Enoxaparin or aspirin for the prevention of recurrent thromboembolism in newly diagnosed myeloma patients treated with melphalan and prednisone plus thalidomide or lenalidomide
2006; Elsevier BV; Volume: 4; Issue: 8 Linguagem: Inglês
10.1111/j.1538-7836.2006.02059.x
ISSN1538-7933
AutoresAntonio Palumbo, Carla P. Rus, Jerome B. Zeldis, Francesco Rodeghiero, Mario Boccadoro,
Tópico(s)Myeloproliferative Neoplasms: Diagnosis and Treatment
ResumoVenous thromboembolism (VTE) is a common complication in cancer patients [1Blom J.W. Doggen C.J. Osanto S. Rosendaal F.R. Malignancies, prothrombotic mutations, and the risk of venous thrombosis.JAMA. 2005; 293: 715-22Crossref PubMed Scopus (1519) Google Scholar]. The risk is particularly high after surgery, during chemotherapy and in association with central vein catheters [2Baron J.A. Gridley G. Weiderpass E. Nyren O. Linet M. Venous thromboembolism and cancer.Lancet. 1998; 351: 1077-80Abstract Full Text Full Text PDF PubMed Scopus (465) Google Scholar]. Aggressive antitumor therapy with thalidomide or lenalidomide increases the risk of thrombosis. The underlying mechanisms are poorly understood, but these therapeutic agents induce vascular damage [3Zangari M. Saghafifar F. Anaissie E. Badros A. Desikan R. Fassas A. Mehta P. Morris C. Toor A. Whitfield D. Siegel E. Barlogie B. Fink L. Tricot G. Activated protein C resistance in the absence of factor V Leiden mutation is a common finding in multiple myeloma and is associated with an increased risk of thrombotic complications.Blood Coagul Fibrin. 2002; 13: 187-92Crossref PubMed Scopus (137) Google Scholar, 4Lee A.Y.Y. Levine M.N. The thrombophilic state induced by therapeutic agents in the cancer patient.Semin Thromb Hemost. 1999; 25: 137-46Crossref PubMed Scopus (188) Google Scholar, 5Zangari M. Barlogie B. Thertulien R. Jacobson J. Eddleman P. Fink L. Fassas A. Van Rhee F. Talamo G. Lee C.K. Tricot G. Thalidomide and deep vein thrombosis in multiple myeloma: risk factors and effect on survival.Clin Lymph. 2003; 4: 32-5Abstract Full Text PDF PubMed Scopus (111) Google Scholar, 6Hussein M.A. Lenalidomide: patient management strategies.Semin Hematol. 2005; 42: S22-5Crossref PubMed Scopus (23) Google Scholar, 7Minnema M.C. Fijnheer R. De Groot P.G. Lokhorst H.M. Extremely high levels of von Willebrand factor antigen and of procoagulant factor VIII found in multiple myeloma patients are associated with activity status but not with thalidomide treatment.J Thromb Haemost. 2003; 1: 445-9Abstract Full Text Full Text PDF PubMed Scopus (121) Google Scholar]. The risk of thrombosis is higher for myeloma patients receiving thalidomide at diagnosis in comparison with those treated at relapse [8Zangari M. Anaissie E. Barlogie B. Badros A. Desikan R. Gopal A.V. Morris C. Toor A. Siegel E. Fink L. Tricot G. Increased risk of deep-vein thrombosis in patients with multiple myeloma receiving thalidomide and chemotherapy.Blood. 2001; 98: 1614-5Crossref PubMed Scopus (435) Google Scholar, 9Rajkumar S.V. Gertz M.A. Lacy M.Q. Dispenzieri A. Fonseca R. Geyer S.M. Iturria N. Kumar S. Lust J.A. Kyle R.A. Greipp P.R. Witzig T.E. Thalidomide as initial therapy for early-stage myeloma.Leukemia. 2003; 17: 775-9Crossref PubMed Scopus (205) Google Scholar, 10Palumbo A. Bertola A. Falco P. Rosato R. Cavallo F. Giaccone L. Bringhen S. Musto P. Pregno P. Caravita T. Ciccone G. Boccadoro M. Efficacy of low dose thalidomide and dexamethasone as first savage regimen in multiple myeloma.Hematol J. 2004; 5: 318-24Crossref PubMed Scopus (126) Google Scholar, 11Palumbo A. Bertola A. Musto P. Caravita T. Callea V. Nunzi M. Grasso M. Falco P. Cangialosi C. Boccadoro M. Oral melphalan, prednisone, and thalidomide for newly diagnosed patients with myeloma.Cancer. 