TO THE EDITOR

Myelodysplastic syndromes (MDS) comprise a group of clonal hematological disorders characterized by dysplastic features of bone marrow cells, ineffective hematopoiesis, and cytopenia. There is a more than 30% overall risk of progression to acute myeloid leukemia (post-MDS AML). Since the median age of patients is 60–70 years, allogenic bone marrow transplantation can be performed only in a small population of these patients.12 High-dose chemotherapy achieves an acceptable response rate, but the high incidence of treatment-related death and the short duration of complete remission mean that there is no survival benefit.34 The establishment of new therapeutic strategies for high risk MDS and post-MDS AML, especially for elderly patients, is therefore an important clinical issue.

We previously reported that vitamin K2 (VK2: menaquinone-4) but not vitamin K1 induces apoptosis of primary cultured leukemia cells and leukemia cell lines in vitro.5 Using bone marrow cells derived from patients with refractory anemia with excess of blast (RAEB) and RAEB in transformation (RAEB-T), we further demonstrated that this apoptosis-inducing effect of VK2 was rather specific toward blastic cells compared with non-blastic population in vitro as assessed by multi-color flow cytometry.6 In contrast, it has been reported by others that VK2 also has differentiation-inducing activity in myeloid leukemia cell lines such as HL-60 and U937.7 Several recent clinical case reports suggest the clinical benefit of using VK2 for treating patients with MDS.89 In a refractory anemia (RA) case, daily oral administration of 45 mg of VK2 resulted in dramatic improvement of cytopenia leading to complete independence from blood transfusions.8 We have reported reduction in numbers of peripheral blast cells and concomitant improvement of anemia and thrombocytopenia in a case of RAEB-T with myelofibrosis after treatment with 90 mg/day of VK2.9 Since VK2 has been used to treat patients with osteoporosis, its non-toxicity and safety for long-term daily administration have already been well established,10 which appears to be of clinical benefit in treating elderly patients with MDS. Under these circumstances, the time is ripe for a large-scale randomized trial for VK2 therapy in MDS. As the first step toward a prospective clinical study, we performed a questionnaire survey on the results of individual pilot studies of VK2 for MDS and post-MDS AML to collect information regarding efficiency, effective subgroup of MDS for VK2 therapy, optimal dose and administration route, and length of time until clinical response.

A questionnaire was sent to the institutes which belong to the Research Committee for Idiopathic Hemopoietic Disorders of the Ministry of Health and Welfare in Japan regarding the pilot studies in patients with MDS or post-MDS who received VK2 during the previous 2 years. Questions were as follows: (1) age of patient, (2) gender, (3) diagnosis at initiating VK2 therapy, (4) dosage, route and duration of VK2 administration, (5) combined medicines, if any, (6) efficacy (either (i) good response, (ii) partial response, (iii) no effect, or (iv) not evaluable), (7) grounds for evaluation (either (i) improvement of cytopenia (a) hemoglobin concentration, (b) absolute number of neutrophils, (c) platelet counts), (ii) reduction of blastic cells, (iii) appearance of normal karyotype or reduction/disappearance of abnormal karyotype, (iv) reducing the amount of transfusions/becoming transfusion independent, or (v) suppressing the growth speed of transformed blastic cells), (8) duration of administration of VK2, (9) the time required to obtain hematologic response, and (10) adverse effects if any.

Fifty patients with MDS and post-MDS AML who received VK2 therapy were registered from 11 distinct institutes, and 47 cases, which consisted of 15 cases of RA, six RAEB, 11 RAEB-T, three chronic myelomonocytic leukemia (CMML), and 12 cases of post-MDS AML, were eligible for evaluation. The patients’ backgrounds are summarized in Table 1. The dosage of VK2 (menaquinone-4) ranged from 20 to 135 mg/day orally, and 10 to 50 mg/day intravenously; however, 83% (39/47) of the patients received 45 mg/day orally, and 55.3% (26/47) of the patients received VK2 plus other medications such as predonisolone, ubenimex, vitamin D3, ascorbic acid, or cytarabine ocfosfate (oral cytosine arabinoside).

Table 1  Background of 47 cases of MDS and post-MDS AML
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Three out of 15 cases (20%) of RA showed improvement of cytopenia after treatment with VK2; one treated with VK2 plus vitamin D3 and ascorbic acid showed an increased number of peripheral neutrophils, and the other two RA cases treated with VK2 alone showed an improvement of pancytopenia and an increased number of neutrophils, respectively. Interestingly, in 72.7% (8/11) of the patients with RAEB-T and in 50% (6/12) with post-MDS AML, the administration of VK2 was effective in reducing blastic cell numbers in bone marrow and/or peripheral blood, although 71.4% (10/14) of those with this reduction received other medications simultaneously. Regarding patients treated with VK2 alone for RAEB-T and post-MDS AML, 44.4% (4/9) showed hematological improvement in response to VK2. A case of RAEB-T showed a reduction of the peripheral blast cell number by an oral treatment of 45 mg/day of VK2, and finally converted to RA within 3 months. In a case of a patient with post-MDS AML with chronic renal failure, who required hemodialysis and periodic erythropoietin injections, an oral dose of 45 mg/day of VK2 resulted in the reduction of leukemic blast cells in bone marrow, and the improvement of pancytopenia, leading to transfusion independence within 1 month. In contrast to the patients with RAEB-T and post-MDS AML, no effect of VK2 was noted in RAEB and CMML patients, which may be because of the small number of patients assessed, and also perhaps because it is difficult to evaluate the reduction of blast cell numbers by VK2 in these patients (Figure 1). No adverse effect of VK2 was found. The time required before obtaining some hematologic improvement after initiation of VK2 therapy ranged from 1 to 3 months (average: 1.5 months in RA, and 1.6 months in RAEB-T and post-MDS AML). However, the optimal dosage and a route for VK2 administration were not determined because most patients received 45 mg/day of VK2 orally.

Figure 1
figure 1

 Efficacy of VK2 therapy in MDS and post-MDS AML.

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Although these data were not based on a complete objective trial and effects of the other combined medicines cannot be ruled out, the data shown here collected from 11 independent institutes are strongly encouraging for VK2 therapy for MDS and post-MDS AML, especially for elderly patients who cannot tolerate intensive myeloablative chemotherapy and stem cell transplantation. In addition, although some effect of VK2 for cytopenia can be expected in RA patients, VK2 appears to be rather effective in reducing the number of blast cells in RAEB-T and post-MDS AML as suggested by our in vitro studies.56 Since VK2 is non-toxic and can be administrated safely for long periods, ‘chemo-prevention’ with VK2 against leukemic transformation or disease progression in MDS might also be a useful strategy. We should emphasize that a large-scale prospective randomized trial of VK2 therapy in MDS is warranted.