Prospective study of combination therapy with low-dose thalidomide plus prednisolone ameliorating cytopenia in primary myelofibrosis

Abstract

Recent studies reported that thalidomide attenuates anemia, thrombocytopenia and splenomegaly in patients with primary myelofibrosis (PMF) probably via anti-angiogenic effect [1–6]. However, many patients, who had been treated with 100–800 mg per day of thalidomide, discontinued therapy because of its toxicity. A combination therapy of low-dose thalidomide (50 mg/day) with prednisolone (PSL) conducted by Mesa et al. at Mayo Clinic [7] was well tolerated, and revealed an excellent clinical effect on anemia with a response rate of 62%. Based on the data, we have conducted the same prospective study for the treatment of Japanese patients with advanced PMF. According to the regimen conducted by Mesa et al. [7], patients received 50 mg daily dose of thalidomide together with a tapering regimen of PSL for the first 3 months (0.5 mg/kg/day for 1 month; 0.25 mg/kg/day for the second month; 0.125 mg/kg/day for the third month). This study was approved by the ethical committee of the Keio University School of Medicine, and written informed consent was obtained from all patients. Four patients were enrolled in this study from July 2003 to June 2004. At the time of study entry, genetic mutations of Jak2 could not be examined. One patient discontinued therapy within the first month because of grade 3 vertigo. The rest of three patients received thalidomide and PSL for longer than 1 month, and thus they were considered to be evaluable for response to therapy. The response and the changes in laboratory data during the treatment were summarized in Fig. 1a. Hemoglobin level was slightly increased in patient 1 while platelet counts increased in all three patients. However, the sizes of spleen measured by CT-based volumetry remained unchanged. Regarding side effects of this treatment, grade 3 vertigo was observed in a 76-year-old female as described above. Therefore, this combination therapy should be carefully performed especially in the elderly patients. Grade 3 lymphopenia also occurred in two patients, which was likely caused by PSL. Other toxicities were generally mild, including somnolence, constipation, fatigue, dyspnea, dry mouth, chest pain, common cold, headache, leukocytosis and thrombocytosis. In order to elucidate the mechanism of the hematological response, megakaryocyte count, microvessel density and degree of fibrosis in the bone marrow were examined (Fig. 1b). However, pathological examinations did not show consistent improvement of either one of them. Vertebral MRI scan also failed to demonstrate obvious improvement of bone marrow fibrosis or recovery of fatty component (data not shown). We also examined the plasma concentrations of hematopoietic growth factors including EPO and TPO before and after the therapy. Pre-treatment EPO and TPO levels were elevated compared to healthy controls in all three patients (Fig. 1a). Plasma EPO level was slightly increased in patient 1, but it was decreased in the other two patients after initiating thalidomide plus PSL Y. Hattori (&) Division of Clinical Physiology and Therapeutics, Faculty of Pharmacy, Keio University, 1-5-30, Shibakoen, Minato-ku, Tokyo 105-8512, Japan e-mail: hattori-yt@pha.keio.ac.jp