2005; 104: 1428-33Crossref PubMed Scopus (73) Google Scholar]. Similarly, the risk is higher for combinations including chemotherapeutic agents such as melphalan or doxorubicin in comparison with combinations including corticosteroids only [12Dimopoulos M.A. Anagnostopoulos A. Weber D. Treatment of plasma cell dyscrasias with thalidomide and its derivatives.J Clin Oncol. 2003; 21: 4444-54Crossref PubMed Scopus (112) Google Scholar]. Low-molecular-weight heparin (LMWH) is considered the standard prophylaxis in these patients [13Alikhan R. Cohen A.T. Combe S. Samama M.M. Desjardins L. Eldor A. Janbon C. Leizorovicz A. Olsson C.G. Turpie A.G. Prevention of venous thromboembolism in medical patients with enoxaparin: a subgroup analysis of the MEDENOX study.Blood Coagul Fibrin. 2003; 14: 341-6Crossref PubMed Scopus (245) Google Scholar]. Low-intensity warfarin and aspirin have been used in these conditions [14Zangari M. Barlogie B. Anaissie E. Saghafifar F. Eddlemon P. Jacobson J. Lee C.K. Thertulien R. Talamo G. Thomas T. Van Rhee F. Fassas A. Fink L. Tricot G. Deep vein thrombosis in patients with multiple myeloma treated with thalidomide and chemotherapy: effects of prophylactic and therapeutical anticoagulation.Br J Haematol. 2004; 126: 715-21Crossref PubMed Scopus (210) Google Scholar, 15Baz R. Li L. Kottke-Marchant K. Srkalovic G. McGowan B. Yiannaki E. Karam M.A. Faiman B. Jawde R.A. Andresen S. Zeldis J. Hussein M.A. The role of aspirin in the prevention of thrombotic complications of thalidomide and anthracycline-based chemotherapy for multiple myeloma.Mayo Clin Proc. 2005; 80: 1568-74Abstract Full Text Full Text PDF PubMed Scopus (210) Google Scholar, 16Cavo M. Zamagni E. Cellini C. Tosi P. Cangini D. Cini M. Valdre L. Palareti G. Masini L. Tura S. Baccarani M. Deep-vein thrombosis in patients with multiple myeloma receiving first-line thalidomide-dexamethasone therapy.Blood. 2002; 100: 2272-3Crossref PubMed Scopus (128) Google Scholar]. In a recent report, nine of the first 12 newly diagnosed myeloma patients, who received lenalidomide and dexamethasone, developed thromboembolism [17Zonder J.A. Durie B.G.M. McCoy J. Crowley J. Zeldis J.B. Ghannam L. Barbogie B. High incidence of thrombotic events observed in patients receiving lenalidomide (L) + dexamethasone (D) (LD) as first-line therapy for multiple myeloma (MM) without aspirin (ASA) prophylaxis.Blood. 2005; 106: 3455Crossref Google Scholar]. In this retrospective analysis of different trials, the incidence of VTE was evaluated in newly diagnosed myeloma patients, whose characteristics are listed in Table 1.Table 1Patients’ characteristics according to treatment groupCharacteristicMP (n = 144)MPT (n = 65)MPT enoxaparin (n = 78)RMP aspirin (n = 50)Age (years)Median age7271.57371Range54–8659–8263–8957–78Stage, n (%)II59 (41)29 (44)28 (36)21 (42)III85 (59)36 (66)50 (64)29 (58)M-protein class, n (%)IgG80 (56)43 (66)48 (61)20 (40)IgA44 (30)12 (18)22 (28)17 (34)Bence Jones protein20 (14)10 (16)8 (10)10 (20)Non-secretory–––3 (6)Bone marrow plasmocytosis (%)Median50454560Range5–955–755–956–90Serum β2-microglobulinMedian (mg L−1)3.73.443.4Range (mg L−1)0.2–37.50.36–14.80.38–400.2–13.5Plasma C-reactive proteinMedian (mg L−1)1.7232.53Range (mg L−1)0.001–1280.005–1570.1–1110.01–17.2HemoglobinMedian (g dL−1)10.110.910.212Range (g dL−1)6.7–15.57.3–14.77.4–156.8–15.5Serum creatinineMedian (mg dL−1)10.80.81Range (mg dL−1)0.6–6.80.6–10.80.5–4.20.5–1.3MP, melphalan and prednisone; MPT, melphalan, prednisone and thalidomide; RMP, lenalidomide (Revlimid®) melphalan and prednisone. Open table in a new tab MP, melphalan and prednisone; MPT, melphalan, prednisone and thalidomide; RMP, lenalidomide (Revlimid®) melphalan and prednisone. Patients were treated with: (i) melphalan and prednisone alone (MP) as previously reported [18Palumbo A. Bringhen S. Caravita T. Merla E. Capparella V. Callea V. Cangialosi C. Grasso M. Rossini F. Galli M. Catalano L. Zamagni E. Petrucci M.T. De Stefano V. Ceccarelli M. Ambrosini M.T. Avonto I. Falco P. Ciccone G. Liberati A.M. et al.Italian Multiple Myeloma Network, GIMEMAOral melphalan and prednisone chemotherapy plus thalidomide compared with melphalan and prednisone alone in elderly patients with multiple myeloma: randomised controlled trial.Lancet. 