosis which is reported to occur in 1-3% of patients [9,11]. A large retrospective population-based study of VTE in 5394 leukemia patients was conducted in California using administrative dataset [7]. The two-year cumulative incidence of VTE was 5.2% in AML and 4.5% in ALL: also in this series most events occurred in the first months from diagnosis of leukemia. They observed a higher incidence of pulmonary thromboembolism (20% of VTE events in AML and 17% in ALL) and upper vein thromboses (31% of VTE in AML, but a sensitivity analysis calculated 58% of upper vein thromboses when possible miscoded events were counted). Upper extremities deep vein thromboses were highly associated with the presence of a CVC. In a multivariate analysis of the Californian series, the following risk factors were significant predictors of VTE: age >25 years, multiple comorbidities, presence of a CVC, female sex (only for AML)[7]. In the Italian study previously described, leucocyte or platelet count was not found to influence the risk of thrombosis [6]. A single center study of inherited and acquired prothrombotic risk factors in adult leukemia patients found that only hyperhomocysteinemia was significantly associated with VTE in multivariate analysis, concluding that systematic thrombophilia screening is not recommended in these patients [12]. In the group of adult ALL patients, prolonged treatment with lower doses of asparaginase, use of prednisone (instead of dexamethasone) and use of anthracyclines were associated with an increased risk of VTE [10]. More recently, use of contraceptives in women before the diagnosis of ALL was identified as a risk factor for VTE, while administration of antithrombin concentrates during induction decreased the VTE rate [13]. Thrombosis in acute promyelocytic leukemia APL is a particular subtype of acute myeloid leukemia, characterized by a specific translocation between chromosome 15 and 17, which involves the retinoic acid receptor RAR-alpha and the PML gene (PML/ RARα translocation) and induces an accumulation of promyelocytic blasts . This disease typically presents with hemorrhagic symptoms due to disseminated intravascular coagulation (DIC) and lifethreatening consumption coagulopathy is often present at diagnosis, in particular in patients with hyperleukocytosis. Chemotherapy can further enhance this coagulopathy in the first days of treatment. Fatal thrombotic events also occur at the beginning of the disease: thrombosis (myocardial infarction and pulmonary embolism) was the cause of 3 out of 68 early death observed in a series of 268 APL patients [14]. Since the introduction of therapy with all-trans-retinoic acid (ATRA) and, more recently, arsenic trioxide (ATO), a rapid resolution of the coagulopathy and of the hemorrhagic symptoms has been obtained. In fact, these drugs promote the terminal differentiation of promyelocytic blasts and normalization of clotting and fibrinolytic variables. However, thrombotic events seem to be increased, although the overall incidence is still low. Rates of thrombosis reported at the time of (or just before) diagnosis of APL were 9.6% considering both arterial and venous, 3.2- 6.5% including only venous thromboses [4,6]. In two different series of APL patients treated with ATRA and chemotherapy (AIDA protocol), incidence of thrombosis was 5.6% and 4.5%, but among patients who died before initiation of chemotherapy, 23% had severe thrombotic complications (both arterial and venous), indicating that this complication is clinically
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relevant. In a Spanish study, a correlation has been observed between thrombosis and the differentiation syndrome, which may occur in the first days of treatment with ATRA or ATO. Also in this case, hyperleukocytosis is a risk factor for thrombosis [15]. Pathogenesis of thrombosis in acute leukemia The hypercoagulable state in leukemia derives from the development of DIC and thrombin generation as a result of the presence of a high number of circulating leukemic blasts, which have been shown to express tissue factor (TF) and release cancer procoagulant from their granular fractions [16]; leukemic promyelocites show the highest procoagulant activity and thrombin generation correlates with blast cell count in APL [17]. The treatment can also enhance the hypercoagulable state: asparaginase and steroids have been shown to suppress natural anticoagulants, especially antithrombin and plasminogen, and cause elevations in factor VIII/von Willebrand factor complex [18]. Acute infections, which often complicates the course of the disease or its treatment, are another important prothrombotic factor: endotoxins from gramnegative bacteria induce the release of TF, tumor necrosis factor (TNF) and interleukin-1, and gram-positive organisms can release bacterial mucopolysaccharides that directly activate factor XII [19]. Age, hospitalization-related immobility and especially the presence of a CVC are additional important factors which contribute to the development of thrombosis. Thrombosis in lymphoma The risk of thrombosis in lymphoma patients is clearly increased, with VTE rates comparable with those of solid tumor patients. The reported incidences of thrombosis in lymphoma patients show a broad range, mainly due to the different study type (prospective or retrospective, with hospitalized or ambulatory patients), the different intensity of the chemotherapeutic protocols used and the different proportion of aggressive or indolent lymphomas in the studied population (see Table 1). In fact, a prospective study with ambulatory patients reported a 1.5% rate of VTE, while the same authors reported a 4.8% VTE rate in a large population of hospitalized patients studied retrospectively [20,21]. In all studies, most events occurred in the first months of treatment (within 3–6 months). In a large single-center retrospective analysis [22], 7.7% of the 1038 lymphoma patients experienced at least one thrombotic event: most episodes occurred during treatment (72%), while only a minority was observed prior to (17%) or after completion (11%) of chemotherapy, thus confirming the known thrombogenic effect of chemotherapy also in this group of patients. Deep vein thrombosis (53% ), pulmonary emobolism (20%), CVC-related thrombosis (11%) were the most common sites of VTE, arterial thrombosis was observed in only 2% of cases. Histology was very important for the thrombotic risk, with highest rate of thromboembolism in highgrade non Hodgkin lymphomas (10.6%), followed by Hodgkin lymphomas (7.25%) and the lowest risk in low-grade non Hodgkin lymphomas (5.8%). These figures were confirmed by data from several studies including patients with different types of lymphoma: for high-grade lymphomas the prospective study of Ottinger et al. [23] showed a 6.6% VTE rate while the retrospective study of Komrokji et al. [24] found a 12.8% VTE rate in a group of patients with diffuse large B-cell lymphoma (the most common high-grade lymphoma); rate of VTE in Hodgkin lymphoma ranges from 4.6% reported by Khorana et al. [21] in his large retrospective analysis to 8.1% in the prospective analysis of the same author [20], up to 11.5% in a retrospective study in pediatric patients [18]. A registry-based analysis performed in California found a 2-year cumulative incidence of VTE of 2.2%, 4.7% and 4.5% in low-, intermediate- and high-grade lymphomas respectively [25].
