Thrombogenic activity of doxorubicin in myeloma patients receiving thalidomide: implications for therapy

Abstract

Ten percent of newly diagnosed myeloma patients treated with any type of chemotherapy develop deep venous thrombosis (DVT). Thalidomide has proven activity in refractory multiple myeloma (MM), and although single-agent thalidomide has minimal prothrombogenic activity, its combination with cytotoxic chemotherapy is associated with a significantly increased risk of DVT. We analyzed the incidence of DVT in 232 MM patients who received a combination of chemotherapy and thalidomide on 2 protocols that differed only by the inclusion of doxorubicin in one. DT-PACE (dexamethasone/thalidomide/cisplatin/doxorubicin/cyclophosphanide/etoposide) was offered to patients with preceding standard dose therapy, but no prior autotransplantation, while DCEP-T (dexamethasone/cyclophosphamide/etoposide/cisplatin/thalidomide) was administered for relapse after transplantation. If there were signs or symptoms suggestive of DVT, patients received additional investigations, including Doppler ultrasonography, followed by venography if indicated. Only patients on DT-PACE but not DCEP-T experienced an increased incidence of DVT. A statistical association between the incidence of DVT and combination chemotherapy including doxorubicin (P ‫؍‬ .02) was observed; this association was confirmed on multivariate analysis. MM patients treated with thalidomide and doxorubicin have a high risk of developing

Hyperfractionated cyclophosphamide in combination with pulsed dexamethasone and thalidomide (HyperCDT) in primary refractory or relapsed multiple myeloma

“…This notion is supported by the combined analysis of published data, including our own study, on thalidomide combinations with or without doxorubicin, as shown in Table V. Irrespective of the particular combination therapy, the risk of venous thromboembolism in multiple myeloma seems to be enhanced during the early course of induction therapy, a phenomenon that may relate to tumour burden and tumour cell reduction (Cavo et al, 2002;Zangari et al, 2002b). In line with this hypothesis, four of the five venous thromboembolic events observed in the present study occurred during the first or second treatment cycle in responding patients.…”

“…First, the combination of thalidomide with cytotoxic chemotherapy has been associated with a high risk of DVT (Osman et al, 2001;Zangari et al, 2001). Recent data demonstrate that the incidence of venous thromboembolic disease is particularly increased in thalidomide/doxorubicin-containing regimens (Zangari et al, , 2002b. In contrast, combinations of thalidomide with cyclophosphamide, etoposide, cisplatinum or dexamethasone at the doses used in published studies appear not to enhance the venous thromboembolic risk inherent to multiple myeloma under treatment (Dimopoulos et al, 2001a;Palumbo et al, 2001;Zangari et al, 2001Zangari et al, , 2002bMoehler et al, 2002).…”

“…Recent data demonstrate that the incidence of venous thromboembolic disease is particularly increased in thalidomide/doxorubicin-containing regimens (Zangari et al, , 2002b. In contrast, combinations of thalidomide with cyclophosphamide, etoposide, cisplatinum or dexamethasone at the doses used in published studies appear not to enhance the venous thromboembolic risk inherent to multiple myeloma under treatment (Dimopoulos et al, 2001a;Palumbo et al, 2001;Zangari et al, 2001Zangari et al, , 2002bMoehler et al, 2002). This notion is supported by the combined analysis of published data, including our own study, on thalidomide combinations with or without doxorubicin, as shown in Table V.…”

“…In line with this hypothesis, four of the five venous thromboembolic events observed in the present study occurred during the first or second treatment cycle in responding patients. Importantly, the thrombotic risk seems to be linked to the disease and its treatment, rather than to pre-existing thrombophilic risk factors (Cavo et al, 2002;Zangari et al, 2002b). This conclusion would at least appear to be true for HyperCDT therapy as none of four patients with venous thromboembolism who were tested for thrombophilic abnormalities had evidence of natural anticoagulant deficiencies, antiphospholipid antibodies, activated protein C resistance, or factor V Leiden and prothrombin 20210 mutations respectively.…”

Effects of Exercise in Combination With Epoetin Alfa During High-Dose Chemotherapy and Autologous Peripheral Blood Stem Cell Transplantation for Multiple Myeloma

“…The risk of DVT is known to be high with cancer (Naess et al, 2007), with central venous catheters (Monreal et al, 2006), and with chemotherapy and thalidomide (Zangari et al, 2003), particularly with doxorubicin and thalidomide (Zangari et al, 2002). Additional studies are being conducted using medical record reviews to compare the incidence of DVT among patients in the current study with patients who were treated with the same high-dose chemotherapy and autologous PBSCT protocol but did not receive ESA therapy according to the current study's algorithm.…”