2006; 367: 825-31Abstract Full Text Full Text PDF PubMed Scopus (754) Google Scholar]; (ii) MP plus thalidomide administered at 100 mg day−1 (MPT) without any anticoagulant prophylaxis [18Palumbo A. Bringhen S. Caravita T. Merla E. Capparella V. Callea V. Cangialosi C. Grasso M. Rossini F. Galli M. Catalano L. Zamagni E. Petrucci M.T. De Stefano V. Ceccarelli M. Ambrosini M.T. Avonto I. Falco P. Ciccone G. Liberati A.M. et al.Italian Multiple Myeloma Network, GIMEMAOral melphalan and prednisone chemotherapy plus thalidomide compared with melphalan and prednisone alone in elderly patients with multiple myeloma: randomised controlled trial.Lancet. 2006; 367: 825-31Abstract Full Text Full Text PDF PubMed Scopus (754) Google Scholar]; MPT plus enoxaparin at 40 mg day−1 during the first four months of treatment [18Palumbo A. Bringhen S. Caravita T. Merla E. Capparella V. Callea V. Cangialosi C. Grasso M. Rossini F. Galli M. Catalano L. Zamagni E. Petrucci M.T. De Stefano V. Ceccarelli M. Ambrosini M.T. Avonto I. Falco P. Ciccone G. Liberati A.M. et al.Italian Multiple Myeloma Network, GIMEMAOral melphalan and prednisone chemotherapy plus thalidomide compared with melphalan and prednisone alone in elderly patients with multiple myeloma: randomised controlled trial.Lancet. 2006; 367: 825-31Abstract Full Text Full Text PDF PubMed Scopus (754) Google Scholar]; MP plus lenalidomide (Revlimid®; Celgene Corp, Summit, NJ, USA) administered at 5–10 mg day−1 (MPR) and aspirin 100 mg once a day continuously [19Palumbo A. Falco P. Musto P. Corradini P. Di Raimondo F. Rossi G. Giuliani N. Morabito F. Luraschi A. Falcone A. Omedè P. Gay F. Avonto I. Ambrosini M.T. Bringhen S. Zeldis J. Knight R. Boccadoro M. Petrucci M.T. Oral RevlimidR plus melphalan and prednisone (R-MP) for newly diagnosed multiple myeloma.Blood. 2005; 106: 785Crossref Google Scholar]. Thrombosis was reported to the data center as a serious adverse event. The reporting hospitals were then contacted for further details. As control, a separate questionnaire was sent to all participating centers. All types of venous thrombosis and pulmonary embolism (PE) were included. They were all symptomatic and objectively diagnosed. Diagnosis was confirmed by Doppler ultrasonography or spiral computer tomography. In the MP group, one superficial venous thrombosis and one deep vein thrombosis (DVT) of the leg were reported in two of 144 patients after a median of 4 months (range: 1–6 months) from the start of therapy. In the MPT group who did not receive any anticoagulant prophylaxis, symptomatic DVT, PE, or both occurred in 12 of the 65 patients after a median of 3 months (range: 1–7 months). There were seven DVT of the legs, two DVT with PE, one fatal PE, one superficial vein thrombosis of the leg. One arterial thrombosis of the leg was also reported. Four cases of DVT of the leg were observed in the group of 78 MPT patients who received enoxaparin prophylaxis after a median of 3 months (range: 1–5 months). The prophylaxis was given for 4 months. Two patients had evidence of thromboembolism within 2 months after the discontinuation of enoxaparin. In the RMP group, one of 50 patients, who received aspirin, experienced PE after 1 month from the start of therapy. After a median time of 24 months the incidence of VTE was 1.5% in the MP group, 18.5% in the MPT patients without prophylaxis, 5.2% in the MPT patients with enoxaparin, and 2.1% in the MPR patients with aspirin (Fig. 1). In comparison with MP, the hazard ratio for recurrent VTE in the MPT group without any prophylaxis was 14.3 (95% CI: 3.2–64.3; P < 0.0001); in the MPT group with enoxaparin it was 3.76 (95% CI: 0.69–20.52; P = 0.11); in the MPR group with aspirin it was 1.72 (95% CI: 0.15–19.8; P = 