The highest incidence of VTE was reached in a study of patients with central nervous system lymphoma, where thrombotic complications were observed in 59.5% and 7% were fatal [26]. This reflects the very high rate of thrombosis observed in other brain tumors, probably due to the restricted mobility often associated with this localization of the malignancy. In contrast with the studies in leukemia patients, platelet count before the initiation of chemotherapy was found to predict thrombosis in a prospective study with ambulatory lymphoma patients [20]. In patients with diffuse large B-cell lymphoma a high international prognostic index (IPI) score, indicating a more aggressive disease, was associated with a higher VTE rate [24] The presence of a mediastinal mass was predictive of an increased VTE rate in pediatric patients [18]: this observation suggests the important role of the tumor mass effect in lymphoma patients, like in solid tumor patients, as additional risk factor for thrombosis. Other common risk factors like age, stage, immobility, infection, presence of a CVC and intensive chemotherapy are associated with thrombosis also in lymphoma patients, even if a statistically significant correlation was only variably reported. Thrombosis in multiple myeloma and related disorders Patients with a monoclonal gammopathy have a higher incidence of VTE compared to the general population. The presence of a serum monoclonal protein is associated to thromboembolism; incidence of thrombosis in patients with benign monoclonal gammopathy of undetermined significance (MGUS) was 6.1% in a prospective analysis of 310 individuals [27] and 7.5% in a retrospective study with 174 patients [28]. Two large population-based studies were performed in order to better define thrombotic risk in MGUS and in multiple myeloma (MM) patients: the first included data of more than 4 million veterans in the USA and the second was conducted in Sweden using data of a medical care registry from 1958 to 2006. Among veterans hospitalized at least once 23374 cases of MGUS and 6192 cases of MM were identified: the crude incidence of deep venous thrombosis (DVT) was 3.1/1000 person-year for MGUS and 8.7 for MM [29]. In the Swedish study, patients with MGUS showed a higher risk of VTE and a slight increase of arterial thrombosis compared to a matched control group: hazard ratios at 1 and at 10 years were 3.4 and 2.1 for VTE and 1.7 and 1.3 for arterial thrombosis [30]. Interestingly, only IgG and IgA MGUS (but not IgM) had an increased risk of thrombosis and the levels of the monoclonal protein did not affect thrombotic risk. In addition, occurrence of a thrombotic event was not associated with progression to MM, suggesting that the presence of an IgG or IgA immunoglobulin or other plasma cell activities plays an intrinsic role in the development of thrombosis. The presence of MM, the malignant disease associated with a monoclonal immunoglobulin, can further increase this risk, in particular in conjunction with specific treatments. In fact, about 10% of MM patients treated with standard chemo- and radiotherapy experience a thrombotic complication [28,31]. In the Swedish study, hazard ratios for VTE or arterial thrombosis in MM patients were 7.5 and 1.9 respectively at one year (the period with the highest thrombotic risk) and 4.1 and 1.5 at 10 years [30]. With the introduction of new agents with immunomodulatory activity (IMiDs) in the treatment of MM and other solid tumors, an unexpected high rate of VTE was observed. Thromboembolism did not appear as a major complication when thalidomide or its derivative lenalidomide were used as single agents for relapsed or refractory MM patients. A modest VTE incidence (b5%) was observed in a phase II study with thalidomide in 169 extensively pre-treated patients [32]; a similar experience was later reported by other investigators in similar settings [33,34]. Also in the case of lenalidomide, the first phase I and II trials in relapsed/refractory patients did not show any increase in thrombotic risk [35]. However, in newly diagnosed myeloma patients treated with thalidomide and high-dose dexamethasone the
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incidence of VTE increased up to 26% [36]. Similarly, two multicenter randomized phase III trials comparing lenalidomide plus dexamethasone versus dexamethasone alone in relapsed/refractory MM patients (MM-009 study in North America and MM-010 study internationally) showed a higher VTE incidence in the lenalidomide arm: in MM-009 VTE rate was 14.7% vs 3.4%, in MM-010: 11.4% vs 4.6% [37,38]. An increased rate of thrombosis was reported in a trial comparing dexamethasone alone versus dexamethasone plus lenalidomide in newly diagnosed patients; 9 out of the first 12 patients enrolled in the lenalidomide/dexamethasone arm without anticoagulation developed thrombosis, including one ischemic stroke, while no events were reported in 9 patients of the control arm [39]. The thrombogenic potential of this class of drugs was definitively confirmed by a phase III trial with upfront randomization to chemotherapy with or without thalidomide; the observed incidence of VTE was significantly higher in the thalidomide arm (28% vs. 4%; P = .002) [40]. Other studies confirmed such observation, as summarized in Table 2. Among the different chemotherapy agents used in combination with thalidomide, doxorubicin (doxo) was shown to carry the highest risk of thrombosis: in 232 MM patients treated with two protocols that differed only by the inclusion of doxorubicin in one, VTE incidence was significantly higher in the doxo group (16% vs. 3.5%, P = .02) [41]. All events reported in these studies were clinically significant, producing symptoms that prompted instrumental investigations, not otherwise planned. Amyloidosis has been frequently associated with venous and arterial thrombosis. In a group of 56 amyloidosis patients with a median age of 67 years, 11% developed VTE after a median of 12.5 months from diagnosis [42]. Surprisingly, the presence of circulating monoclonal protein was not a risk factor for VTE, while older age, immobility and personal history of DVT were found to increase the thrombotic risk. Risk factors and pathogenetic mechanisms of thrombosis in plasma cell disorders Tumor procoagulant activity of malignant cells, host inflammatory responses and extrinsic factors, which are frequently iatrogenic, contribute to the pathogenesis of thrombosis in cancer. For MM and related diseases, monoclonal immunoglobulin-specific mechanisms may also be involved: hyperviscosity, decreased fibrinolysis, procoagulant autoantibody
Table 2 Incidence of thrombotic complications in multiple myeloma patients treated with different regimens including thalidomide or lenalidomide without antithrombotic prophylaxis. No data are available for lenalidomide plus chemotherapy, because all trials with this type of combination included a thromboprophylaxis. Reference
N.
Treatment
% Thrombosis
Newly diagnosed patients Rajkumar, 2003 Cavo, 2004 Rajkumar, 2006 Zangari, 2001 50 Thal /Doxo-chemo Palumbo, 2006 Zonder, 2006 Niesvizky, 2005
31 19 102 28 65 12 22
Thal Thal /Dex Thal /Dex
3 26 17
Thal /MP Lena/Dex Lena/Dex
18 75 14
Relapsed/refractory patients Singhal, 1999 Anagnostopoulos, 2003 Oakervee, 2002 Urbauer, 2002 Zangari, 2002 Zangari, 2002 Weber, 2007 Dimopoulos, 2007
169 47 9 14 40 192 177 176
Thal Thal /Dex Thal /MP Thal /DCEP Thal /DCEP Thal /Doxo-chemo Lena/Dex Lena/Dex
b2 8 11 21 3 16 15 11
Abbreviations : Thal: Thalidomide; Lena: Lenalidomide; Dex: Dexamethasone; Doxo: doxorubicin; DCEP: dexamethasone/ cyclophosphamide/ etoposide/ cisplatin; MP: melphalan/ prednisone.
