Abstract

Vitamin K2 (VK2) analogs, including menaquinone-4 (MK4) but not vitamin K1, effectively induce apoptosis in acute myeloid leukemia cells (AML). Apoptosis induction by VK2 is specific toward leukemia cells, and almost no effect is observed in normal hematopoietic progenitor cells (Miyazawa K, Leukemia 1999, 2000, 2001). Combined treatment with VK2 plus 1α, 25-dihydroxy-vitamin D3 (D3) dramatically enhanced differentiation of leukemia cells as compared to the cells treated with D3 alone. Concomitant with the induction of differentiation and final maturation by VK2 plus D3, the cells became resistant to various apoptotic stimuli (Funato K, Leukemia, 2002). VK2 has been shown to improve the supportive hematopoietic functions of bone marrow stromal cells (Miyazawa K, Stem Cell Dev. 2004). Since VK2 (MK4, GlakayR) has been used to treat patients with osteoporosis in Japan, its non-toxicity and safety for long-term daily administration have already been well established. Case reports demonstrating the clinical benefits of using VK2 with or without D3 for treating patients with myelodysplastic syndrome (MDS) and AML have been accumulating, i.e. improving cytopenias in refractory anemia (RA) and reduction of blast cells in AML. We performed a multicenter prospective trial to determine the therapeutic benefit of VK2 with or without D3 in MDS. Patients with RA/RCMD with low/ int-1 by IPSS received VK2 (Glakay, 45 mg/day, po) for 16 weeks. The therapeutic response was assessed according to the International Working Group Criteria. Patients who did not respond to VK2 were sequentially re-registered and received a combination of VK2 plus D3 (alfacalcidol, AlfarolR, 0.75 microgram/day, po) for 16 weeks. Patients showing response to VK2 alone or VK2 plus D3 after 16 weeks continued to receive therapy for a total of 12 months. Forty-three patients have been enrolled and 29 patients were evaluable for their response to VK2. Five patients (17.2 %) showed improvement of cytopenia (major HI-E (1), minor HI-E (2), major HI-P (3), and minor HI-P (1)). Twenty out of 24 patients who showed no response to VK2 alone subsequently received VK2 plus D3. Eleven patients were eligible for evaluation and 4 patients (36.4%) showed improvement of cytopenia in response to VK2 plus D3 (major HI-E (3), minor HI-E (1) and major HI-P (1)). Four out of 7 patients (57 %) with anemia showed hematologic response. No adverse events were observed, except for one case of skin rash (Grade I) during VK2 plus D3 therapy. These data suggest that the therapeutic response rate is improved by combined treatment with VK2 plus D3 as compared with that by VK2 monothrapy. Safety and low price also support the therapeutic benefit of VK2 with D3 for improving cytopenia in RA.

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