0.67). No significant interactions between treatment group and risk factors were detected. No serious bleeding was observed during both aspirin and enoxaparin prophylaxis. This study shows that the enoxaparin significantly reduces the risk of VTE in patients receiving MPT and that the combination of MPR and aspirin is not associated with any risk of VTE. In newly diagnosed patients, a high incidence of VTE (around 10–30%) was observed during chemotherapy combined with thalidomide [8Zangari M. Anaissie E. Barlogie B. Badros A. Desikan R. Gopal A.V. Morris C. Toor A. Siegel E. Fink L. Tricot G. Increased risk of deep-vein thrombosis in patients with multiple myeloma receiving thalidomide and chemotherapy.Blood. 2001; 98: 1614-5Crossref PubMed Scopus (435) Google Scholar, 9Rajkumar S.V. Gertz M.A. Lacy M.Q. Dispenzieri A. Fonseca R. Geyer S.M. Iturria N. Kumar S. Lust J.A. Kyle R.A. Greipp P.R. Witzig T.E. Thalidomide as initial therapy for early-stage myeloma.Leukemia. 2003; 17: 775-9Crossref PubMed Scopus (205) Google Scholar, 10Palumbo A. Bertola A. Falco P. Rosato R. Cavallo F. Giaccone L. Bringhen S. Musto P. Pregno P. Caravita T. Ciccone G. Boccadoro M. Efficacy of low dose thalidomide and dexamethasone as first savage regimen in multiple myeloma.Hematol J. 2004; 5: 318-24Crossref PubMed Scopus (126) Google Scholar, 11Palumbo A. Bertola A. Musto P. Caravita T. Callea V. Nunzi M. Grasso M. Falco P. Cangialosi C. Boccadoro M. Oral melphalan, prednisone, and thalidomide for newly diagnosed patients with myeloma.Cancer. 2005; 104: 1428-33Crossref PubMed Scopus (73) Google Scholar]. Some non-randomized experiences show that the high frequency of thrombosis after thalidomide-combining chemotherapy can be safely reduced by the prophylactic use of LMWH [14Zangari M. Barlogie B. Anaissie E. Saghafifar F. Eddlemon P. Jacobson J. Lee C.K. Thertulien R. Talamo G. Thomas T. Van Rhee F. Fassas A. Fink L. Tricot G. Deep vein thrombosis in patients with multiple myeloma treated with thalidomide and chemotherapy: effects of prophylactic and therapeutical anticoagulation.Br J Haematol. 2004; 126: 715-21Crossref PubMed Scopus (210) Google Scholar]. Others have tried fixed low-dose warfarin or aspirin as VTE prophylaxis but reported conflicting results. In one trial, low dose coumadin (1 mg day) failed to provide a significant benefit [14Zangari M. Barlogie B. Anaissie E. Saghafifar F. Eddlemon P. Jacobson J. Lee C.K. Thertulien R. Talamo G. Thomas T. Van Rhee F. Fassas A. Fink L. Tricot G. Deep vein thrombosis in patients with multiple myeloma treated with thalidomide and chemotherapy: effects of prophylactic and therapeutical anticoagulation.Br J Haematol. 2004; 126: 715-21Crossref PubMed Scopus (210) Google Scholar]. Cavo et al. [16Cavo M. Zamagni E. Cellini C. Tosi P. Cangini D. Cini M. Valdre L. Palareti G. Masini L. Tura S. Baccarani M. Deep-vein thrombosis in patients with multiple myeloma receiving first-line thalidomide-dexamethasone therapy.Blood. 2002; 100: 2272-3Crossref PubMed Scopus (128) Google Scholar] used 1.25 mg warfarin daily and demonstrated a decrease in VTE incidence from 26% to 9% when treating de novo multiple myeloma (MM) patients with dexamethasone and thalidomide. Baz et al. showed that low-dose aspirin was associated with a lower relative risk of VTE (hazard ratio 0.22; 95% CI: 0.10–0.47; P < 0.001) [15Baz R. Li L. Kottke-Marchant K. Srkalovic G. McGowan B. Yiannaki E. Karam M.A. Faiman B. Jawde R.A. Andresen S. Zeldis J. Hussein M.A. The role of aspirin in the prevention of thrombotic complications of thalidomide and anthracycline-based chemotherapy for multiple myeloma.Mayo Clin Proc. 2005; 80: 1568-74Abstract Full Text Full Text PDF PubMed Scopus (210) Google Scholar]. In several studies, the highest incidence of thromboembolism was noticed during the first 6 months of thalidomide-containing chemotherapy, and all episodes occurred during the first 12 months [14Zangari M. Barlogie B. Anaissie E. Saghafifar F. Eddlemon P. Jacobson J. Lee C.K. Thertulien R. Talamo G. Thomas T. Van Rhee F. Fassas A. Fink L. Tricot G. Deep vein thrombosis in patients with multiple myeloma treated with thalidomide and chemotherapy: effects of prophylactic and therapeutical anticoagulation.Br J Haematol. 