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production, effects of inflammatory cytokines, acquired activated protein C (APC) resistance. Multiple clinical experiences (Table 2) suggest that newly diagnosed patients treated with chemotherapy plus thalidomide have the highest risk to develop a thrombotic event. In a multivariate analysis of 535 MM patients treated with thalidomide in various combinations, newly diagnosed status, thalidomide/doxorubicin regimen and presence of chromosome 11 abnormalities were the only independent risk factors for VTE [43]. A retrospective analysis conducted in 1178 patients confirmed higher thrombotic risk in newly diagnosed and thalidomide-treated patients, but also identified light chain disease, elevated C-reactive protein (CRP) and acquired resistance to APC as independent risk factors for thrombosis [44]. Because most of thromboembolic episodes occurred in the first months of treatment (50% within 2 months), a thrombogenic role was postulated for the release of myeloma cell factors rather than for a direct toxic effect of drugs. However, disease stage and serum monoclonal protein levels failed to show a significant direct correlation with VTE in two different analyses [41,44]. The thrombophilic state associated with myeloma derives from the activation of the coagulation pathways and from the decrease of natural anticoagulant mechanism. In fact, high levels of inflammatory cytokines have been described in patients with myeloma [45], in particular TNF, CRP and interleukin 6 (IL-6); the latter reflects the proliferative activity of myeloma cells and has been shown in vitro to activate the clotting cascade by increasing fibrinogen, TF and factor VIII concentrations [46,47]. Indeed, high serum levels of IL-6, factor VIII and von Willebrand factor antigen have been described in patients with active disease [48]. In addition, reduced anticoagulant response to APC and reduced protein S levels have been described in a significant proportion of patients, and correlated with the risk of VTE [44,49]. Under normal conditions, APC together with protein S are essential anticoagulant mechanisms which can inhibit activated factor V and factor VIII. The observation of an acquired resistance to APC was described with an unexpected high incidence (23%) in a group of 62 newly diagnosed MM patients with active disease [50]; such abnormality was associated with an increased incidence of VTE, as later confirmed in a much larger population, and was noted to be a transient condition linked to the activity of the disease [44]. Other mechanisms related to the monoclonal protein or plasma cell activities can enhance the risk of thrombosis in MM. High levels of immunoglobulin and increased blood viscosity can impair fibrin polymerization, causing the formation of abnormal clots, which impair fibrinolyis by interfering with the binding sites of plasmin and factor XIII [51]. Furthermore, abnormal fibrin assembly has been observed in patients with production of thinner and weaker strands that are more resistant to fibrinolytic activity of plasmin. Yagci et al. [52] reported an inverse correlation between global fibrinolytic capacity (GFC) and levels of plasminogen activator inhibitor 1 (PAI-1), suggesting that decreased GFC is mainly caused by elevation of PAI-1 activity. Interestingly, PAI-1 levels correlated with CRP and IL-6 levels, which are often elevated in MM. The monoclonal protein may have intrinsic prothrombotic properties itself. Indeed, several studies have shown the presence of immunoglobulins with lupus anticoagulant activity: most probably this activity depends on the electrostatic charge of the immunoglobulin [53]. Thrombosis and survival Although a thrombotic event can be very difficult to manage in patients with severe thrombocytopenia, like most leukemia patients, the prognosis seems not to be significantly affected: In the study of Ziegler et al. [4], VTE before or at the time of diagnosis of acute leukemia was not associated with reduced overall or disease-free survival. In the registry-based Californian study a worse prognosis was associated with VTE only in ALL patients, but not in AML patients [7]. In one
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study with diffuse large B-cell lymphoma patients, the occurrence of a thrombotic complication predicts a worse prognosis, with a median OS of 1.04 years in patients with VTE compared to 5.2 years in those without VTE [24]. In MM patients treated with chemotherapy or with IMiDs, the development of VTE did not affect overall or event-free survival [54,55]. Also in the American and in the Swedish population-based studies, thrombotic complications in MM patients or in MGUS patients who progressed to MM had no effect on survival [29,30]. However, thrombosis was associated with reduced survival in MGUS patients [29]. In the case of amyloidosis, the development of a thrombotic event results in a substantial morbidity and mortality and complicates the management of an already complex clinical condition: the median survival was 3 months in patients with arterial thrombosis and 16 months in those with venous thrombosis was [56]. The absence of prognostic value of VTE in leukemia or MM can be explained considering that whereas in solid tumors metastatic spread occurs in the most advanced phases, leukemia or myeloma are always disseminated from the beginning and this feature does not translate in a more aggressive behavior. As procoagulant activation and TF expression are associated with metastatic spread, VTE in solid tumor is often a sign of advanced disease, but this is not the case for acute leukemia or MM. Prophylaxis and therapy of thrombosis in hematologic malignancies Prevention of thrombotic complications in hematologic malignancies remains a challenging issue and no evidence-based guidelines are available. The few data available in the literature usually come from subanalyses of trials in which thrombotic complications or their prophylaxis were not included in the endpoints. The consensus is that primary antithrombotic prophylaxis should be carried out in cancer patients undergoing surgical procedures; AIOM (Italian Association of Medical Oncology) and ACCP (American College of Chest Physicians) guidelines recommends prophylaxis also for oncologic medical patients if bedridden or with an acute illness; ASCO (American Society of Clinical Oncology) and NCCN (National Comprehensive Cancer Network) guidelines recommends prophylaxis for all cancer patients during hospitalization [57]. While there are no recommendations on prophylaxis for ambulatory cancer patients with other risk factors (e.g. chemotherapy, hormone therapy or use of antiangiogenic agents), in the case of ambulatory MM patients treated with thalidomide or lenalidomide in combination with dexamethasone or chemotherapy, ASCO and ESMO (European Society of Medical Oncology) guidelines recommend prophylaxis with low molecular weight heparin (LMWH) or adjusted-dose warfarin (INR 2–3) [58,59]. Current guidelines cover only a little part of oncohematologic patients. Hemorrhagic complications associated with anticoagulant or antiaggregant therapy pose particular problems in these patients because they are thrombocytopenic for prolonged time. In leukemia and lymphoma patients preventive strategies are hampered by the lack of validated markers of increased thrombotic risk for patient selection. An exploratory small multicenter study [60] suggested the possibility to reliably stratify children with ALL for the risk of thrombosis considering type of chemotherapy, presence of a genetic thrombophilic factor and presence of CVC. Most data available on the prevention of thrombosis in oncohematologic diseases come from studies in MM patients. In fact, the increased rate of thrombosis observed after the introduction of antiangiogenic agents in MM therapy warranted the introduction of antithrombotic prophylaxis in new trials with these drugs. Table 3 summarizes VTE incidence using different strategies of thromboprophylaxis in myeloma patients treated with thalidomide or lenalidomide. In the first thalidomide and dexamethasone combination trials, prophylactic fixed low dose warfarin or aspirin modestly reduced the incidence of VTE [61,62]. In patients treated upfront with a combination
of thalidomide and chemotherapy in Arkansas, fixed 1 mg daily dose of warfarin did not change significantly the incidence of VTE in patients treated [63]. The prothrombotic effect of doxorubicin-containing chemotherapy combined with thalidomide (see Table 2) was completely abrogated by the prophylactic use of the LMWH enoxaparin (40 mg/ d) or comparable doses of other LMWH (nadroparin) [63,64]. Reduction of VTE incidence (18%) was observed also with prophylactic fixed low dose aspirin in patients treated with thalidomide, dexamethasone and chemotherapy [62]. Aspirin has been widely used in protocols with lenalidomide/dexamethasone: reports from different centers ranges from 3% to 19% [39,65]. The strength of the evidence supporting the efficacy of aspirin in the prevention of VTE in lenalidomide-treated patients is low, because it is based on retrospective studies [66], but this is the case of almost all studies in this setting. Recently, two prospective randomized trials of the GIMEMA group have been published in MM patients. One prospective randomized trial compared prophylaxis with enoxaparin 40 mg/d, aspirin 199 mg/d or fixed-dose warfarin (1.25 mg/d) in newly diagnosed MM patients treated with thalidomide and dexamethasone as pretranplantation induction (if younger than 65 years) or with bortezomib-melphalan-prednisone-thalidomide (if older than 65 years) [67]. Incidence of venous or arterial thromboembolic events and sudden deaths in the first 6 months of treatment were not significantly different with the three types of prophylaxis: 5% in the LMWH arm, 6.4% in the aspirin arm and 8.2% in the warfarin arm. Bleeding complications were also similar in the three arms. However, in the group of elderly patients, warfarin was less effective than LMWH. As reported by other studies, bortezomib reduced thalidomideassociated risk of thrombosis (not statistically significant in this trial). The second trial compared prophylaxis with LMWH (enoxaparin 40 mg/d) or low-dose aspirin (100 mg) in 342 newly diagnosed MM patients treated with lenalidomide and low-doses of steroids
Table 3 Incidence of thromboembolic events with prophylactic anticoagulation in thalidomidetreated patients. Status No Warfarin Low molecular Aspirin References (D/R) prophylaxis 1- 1.25 mg/d weight heparin % VTE
% VTE
% VTE
Thalidomide + dexamethasone D 20-26% 13-25%
R
% VTE 7%*
2-8%
Thalidomide + melphalan/ prednisone D 12-18% 5%
Facon [77]; Palumbo [78]
Thalidomide + chemotherapy with doxorubicin D 10-34% 14-31% 10-15%
R
Zangari [63]; Zervas et [79]; Minnema [64] Zangari [63]
16%
Lenalidomide + dexamethasone D 75%
Rajkumar [72], Cavo [61], Weber [73], Hassoun [74] Palumbo [75]; Anagnostopoulos [76]
3-19%
Rajkumar [65]; Zonder[39] Dimopoulos [38]
Lenalidomide + melphalan and prednisone R
2%
Palumbo [69]
Lenalidomide + chemotherapy with doxorubicin R
9%
Baz [62]
R
8%
Abbreviations: D, diagnosis; R, relapsed/refractory. *Thalidomide and dexamethasone were administered to newly diagnosed patients after an initial debulking chemotherapy.
