Multicenter phase II trial of vitamin K2 monotherapy and vitamin K2 plus 1α-hydroxyvitamin D3 combination therapy for low-risk myelodysplastic syndromes
Introduction
Myelodysplastic syndromes (MDS) are clonal stem cell disorders characterized by dysplastic features of hematopoietic and blood cells, cytopenias caused by ineffective hematopoiesis, and a variable risk of progression to acute myeloid leukemia (AML) due to accumulation of genetic abnormalities [1]. The treatment options available to patients with MDS are largely based upon the patient's age and prognosis as determined by the International Prognostic Scoring System (IPSS) [2]. For patients in the low to intermediate-1 by IPSS score categorized as “low-risk MDS”, the goal of treatment is to improve ineffective hematopoiesis while providing the appropriate supportive care. The US National Comprehensive Cancer Network MDS recommendations are that therapies for the patients with low-risk with clinically significant cytopenias should be stratified into several groups, for example lenalidomide for del(5q), erythropoietin (Epo) for patients with low serum Epo [3]. DNA-hypomethylating agents as azacitidine or decitabine are also recommended for non-responders to these treatments. However, these therapeutic effects are not satisfactory for every patient and other options for low-risk MDS, especially elderly MDS patients, are still required [4].
Vitamin Ks are known to act as cofactors for γ-carboxylation of vitamin K-dependent coagulation factors. Menatetrenone, a vitamin K2 analog, is approved as an active agent for osteoporosis in Japan [5], [6]. As a coenzyme of γ-carboxylase, it promotes osteogenesis through γ-carboxylation of glutamate residues in osteocalcin. The safety of long term administration of menatetrenone has been well established [5], [6]. The efficacy of oral menatetrenone therapy in RA and other types of MDS has been reported in Japan [7], [8], [9], [10]. Regarding with the effect for improvement of cytopenias in clinical trials including pilot studies, the response varies 20–75%, and toxicity is tolerable [8], [9], [10]. The underlying mechanism of improvement of cytopenias by vitamin K2 (VK2) remains to be cleared. However, VK2 has been reported to induce apoptosis and differentiation in some leukemic cell lines in vitro[11], [12], [13]. VK2 was also reported to improve hematopoietic supportive functions of the stromal cell lines established from MDS patients [14].
The active form of vitamin D3, 1α,25-dihydroxyvitamin D3 inhibits the proliferation and induces the differentiation of normal and leukemic myeloid cells in vitro[15]. There are reports demonstrating that vitamin D3 analogs such as alfacalcidol (1α-hydroxyvitamin D3), calcifediol (25-hydroxyvitamin D) and calcitriol (1α,25-dihydroxyvitamin D3) have some therapeutic effects in patients with MDS [15], [16], [17], [18], [19]. Mellibovsky et al. reported that treatment with calcifediol showed some hematological improvements in 10 out of 14 MDS patients with low/intermediate risk [18]. Motomura et al. reported that alfacalcidol prevents the progression of MDS to overt leukemia under the effect of differentiation capacity from blasts to monocytes [19]. However, these therapeutic effects of VD3 analogs in MDS were controversial [20], [21]. The therapeutic serum concentrations of these VD3 analogs based on in vitro studies were supposed to be practically difficult to achieve because of hypercalcaemia in vivo, a well known dose-limiting toxicity of vitamin D3 (VD3) [21]. It is noteworthy that combination of VK2 plus either 22-oxa-1,25-dihydroxyvitamin D3 or 1,25-dihydroxyvitamin D3 synergistically enhances the induction of cellular differentiation in HL-60 cells along with inhibition of VK2-induced apoptosis in vitro[22], [23]. The optimal concentration of VD3 analogs for differentiation induction could be reduced less than one tenth by combining with VK2. This may provide a therapeutic benefit for combining VK2 plus VD3 by preventing hypercalcemia as well as enhancement of cellular differentiation induction.
Although the precise therapeutic mechanism still remains to be clarified, all these data suggest that VK2 and VD3 may improve cytopenias in MDS by either differentiation induction, eradication of MDS clone by apoptosis, or improvement of hematopoietic microenvironment. Based on the previous clinical reports and in vitro studies, we conducted an open-labeled single-arm prospective phase II clinical trial to clarify the effectiveness of VK2 monotherapy for improving cytopenias in low-risk MDS, as a primary endpoint. Furthermore, the study was designed to investigate the therapeutic effects of VK2 plus VD3 (alfacalcidol) combination therapies for non-responders to VK2 monotherapy as a secondary endpoint.
Section snippets
Patients
The protocol was approved by all local medical ethical committees, and the patients were required to provide written informed consent. From January 2003 to August 2005, 46 patients were enrolled in this clinical trial from 10 institutes involved in 2 Japanese clinical study groups; the Japan Hematology-Oncology Clinical Study Group (J-HOCS) and Japanese Research Committee for Research on Epoch-making Therapy for Myelodysplastic Syndrome. After obtaining informed consent, consecutive MDS
Patient characteristics
Thirty-eight out of 46 enrolled patients were evaluable. The enrolled cases who received menatetrenone for more than 8 weeks were all included for evaluation. Characteristics of evaluable patients are summarized in Table 1. The median age was 65 years. These were 27 and 11 patients with RA and RCMD, respectively. According to IPSS, 13 patients were at low-risk, 24 had intermediate-1, and 1 case was not assessable because of lack of cytogenetic data. The numbers of patients with a Hb level less
Discussion
The response rates in hematological improvement of VK2 monotherapy were largely different in previous reports (Table 4). Three retrospective studies demonstrated that the response rates ranged from 20 to 29%, whereas 4 prospective studies revealed that it ranged from 46 to 75%. Several factors appears to contribute to this variation such as the small number of patients enrolled, concomitant use of other medications including VD3 and anabolic steroid, difference of background of recruited
Conflict of interest statement
The authors have no conflicts of interest to declare.
Acknowledgements
We thank Esai Co., Ltd. (Tokyo, Japan) for kindly providing Glakay (menatetrenone) and also Chugai Pharmaceutical Co., Ltd. (Tokyo, Japan) for kindly providing for Alfarol (alfacalcidol) for this clinical study. This work was supported in part by a grant-in-aid from the Ministry of Health, Welfare and Labor of Japan (Japanese Research Committee for Research on Epoch-making Therapy for Myelodysplastic Syndrome; Chief researcher, Prof. Kinuko Mitani, Dokkyo Medical University School of Medicine).
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