2004; 126: 715-21Crossref PubMed Scopus (210) Google Scholar]. In our experience, enoxaparin was instituted for a period of 4 months only. In two of 78 patients who received anticoagulant prophylaxis, thromboembolism was observed within 2 months after the discontinuation of enoxaparin. Although based on only two patients, this observation suggests the prolongation of enoxaparin prophylaxis for the entire period of induction chemotherapy. Further studies are required to assess if 4, 6 or even 12 months of enoxaparin prophylaxis should be delivered. In a large randomized study, VTE was observed in 44 of 246 refractory myeloma patients who received lenalidomide and dexamethasone [20Dimopoulos M.A. Spencer A. Attal M. Prince M. Harousseau J.L. Dmoszynska A. Yu Z. Olesnyckyj M. Zeldis J. Knight R. Study of lenalidomide plus dexamethasone versus dexamethasone alone in relapsed or refractory multiple myeloma (MM): results of a phase 3 study.Blood. 2005; 106: 6Crossref Google Scholar], but nine of 12 newly diagnosed patients who received the same combination developed VTE [17Zonder J.A. Durie B.G.M. McCoy J. Crowley J. Zeldis J.B. Ghannam L. Barbogie B. High incidence of thrombotic events observed in patients receiving lenalidomide (L) + dexamethasone (D) (LD) as first-line therapy for multiple myeloma (MM) without aspirin (ASA) prophylaxis.Blood. 2005; 106: 3455Crossref Google Scholar]. In another trial, three of 22 refractory patients showed VTE during lenalidomide and dexamethasone therapy, but no thrombotic events occurred when low-dose aspirin was added [21Niesvizky R. Martinez-Banos D.M. Gelbshtein U.Y. Cho H.J. Pearse R.N. Zafar F. Pekle K. Furman R. Leonard J.P. Coleman M. Prophylactic low-dose aspirin is effective as antithrombotic therapy in patients receiving combination thalidomide or lenalidomide.Blood. 2005; 106: 3454Crossref Google Scholar]. In our experience, one of 50 patients developed VTE during treatment with RMP and aspirin. The exact length of aspirin prophylaxis has not been established yet. It might be reduced to the first months of therapy, but a detailed time course description of the incidence of VTE must be shown before any change in the duration of prophylaxis can be suggested. We did not observe any bleeding complication after either enoxaparin or aspirin prophylaxis. This observation might be important because thrombocytopenia is a common side effect of chemotherapy. In conclusion, standard LMWH (enoxaparin) prophylaxis seems safe and effective in reducing the incidence of thalidomide-associated VTE in newly diagnosed MM patients. Aspirin seems an appropriate prophylaxis of the lenalidomide-associated VTE. A. Palumbo and M. Boccadoro have received scientific adviser board and lecture fees from Pharmion and Celgene. Their association with Pharmion involves thalidomide, while Celgene involves lenalidomide. J.B. Zeldis is a major stockholder and an employee with sole income from Celgene. This work was supported by Associazione Italiana Leucemie; Compagnia di S. Paolo; Associazione per lo Studio e la Cura delle Malattie del Sangue; Fondazione Neoplasie Sangue Onlus; Fondazione Cassa di Risparmio di Torino; Ministero Università Ricerca Scientifica e Tecnologica (MIUR); Consiglio Nazionale delle Ricerche (CNR); Celgene Corporation; Regione Piemonte. Our thanks to the patients, nurses, and physicians; to Dr Alessandra Borchiellini for helpful discussion; and to the data managing staff (Tiziana Marangon, Federica Leotta, and Antonella Bono, Maria Josè Fornaro, and Valeria Magarotto).
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