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followed by consolidation with melphalan-prednisone-lenalidomide: VTE incidence was 2.27% in the aspirin arm and 1.2% in the LMWH arm (not statistically different), with 1.7% of pulmonary embolism in the aspirin arm and none in the LMWH arm [68]. Both studies showed only a trend for a more effective thrombophylaxis with LMWH, but aspirin and warfarin are more manageable and less expensive alternatives. Before GIMEMA trials were available, given the absence of evidencebased data, an international panel recommended the use of LMWH in MM treated with thalidomide or lenalidomide combined with highdose dexamethasone or chemotherapy when two or more other risk factors are present, otherwise aspirin should be used. Adjusted-dose warfarin was considered an alternative to LMWH. Risk factors identified by the panel were the following: obesity, previous VTE, presence of CVC, diabetes mellitus, chronic renal or cardiac disease, immobilization, acute infection, surgery, use of erythropoietin. However, no clear supporting evidences for these recommendations are offered [69]. Recommended treatment of VTE in patients with hematologic malignancies is LMWH. In fact, anticoagulation with warfarin is associated with high rates of recurrent VTE and bleeding in patients with cancer. This therapy is also difficult to supervise in this group of patients. In the CLOT trial, low molecular weight heparin appeared more efficacy than warfarin for the secondary prevention of VTE in cancer patients [70]. In thalidomide-treated MM patients who developed VTE, the single institution experience of the Arkansas group indicated that it is reasonable to resume the thalidomide treatment when full anticoagulation has been established and continued for the total duration of therapy [63]. The rate of VTE recurrence was overall 13.8%, not significantly different from the rate observed in other cancers (9-17%) [70]. Summary and conclusions Patients with hematologic malignancies have an increased risk of VTE, particularly at diagnosis and during the treatment with chemotherapy, asparaginase or IMiDs. A disease-dependent hypercoagulable condition associated with other risk factors like drugs, CVC, immobility and infections are responsible for this high VTE rate. Thrombotic complications have a significant impact on morbidity and in some cases also on mortality of patients with onco-hematologic diseases, therefore thromboprophylaxis to prevent VTE in this setting is needed. However, thrombocytopenia and hemorrhagic complications pone many difficulties in the management of an anticoagulant or antiaggregant treatment in these patients. Recommendations from current guidelines are limited to myeloma patients treated with thalidomide or lenalidomide associated with dexamethasone or chemotherapy, but hematological clinical departments should implement a policy for prevention and treatment of thromboembolic complications in hematologic malignancies. Conflict of interest statement No conflict of interest References [1] Scates SM. Diagnosis and treatment of cancer-related thrombosis. Semin Thromb Hemost 1992;18:373–9. [2] Rickles FR, Levine MN. Epidemiology of thrombosis in cancer. Acta Haematol 2001;106(1–2):6–12. [3] Piccioli A, Prandoni P. Venous thromboembolism as first manifestation of cancer. Acta Haematol 2001;106(1–2):13–7. [4] Ziegler S, Sperr WR, Knöbl P, Lehr S, Weltermann A, Jäger U, et al. Symptomatic venous thromboembolism in acute leukemia. Incidence, risk factors, and impact on prognosis. Thromb Res 2005;115(1–2):59–64. [5] Mohren M, Markmann I, Jentsch-Ullrich K, Koenigsmann M, Lutze G, Franke A. Increased risk of venous thromboembolism in patients with acute leukaemia. Br J Cancer Jan. 30 2006;94(2):200–2.
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Thrombosis Research journal homepage: www.elsevier.com/locate/thromres
Review Article
Hematologic malignancies and thrombosis F. Elice, F. Rodeghiero ⁎ Department of Cell Therapy and Hematology, San Bortolo Hospital, Vicenza, Italy
a r t i c l e
i n f o
Article history: Received 22 September 2011 Received in revised form 17 November 2011 Accepted 20 November 2011 Available online 22 December 2011
a b s t r a c t Patients with hematologic malignancies have an increased risk of venous thromboembolism (VTE), particularly at diagnosis and during the treatment with chemotherapy, asparaginase or immunomodulatory drugs (IMiDs). A disease-dependent hypercoagulable condition associated with other risk factors like drugs, central venous catheter (CVC), immobility and infections are responsible for this high VTE rate. Thrombotic complications have a significant impact on morbidity and in some cases also on mortality of patients with oncohematologic diseases, therefore thromboprophylaxis to prevent VTE in this setting is needed. However, thrombocytopenia and hemorrhagic complications pone many difficulties in the management of an anticoagulant or antiaggregant treatment in these patients. Recommendations from current guidelines are limited to multiple myeloma patients treated with thalidomide or lenalidomide associated with dexamethasone or chemotherapy, but hematological clinical departments should implement a policy for prevention and treatment of thromboembolic complications in hematologic malignancies. © 2011 Elsevier Ltd. All rights reserved.
Contents Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Thrombosis in acute leukemia . . . . . . . . . . . . . . . . . . . . . . . . . Thrombosis in acute promyelocytic leukemia . . . . . . . . . . . . . . . . . . Pathogenesis of thrombosis in acute leukemia. . . . . . . . . . . . . . . . . . Thrombosis in lymphoma . . . . . . . . . . . . . . . . . . . . . . . . . . . Thrombosis in multiple myeloma and related disorders . . . . . . . . . . . . . Risk factors and pathogenetic mechanisms of thrombosis in plasma cell disorders . Thrombosis and survival . . . . . . . . . . . . . . . . . . . . . . . . . . . . Prophylaxis and therapy of thrombosis in hematologic malignancies . . . . . . . . Summary and conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . Conflict of interest statement . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Introduction Approximately 10-15% of patients with overt cancer will have a thrombotic complication during the course of the illness, but the rate of thrombosis in cancer varies greatly from 0.1% to 60% in relation to the tumor type, stage, and treatment (surgery, chemotherapy, radiotherapy or hormonal treatments) [1,2]. On the other side, in patients with a first episode of apparently idiopathic thrombosis, ⁎ Corresponding author at: Department of Cell Therapy and Hematology, San Bortolo Hospital, Viale Rodolfi, 37, 36100 Vicenza, Italy. Tel.: + 39 0444 753626; fax: + 39 0444 920708. E-mail address: [email protected] (F. Rodeghiero). 0049-3848/$ – see front matter © 2011 Elsevier Ltd. All rights reserved. doi:10.1016/j.thromres.2011.11.034
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20% are discovered to already have a malignancy and in up to 34% a new cancer will be diagnosed within one year [3]. Risk of venous thromboembolism (VTE) in hematologic diseases was considered lower than in solid tumors for long time and frequent fluctuations of platelet count have drawn most attention to the hemorrhagic complications as the major risk. However, recent reports suggest that the incidence of thromboembolic events in oncohematologic diseases may be similar to that found in solid tumors. In addition, the widespread use of central vein catheters (CVC) and the introduction of new immunomodulatory drugs (IMiDs: thalidomide, lenalidomide, pomalidomide) in the treatment of many hematologic neoplams have further enhanced the problem of thrombotic complications.
