Haematologica 2002; 87:(02)ELT07
[Medline] [prev] [index] [next]Diabetic foot disease in a patient with multiple myeloma receiving thalidomide
V. Pitini, C. Arrigo, G. Aloi, D. Azzarello, G. La Gattuta. Department of Oncology, University of Messina, Italy
Correspondence: Dr. Vincenzo Pitini, Oncologia Medica e Trapianto di Midollo Osseo, Pad. H 5° piano ; Policlinico Universitario, Via Consolare Valeria, 98125 &endash; Messina (Italia). Phone international: +39/090/2213241. Fax: international: +39/090/2213231. E-mail: pitini@ciaoweb.it
The antiangiogenic activity of thalidomide, coupled with an increase in bone marrow angiogenesis in multiple myeloma (MM), provided the rationale for use of thalidomide in MM. (VEGF) appears to play a central role in mediating diabetic complications in many organs. We report here a case of a 57-year old man with a relapse of MM who developed diabetic foot disease while receiving thalidomide.Thalidomide is currently used as a very promising drug in patients with recurrent multiple myeloma (MM) including those who have a relapse after high-dose chemotherapy. Thalidomide has anti-angiogenic and immuno-modulatory properties and is an effective inhibitor of tumor necrosis factor-alpha (TNF-alpha).1,2 However, the mechanism of its action in MM remains unclear. Major toxicities of thalidomide include constipation, sedation, skin rash, fatigue and peripheral neuropathy. Recently, a new complication has emerged: a thalidomide induced hypercoagulable state.3 In this report we describe one patient with a relapse of MM who developed diabetic foot disease while receiving thalidomide. We treated 18 patients (10 males, 8 females, median age 53 years) in stage III MM, with thalidomide. Eleven patients had failed stem cell transplantation and 7 received two or more prior chemotherapy regimens before the onset of thalidomide. The median administered dose of thalidomide was 600 mg/day; patients were evaluated monthly for clinical response and for circulating serum levels of the cytokines: b-fibroblast growth factor (b-FGF), vascular endothelial growth factor (VEGF), IL-6 and TNF-alpha. Interestingly VEGF and b-FGF were found to decrease in patients responding to chemotherapy and not in patients who did not achieve a remission.4 A 57-year old man with type I diabetes mellitus started with thalidomide in January 2001 after stem cell transplantation failure. In October he was clinically well: a >50% reduction of monoclonal Ig was observed, both VEGF and b-FGF levels, compared to pre-treatment values (VEGF: 580 pg/mL, b-FGF: 120 pg/mL) were significantly decreased (VEGF: 15 pg/mL, b-FGF: 8 pg/mL). In November 2001 diabetic dermopathy, sensory neuropathy with the loss of the sensation of pain and ischemia became evident in the lower extremities (Figure 1). During the past few years rapid progress has been made in our understanding of the mechanism and molecules involved in the pathogenesis of diabetic microvasculopathy, neuropathy and peripheral vascular disease. VEGF appears to play a central role in mediating diabetic complications in many organs. Experimental diabetic neuropathy results from the destruction of the vasa nervorum and can be reversed by the administration of an angiogenic growth factor. In vivo, VEGF has been identified as a primary initiator of proliferative diabetic retinopathy, in patients with diabetes and a coronary artery or peripheral vascular disease, VEGF may induce the development of cardiac and limb vascular collateralization, respectively. Preliminary clinical studies have demonstrated improvement in signs and symptoms of sensory neuropathy in patients with a lower extremity vascular occlusive disease following an intramuscular injection of naked DNA encoding VEGF.5 These findings suggest that anti-angiogenic properties of thalidomide are strongly implicated in the pathogenesis of diabetic foot disease in our patient. In conclusion close monitoring for diabetes should be carried out in patients with MM receiving thalidomide.
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