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In this review, we will discuss the incidence, risk factors and pathogenesis of thromboembolism in hematologic malingnancies. Philadelphia-negative myeloproliferative neoplasms have not been included because thrombotic events are intrinsic typical manifestations of the disease and require a completely different clinical approach. This report is not intended to be a comprehensive analysis of all works of this large field, so only the most relevant studies have been considered. Thrombosis in acute leukemia Incidence of VTE in acute leukemia ranges from 2.1% in the large retrospective analysis of Ziegler et al. [4] up to 12.1% in the retrospective study of Mohren et al. [5], as summarized in Table 1. However, the first study reported only VTE events observed at diagnosis or within the preceding 4 months. A prospective study including 379 leukemia patients [6] reported a 6.3% rate of thrombosis (80% venous and 20% arterial): about half of them (3.4%) were present at the time of diagnosis and all events occurred within 6 months from diagnosis. Pulmonary embolism was reported in 4 out of 24 patients (17%) and upper vein thrombosis in 4%, a very low rate in comparison with other series. A recurrent event occurred during remission in 5 patients. Fatalities for thrombosis accounted for 1% of all deaths. While no statistically significant differences were found in the incidence of thrombosis at the time of diagnosis between acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL) (1.4% vs. 3.2%, P = 0.1), a significant difference has been observed in the follow-up, with a cumulative 6-month rate of thrombosis of 10.6% in ALL and 1.7% in nonpromyelocytic AML. As in almost all series, acute promyelocytic leukemia (APL) had a higher incidence of thrombosis, both at diagnosis and during follow-up (9.6% and 8.4% respectively); VTE risk APL will be discussed later. The higher rate of thrombosis in ALL can be explained by iatrogenic events associated with the use of steroids and asparaginase in this disease. However this observation was not confirmed in other large series [4,7], in which AML and ALL had similar incidence of VTE. In studies including only children with ALL, incidence of VTE shows a broad range of variation (1-37%), mainly due to the different therapeutic protocols. In a recent meta-analysis, the rate of thrombosis in pediatric patients was 5.2% [8]. Children receiving asparaginase concomitant with prednisone have the highest risk of VTE and surprisingly the risk was higher for those receiving lower doses of asparaginase; Escherichia coli asparaginase seems associated with a higher risk of thrombosis in comparison with Erwinia asparaginase; as expected, prolonged use of asparaginase increases the
Table 1 Incidence of thromboembolic complications in hematologic malignancies. Disease
Overall incidence
Reference
MGUS
6% 3% 10% 10% 5-10% 11% 7,5% 6% 3% 7% 3% 6,5% 6% 2% 12%
Sallah et al. [27] Kristinsson et al. [29] Skralovic et al. [28] Barlogie et al. [31] Rickles et al. [2] Mohren et al. [22] Sgarabotto et al. [71] Mohren et al. [22] Sgarabotto et al. [71] Mohren et al. [22] Sgarabotto 2008 Sgarabotto et al. [71] De Stefano et al. [6] Ziegler et al. [4] Mohren et al. [5]
Myeloma Lymphoma High-grade non-Hodgkin lymphoma Low-grade non-hodgkin lymphoma Hodgkin lymphoma Myelodysplastic syndromes Acute leukemia
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VTE risk. Treatment with prednisone instead of dexamethasone, anthracyclines use, induction phase of treatment, presence of a CVC (strongly associated with upper vein thrombosis), and presence of at least one genetic prothrombotic defect (8-fold increased risk of VTE) were other risk factors for thrombosis in ALL children [8,9]. While deep vein thrombosis of lower limbs was the most common form of VTE in adults with ALL [10], the majority of symptomatic complications in children are localized in the central nervous system and in upper veins; thrombosis involving the cerebral venous sinuses is a unique feature of asparaginase-related thrombosis which is reported to occur in 1-3% of patients [9,11]. A large retrospective population-based study of VTE in 5394 leukemia patients was conducted in California using administrative dataset [7]. The two-year cumulative incidence of VTE was 5.2% in AML and 4.5% in ALL: also in this series most events occurred in the first months from diagnosis of leukemia. They observed a higher incidence of pulmonary thromboembolism (20% of VTE events in AML and 17% in ALL) and upper vein thromboses (31% of VTE in AML, but a sensitivity analysis calculated 58% of upper vein thromboses when possible miscoded events were counted). Upper extremities deep vein thromboses were highly associated with the presence of a CVC. In a multivariate analysis of the Californian series, the following risk factors were significant predictors of VTE: age >25 years, multiple comorbidities, presence of a CVC, female sex (only for AML)[7]. In the Italian study previously described, leucocyte or platelet count was not found to influence the risk of thrombosis [6]. A single center study of inherited and acquired prothrombotic risk factors in adult leukemia patients found that only hyperhomocysteinemia was significantly associated with VTE in multivariate analysis, concluding that systematic thrombophilia screening is not recommended in these patients [12]. In the group of adult ALL patients, prolonged treatment with lower doses of asparaginase, use of prednisone (instead of dexamethasone) and use of anthracyclines were associated with an increased risk of VTE [10]. More recently, use of contraceptives in women before the diagnosis of ALL was identified as a risk factor for VTE, while administration of antithrombin concentrates during induction decreased the VTE rate [13]. Thrombosis in acute promyelocytic leukemia APL is a particular subtype of acute myeloid leukemia, characterized by a specific translocation between chromosome 15 and 17, which involves the retinoic acid receptor RAR-alpha and the PML gene (PML/ RARα translocation) and induces an accumulation of promyelocytic blasts . This disease typically presents with hemorrhagic symptoms due to disseminated intravascular coagulation (DIC) and lifethreatening consumption coagulopathy is often present at diagnosis, in particular in patients with hyperleukocytosis. Chemotherapy can further enhance this coagulopathy in the first days of treatment. Fatal thrombotic events also occur at the beginning of the disease: thrombosis (myocardial infarction and pulmonary embolism) was the cause of 3 out of 68 early death observed in a series of 268 APL patients [14]. Since the introduction of therapy with all-trans-retinoic acid (ATRA) and, more recently, arsenic trioxide (ATO), a rapid resolution of the coagulopathy and of the hemorrhagic symptoms has been obtained. In fact, these drugs promote the terminal differentiation of promyelocytic blasts and normalization of clotting and fibrinolytic variables. However, thrombotic events seem to be increased, although the overall incidence is still low. Rates of thrombosis reported at the time of (or just before) diagnosis of APL were 9.6% considering both arterial and venous, 3.2- 6.5% including only venous thromboses [4,6]. In two different series of APL patients treated with ATRA and chemotherapy (AIDA protocol), incidence of thrombosis was 5.6% and 4.5%, but among patients who died before initiation of chemotherapy, 23% had severe thrombotic complications (both arterial and venous), indicating that this complication is clinically
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relevant. In a Spanish study, a correlation has been observed between thrombosis and the differentiation syndrome, which may occur in the first days of treatment with ATRA or ATO. Also in this case, hyperleukocytosis is a risk factor for thrombosis [15]. Pathogenesis of thrombosis in acute leukemia The hypercoagulable state in leukemia derives from the development of DIC and thrombin generation as a result of the presence of a high number of circulating leukemic blasts, which have been shown to express tissue factor (TF) and release cancer procoagulant from their granular fractions [16]; leukemic promyelocites show the highest procoagulant activity and thrombin generation correlates with blast cell count in APL [17]. The treatment can also enhance the hypercoagulable state: asparaginase and steroids have been shown to suppress natural anticoagulants, especially antithrombin and plasminogen, and cause elevations in factor VIII/von Willebrand factor complex [18]. Acute infections, which often complicates the course of the disease or its treatment, are another important prothrombotic factor: endotoxins from gramnegative bacteria induce the release of TF, tumor necrosis factor (TNF) and interleukin-1, and gram-positive organisms can release bacterial mucopolysaccharides that directly activate factor XII [19]. Age, hospitalization-related immobility and especially the presence of a CVC are additional important factors which contribute to the development of thrombosis. Thrombosis in lymphoma The risk of thrombosis in lymphoma patients is clearly increased, with VTE rates comparable with those of solid tumor patients. The reported incidences of thrombosis in lymphoma patients show a broad range, mainly due to the different study type (prospective or retrospective, with hospitalized or ambulatory patients), the different intensity of the chemotherapeutic protocols used and the different proportion of aggressive or indolent lymphomas in the studied population (see Table 1). In fact, a prospective study with ambulatory patients reported a 1.5% rate of VTE, while the same authors reported a 4.8% VTE rate in a large population of hospitalized patients studied retrospectively [20,21]. In all studies, most events occurred in the first months of treatment (within 3–6 months). In a large single-center retrospective analysis [22], 7.7% of the 1038 lymphoma patients experienced at least one thrombotic event: most episodes occurred during treatment (72%), while only a minority was observed prior to (17%) or after completion (11%) of chemotherapy, thus confirming the known thrombogenic effect of chemotherapy also in this group of patients. Deep vein thrombosis (53% ), pulmonary emobolism (20%), CVC-related thrombosis (11%) were the most common sites of VTE, arterial thrombosis was observed in only 2% of cases. Histology was very important for the thrombotic risk, with highest rate of thromboembolism in highgrade non Hodgkin lymphomas (10.6%), followed by Hodgkin lymphomas (7.25%) and the lowest risk in low-grade non Hodgkin lymphomas (5.8%). These figures were confirmed by data from several studies including patients with different types of lymphoma: for high-grade lymphomas the prospective study of Ottinger et al. [23] showed a 6.6% VTE rate while the retrospective study of Komrokji et al. [24] found a 12.8% VTE rate in a group of patients with diffuse large B-cell lymphoma (the most common high-grade lymphoma); rate of VTE in Hodgkin lymphoma ranges from 4.6% reported by Khorana et al. [21] in his large retrospective analysis to 8.1% in the prospective analysis of the same author [20], up to 11.5% in a retrospective study in pediatric patients [18]. A registry-based analysis performed in California found a 2-year cumulative incidence of VTE of 2.2%, 4.7% and 4.5% in low-, intermediate- and high-grade lymphomas respectively [25].
The highest incidence of VTE was reached in a study of patients with central nervous system lymphoma, where thrombotic complications were observed in 59.5% and 7% were fatal [26]. This reflects the very high rate of thrombosis observed in other brain tumors, probably due to the restricted mobility often associated with this localization of the malignancy. In contrast with the studies in leukemia patients, platelet count before the initiation of chemotherapy was found to predict thrombosis in a prospective study with ambulatory lymphoma patients [20]. In patients with diffuse large B-cell lymphoma a high international prognostic index (IPI) score, indicating a more aggressive disease, was associated with a higher VTE rate [24] The presence of a mediastinal mass was predictive of an increased VTE rate in pediatric patients [18]: this observation suggests the important role of the tumor mass effect in lymphoma patients, like in solid tumor patients, as additional risk factor for thrombosis. Other common risk factors like age, stage, immobility, infection, presence of a CVC and intensive chemotherapy are associated with thrombosis also in lymphoma patients, even if a statistically significant correlation was only variably reported. Thrombosis in multiple myeloma and related disorders Patients with a monoclonal gammopathy have a higher incidence of VTE compared to the general population. The presence of a serum monoclonal protein is associated to thromboembolism; incidence of thrombosis in patients with benign monoclonal gammopathy of undetermined significance (MGUS) was 6.1% in a prospective analysis of 310 individuals [27] and 7.5% in a retrospective study with 174 patients [28]. Two large population-based studies were performed in order to better define thrombotic risk in MGUS and in multiple myeloma (MM) patients: the first included data of more than 4 million veterans in the USA and the second was conducted in Sweden using data of a medical care registry from 1958 to 2006. Among veterans hospitalized at least once 23374 cases of MGUS and 6192 cases of MM were identified: the crude incidence of deep venous thrombosis (DVT) was 3.1/1000 person-year for MGUS and 8.7 for MM [29]. In the Swedish study, patients with MGUS showed a higher risk of VTE and a slight increase of arterial thrombosis compared to a matched control group: hazard ratios at 1 and at 10 years were 3.4 and 2.1 for VTE and 1.7 and 1.3 for arterial thrombosis [30]. Interestingly, only IgG and IgA MGUS (but not IgM) had an increased risk of thrombosis and the levels of the monoclonal protein did not affect thrombotic risk. In addition, occurrence of a thrombotic event was not associated with progression to MM, suggesting that the presence of an IgG or IgA immunoglobulin or other plasma cell activities plays an intrinsic role in the development of thrombosis. The presence of MM, the malignant disease associated with a monoclonal immunoglobulin, can further increase this risk, in particular in conjunction with specific treatments. In fact, about 10% of MM patients treated with standard chemo- and radiotherapy experience a thrombotic complication [28,31]. In the Swedish study, hazard ratios for VTE or arterial thrombosis in MM patients were 7.5 and 1.9 respectively at one year (the period with the highest thrombotic risk) and 4.1 and 1.5 at 10 years [30]. With the introduction of new agents with immunomodulatory activity (IMiDs) in the treatment of MM and other solid tumors, an unexpected high rate of VTE was observed. Thromboembolism did not appear as a major complication when thalidomide or its derivative lenalidomide were used as single agents for relapsed or refractory MM patients. A modest VTE incidence (b5%) was observed in a phase II study with thalidomide in 169 extensively pre-treated patients [32]; a similar experience was later reported by other investigators in similar settings [33,34]. Also in the case of lenalidomide, the first phase I and II trials in relapsed/refractory patients did not show any increase in thrombotic risk [35]. However, in newly diagnosed myeloma patients treated with thalidomide and high-dose dexamethasone the
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incidence of VTE increased up to 26% [36]. Similarly, two multicenter randomized phase III trials comparing lenalidomide plus dexamethasone versus dexamethasone alone in relapsed/refractory MM patients (MM-009 study in North America and MM-010 study internationally) showed a higher VTE incidence in the lenalidomide arm: in MM-009 VTE rate was 14.7% vs 3.4%, in MM-010: 11.4% vs 4.6% [37,38]. An increased rate of thrombosis was reported in a trial comparing dexamethasone alone versus dexamethasone plus lenalidomide in newly diagnosed patients; 9 out of the first 12 patients enrolled in the lenalidomide/dexamethasone arm without anticoagulation developed thrombosis, including one ischemic stroke, while no events were reported in 9 patients of the control arm [39]. The thrombogenic potential of this class of drugs was definitively confirmed by a phase III trial with upfront randomization to chemotherapy with or without thalidomide; the observed incidence of VTE was significantly higher in the thalidomide arm (28% vs. 4%; P = .002) [40]. Other studies confirmed such observation, as summarized in Table 2. Among the different chemotherapy agents used in combination with thalidomide, doxorubicin (doxo) was shown to carry the highest risk of thrombosis: in 232 MM patients treated with two protocols that differed only by the inclusion of doxorubicin in one, VTE incidence was significantly higher in the doxo group (16% vs. 3.5%, P = .02) [41]. All events reported in these studies were clinically significant, producing symptoms that prompted instrumental investigations, not otherwise planned. Amyloidosis has been frequently associated with venous and arterial thrombosis. In a group of 56 amyloidosis patients with a median age of 67 years, 11% developed VTE after a median of 12.5 months from diagnosis [42]. Surprisingly, the presence of circulating monoclonal protein was not a risk factor for VTE, while older age, immobility and personal history of DVT were found to increase the thrombotic risk. Risk factors and pathogenetic mechanisms of thrombosis in plasma cell disorders Tumor procoagulant activity of malignant cells, host inflammatory responses and extrinsic factors, which are frequently iatrogenic, contribute to the pathogenesis of thrombosis in cancer. For MM and related diseases, monoclonal immunoglobulin-specific mechanisms may also be involved: hyperviscosity, decreased fibrinolysis, procoagulant autoantibody
Table 2 Incidence of thrombotic complications in multiple myeloma patients treated with different regimens including thalidomide or lenalidomide without antithrombotic prophylaxis. No data are available for lenalidomide plus chemotherapy, because all trials with this type of combination included a thromboprophylaxis. Reference
N.
Treatment
% Thrombosis
Newly diagnosed patients Rajkumar, 2003 Cavo, 2004 Rajkumar, 2006 Zangari, 2001 50 Thal /Doxo-chemo Palumbo, 2006 Zonder, 2006 Niesvizky, 2005
31 19 102 28 65 12 22
Thal Thal /Dex Thal /Dex
3 26 17
Thal /MP Lena/Dex Lena/Dex
18 75 14
Relapsed/refractory patients Singhal, 1999 Anagnostopoulos, 2003 Oakervee, 2002 Urbauer, 2002 Zangari, 2002 Zangari, 2002 Weber, 2007 Dimopoulos, 2007
169 47 9 14 40 192 177 176
Thal Thal /Dex Thal /MP Thal /DCEP Thal /DCEP Thal /Doxo-chemo Lena/Dex Lena/Dex
b2 8 11 21 3 16 15 11
Abbreviations : Thal: Thalidomide; Lena: Lenalidomide; Dex: Dexamethasone; Doxo: doxorubicin; DCEP: dexamethasone/ cyclophosphamide/ etoposide/ cisplatin; MP: melphalan/ prednisone.
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production, effects of inflammatory cytokines, acquired activated protein C (APC) resistance. Multiple clinical experiences (Table 2) suggest that newly diagnosed patients treated with chemotherapy plus thalidomide have the highest risk to develop a thrombotic event. In a multivariate analysis of 535 MM patients treated with thalidomide in various combinations, newly diagnosed status, thalidomide/doxorubicin regimen and presence of chromosome 11 abnormalities were the only independent risk factors for VTE [43]. A retrospective analysis conducted in 1178 patients confirmed higher thrombotic risk in newly diagnosed and thalidomide-treated patients, but also identified light chain disease, elevated C-reactive protein (CRP) and acquired resistance to APC as independent risk factors for thrombosis [44]. Because most of thromboembolic episodes occurred in the first months of treatment (50% within 2 months), a thrombogenic role was postulated for the release of myeloma cell factors rather than for a direct toxic effect of drugs. However, disease stage and serum monoclonal protein levels failed to show a significant direct correlation with VTE in two different analyses [41,44]. The thrombophilic state associated with myeloma derives from the activation of the coagulation pathways and from the decrease of natural anticoagulant mechanism. In fact, high levels of inflammatory cytokines have been described in patients with myeloma [45], in particular TNF, CRP and interleukin 6 (IL-6); the latter reflects the proliferative activity of myeloma cells and has been shown in vitro to activate the clotting cascade by increasing fibrinogen, TF and factor VIII concentrations [46,47]. Indeed, high serum levels of IL-6, factor VIII and von Willebrand factor antigen have been described in patients with active disease [48]. In addition, reduced anticoagulant response to APC and reduced protein S levels have been described in a significant proportion of patients, and correlated with the risk of VTE [44,49]. Under normal conditions, APC together with protein S are essential anticoagulant mechanisms which can inhibit activated factor V and factor VIII. The observation of an acquired resistance to APC was described with an unexpected high incidence (23%) in a group of 62 newly diagnosed MM patients with active disease [50]; such abnormality was associated with an increased incidence of VTE, as later confirmed in a much larger population, and was noted to be a transient condition linked to the activity of the disease [44]. Other mechanisms related to the monoclonal protein or plasma cell activities can enhance the risk of thrombosis in MM. High levels of immunoglobulin and increased blood viscosity can impair fibrin polymerization, causing the formation of abnormal clots, which impair fibrinolyis by interfering with the binding sites of plasmin and factor XIII [51]. Furthermore, abnormal fibrin assembly has been observed in patients with production of thinner and weaker strands that are more resistant to fibrinolytic activity of plasmin. Yagci et al. [52] reported an inverse correlation between global fibrinolytic capacity (GFC) and levels of plasminogen activator inhibitor 1 (PAI-1), suggesting that decreased GFC is mainly caused by elevation of PAI-1 activity. Interestingly, PAI-1 levels correlated with CRP and IL-6 levels, which are often elevated in MM. The monoclonal protein may have intrinsic prothrombotic properties itself. Indeed, several studies have shown the presence of immunoglobulins with lupus anticoagulant activity: most probably this activity depends on the electrostatic charge of the immunoglobulin [53]. Thrombosis and survival Although a thrombotic event can be very difficult to manage in patients with severe thrombocytopenia, like most leukemia patients, the prognosis seems not to be significantly affected: In the study of Ziegler et al. [4], VTE before or at the time of diagnosis of acute leukemia was not associated with reduced overall or disease-free survival. In the registry-based Californian study a worse prognosis was associated with VTE only in ALL patients, but not in AML patients [7]. In one
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study with diffuse large B-cell lymphoma patients, the occurrence of a thrombotic complication predicts a worse prognosis, with a median OS of 1.04 years in patients with VTE compared to 5.2 years in those without VTE [24]. In MM patients treated with chemotherapy or with IMiDs, the development of VTE did not affect overall or event-free survival [54,55]. Also in the American and in the Swedish population-based studies, thrombotic complications in MM patients or in MGUS patients who progressed to MM had no effect on survival [29,30]. However, thrombosis was associated with reduced survival in MGUS patients [29]. In the case of amyloidosis, the development of a thrombotic event results in a substantial morbidity and mortality and complicates the management of an already complex clinical condition: the median survival was 3 months in patients with arterial thrombosis and 16 months in those with venous thrombosis was [56]. The absence of prognostic value of VTE in leukemia or MM can be explained considering that whereas in solid tumors metastatic spread occurs in the most advanced phases, leukemia or myeloma are always disseminated from the beginning and this feature does not translate in a more aggressive behavior. As procoagulant activation and TF expression are associated with metastatic spread, VTE in solid tumor is often a sign of advanced disease, but this is not the case for acute leukemia or MM. Prophylaxis and therapy of thrombosis in hematologic malignancies Prevention of thrombotic complications in hematologic malignancies remains a challenging issue and no evidence-based guidelines are available. The few data available in the literature usually come from subanalyses of trials in which thrombotic complications or their prophylaxis were not included in the endpoints. The consensus is that primary antithrombotic prophylaxis should be carried out in cancer patients undergoing surgical procedures; AIOM (Italian Association of Medical Oncology) and ACCP (American College of Chest Physicians) guidelines recommends prophylaxis also for oncologic medical patients if bedridden or with an acute illness; ASCO (American Society of Clinical Oncology) and NCCN (National Comprehensive Cancer Network) guidelines recommends prophylaxis for all cancer patients during hospitalization [57]. While there are no recommendations on prophylaxis for ambulatory cancer patients with other risk factors (e.g. chemotherapy, hormone therapy or use of antiangiogenic agents), in the case of ambulatory MM patients treated with thalidomide or lenalidomide in combination with dexamethasone or chemotherapy, ASCO and ESMO (European Society of Medical Oncology) guidelines recommend prophylaxis with low molecular weight heparin (LMWH) or adjusted-dose warfarin (INR 2–3) [58,59]. Current guidelines cover only a little part of oncohematologic patients. Hemorrhagic complications associated with anticoagulant or antiaggregant therapy pose particular problems in these patients because they are thrombocytopenic for prolonged time. In leukemia and lymphoma patients preventive strategies are hampered by the lack of validated markers of increased thrombotic risk for patient selection. An exploratory small multicenter study [60] suggested the possibility to reliably stratify children with ALL for the risk of thrombosis considering type of chemotherapy, presence of a genetic thrombophilic factor and presence of CVC. Most data available on the prevention of thrombosis in oncohematologic diseases come from studies in MM patients. In fact, the increased rate of thrombosis observed after the introduction of antiangiogenic agents in MM therapy warranted the introduction of antithrombotic prophylaxis in new trials with these drugs. Table 3 summarizes VTE incidence using different strategies of thromboprophylaxis in myeloma patients treated with thalidomide or lenalidomide. In the first thalidomide and dexamethasone combination trials, prophylactic fixed low dose warfarin or aspirin modestly reduced the incidence of VTE [61,62]. In patients treated upfront with a combination
of thalidomide and chemotherapy in Arkansas, fixed 1 mg daily dose of warfarin did not change significantly the incidence of VTE in patients treated [63]. The prothrombotic effect of doxorubicin-containing chemotherapy combined with thalidomide (see Table 2) was completely abrogated by the prophylactic use of the LMWH enoxaparin (40 mg/ d) or comparable doses of other LMWH (nadroparin) [63,64]. Reduction of VTE incidence (18%) was observed also with prophylactic fixed low dose aspirin in patients treated with thalidomide, dexamethasone and chemotherapy [62]. Aspirin has been widely used in protocols with lenalidomide/dexamethasone: reports from different centers ranges from 3% to 19% [39,65]. The strength of the evidence supporting the efficacy of aspirin in the prevention of VTE in lenalidomide-treated patients is low, because it is based on retrospective studies [66], but this is the case of almost all studies in this setting. Recently, two prospective randomized trials of the GIMEMA group have been published in MM patients. One prospective randomized trial compared prophylaxis with enoxaparin 40 mg/d, aspirin 199 mg/d or fixed-dose warfarin (1.25 mg/d) in newly diagnosed MM patients treated with thalidomide and dexamethasone as pretranplantation induction (if younger than 65 years) or with bortezomib-melphalan-prednisone-thalidomide (if older than 65 years) [67]. Incidence of venous or arterial thromboembolic events and sudden deaths in the first 6 months of treatment were not significantly different with the three types of prophylaxis: 5% in the LMWH arm, 6.4% in the aspirin arm and 8.2% in the warfarin arm. Bleeding complications were also similar in the three arms. However, in the group of elderly patients, warfarin was less effective than LMWH. As reported by other studies, bortezomib reduced thalidomideassociated risk of thrombosis (not statistically significant in this trial). The second trial compared prophylaxis with LMWH (enoxaparin 40 mg/d) or low-dose aspirin (100 mg) in 342 newly diagnosed MM patients treated with lenalidomide and low-doses of steroids
Table 3 Incidence of thromboembolic events with prophylactic anticoagulation in thalidomidetreated patients. Status No Warfarin Low molecular Aspirin References (D/R) prophylaxis 1- 1.25 mg/d weight heparin % VTE
% VTE
% VTE
Thalidomide + dexamethasone D 20-26% 13-25%
R
% VTE 7%*
2-8%
Thalidomide + melphalan/ prednisone D 12-18% 5%
Facon [77]; Palumbo [78]
Thalidomide + chemotherapy with doxorubicin D 10-34% 14-31% 10-15%
R
Zangari [63]; Zervas et [79]; Minnema [64] Zangari [63]
16%
Lenalidomide + dexamethasone D 75%
Rajkumar [72], Cavo [61], Weber [73], Hassoun [74] Palumbo [75]; Anagnostopoulos [76]
3-19%
Rajkumar [65]; Zonder[39] Dimopoulos [38]
Lenalidomide + melphalan and prednisone R
2%
Palumbo [69]
Lenalidomide + chemotherapy with doxorubicin R
9%
Baz [62]
R
8%
Abbreviations: D, diagnosis; R, relapsed/refractory. *Thalidomide and dexamethasone were administered to newly diagnosed patients after an initial debulking chemotherapy.
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followed by consolidation with melphalan-prednisone-lenalidomide: VTE incidence was 2.27% in the aspirin arm and 1.2% in the LMWH arm (not statistically different), with 1.7% of pulmonary embolism in the aspirin arm and none in the LMWH arm [68]. Both studies showed only a trend for a more effective thrombophylaxis with LMWH, but aspirin and warfarin are more manageable and less expensive alternatives. Before GIMEMA trials were available, given the absence of evidencebased data, an international panel recommended the use of LMWH in MM treated with thalidomide or lenalidomide combined with highdose dexamethasone or chemotherapy when two or more other risk factors are present, otherwise aspirin should be used. Adjusted-dose warfarin was considered an alternative to LMWH. Risk factors identified by the panel were the following: obesity, previous VTE, presence of CVC, diabetes mellitus, chronic renal or cardiac disease, immobilization, acute infection, surgery, use of erythropoietin. However, no clear supporting evidences for these recommendations are offered [69]. Recommended treatment of VTE in patients with hematologic malignancies is LMWH. In fact, anticoagulation with warfarin is associated with high rates of recurrent VTE and bleeding in patients with cancer. This therapy is also difficult to supervise in this group of patients. In the CLOT trial, low molecular weight heparin appeared more efficacy than warfarin for the secondary prevention of VTE in cancer patients [70]. In thalidomide-treated MM patients who developed VTE, the single institution experience of the Arkansas group indicated that it is reasonable to resume the thalidomide treatment when full anticoagulation has been established and continued for the total duration of therapy [63]. The rate of VTE recurrence was overall 13.8%, not significantly different from the rate observed in other cancers (9-17%) [70]. Summary and conclusions Patients with hematologic malignancies have an increased risk of VTE, particularly at diagnosis and during the treatment with chemotherapy, asparaginase or IMiDs. A disease-dependent hypercoagulable condition associated with other risk factors like drugs, CVC, immobility and infections are responsible for this high VTE rate. Thrombotic complications have a significant impact on morbidity and in some cases also on mortality of patients with onco-hematologic diseases, therefore thromboprophylaxis to prevent VTE in this setting is needed. However, thrombocytopenia and hemorrhagic complications pone many difficulties in the management of an anticoagulant or antiaggregant treatment in these patients. Recommendations from current guidelines are limited to myeloma patients treated with thalidomide or lenalidomide associated with dexamethasone or chemotherapy, but hematological clinical departments should implement a policy for prevention and treatment of thromboembolic complications in hematologic malignancies. Conflict of interest statement No conflict of interest References [1] Scates SM. Diagnosis and treatment of cancer-related thrombosis. Semin Thromb Hemost 1992;18:373–9. [2] Rickles FR, Levine MN. Epidemiology of thrombosis in cancer. Acta Haematol 2001;106(1–2):6–12. [3] Piccioli A, Prandoni P. Venous thromboembolism as first manifestation of cancer. Acta Haematol 2001;106(1–2):13–7. [4] Ziegler S, Sperr WR, Knöbl P, Lehr S, Weltermann A, Jäger U, et al. Symptomatic venous thromboembolism in acute leukemia. Incidence, risk factors, and impact on prognosis. Thromb Res 2005;115(1–2):59–64. [5] Mohren M, Markmann I, Jentsch-Ullrich K, Koenigsmann M, Lutze G, Franke A. Increased risk of venous thromboembolism in patients with acute leukaemia. Br J Cancer Jan. 30 2006;94(2):200–2.
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