Vitamin K2 therapy for a patient with myelodysplastic syndrome - Nature

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Vitamin K2 therapy for a patient with myelodysplastic syndrome TO THE EDITOR Myelodysplastic syndrome (MDS) is an acquired stem cell disorder most likely arising from a genetic lesion in a single mulipotent hematopoietic stem cell that often progresses to overt acute myeloid leukemia (post-MDS AML). The syndrome predominantly affects the elderly, with a median age of 60 to 70 years. Intensive 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.1 High-dose chemotherapy supported by allogenic bone marrow transplantation is the only potentially curative treatment for MDS, however, such therapy can only be offered to a few younger patients.2 Since the prognosis of MDS in the elderly is poor, establishment of a novel strategy for treating these patients has been an urgent issue. We have previously reported that vitamin K2 (VK2) analogs such as menaquinone (MK)-3, -4 and -5, but not vitamin K1, have a potent apoptosis-inducing effect on various types of primary cultured leukemic cells, including post-MDS AML cells.3 In addition, we recently demonstrated that this apoptosis-inducing effect is rather selective for blast cells, as assessed by flow cytometry of whole marrow mononuclear cells from patients who had refractory anemia with excess of blast (RAEB) or RAEB in transformation.4 In contrast, VK2 was reported to show some differentiation-inducing activity on acute myeloid leukemic cell lines such as HL-60 and U937 in vitro.5 MK4 has been used clinically for the treatment of the patients with osteoporosis in Japan. The safety of daily doses of MK4 up to 135 mg orally over 24 weeks has already been confirmed in a late phase II trial for osteoporosis.6 These findings suggested that VK2 may be useful for the treatment of patients with MDS in blastic transformation. A 65-year-old man was referred to our department because of thrombocytopenia and anemia. Peripheral blood examination showed leukoerythroblastosis with morphological abnormalities such as hypogranulation and pseudo-Pelger nuclear abnormality of neutrophils, giant platelets, micromegakaryocytes, and binuclear erythroblasts with megaloblastic change. He was diagnosed as having MDS with myelofibrosis by bone marrow trephine. The percentage of blast cells in his peripheral blood soon reached over 30%, indicating progression to the overt acute leukemic phase (Table 1). As we also found previously in other MDS patients,5 culture of his peripheral mononuclear cells in the presence of 3 and 10 ␮m MK4 for 72 h resulted in selective elimination of CD34++/CD33dull+ blast cells in a dose-dependent manner (Figure 1). Because his fibrotic marrow made him unable to tolerate intensive chemotherapy, oral administration of 90 mg of MK4 daily was started after obtaining informed consent. Six weeks after initiation of MK4 therapy, the peripheral blast cell count has significantly decreased and the platelet count has increased from 31 × 109/l to 133 × 109/l (Table 1). Thereafter, the dose of MK4 was reduced to 45 mg/day, and treatment was continued. This has resulted in maintaining a good per-

Correspondence: K Miyazawa, 1st Dept of Internal Medicine (Hematology/Oncology), Tokyo Medical College, 6–7–1 Nishishinjuku, Shinjuku-Ku, Tokyo 160–0023, Japan; Fax: 81 3 5381 6651 Received 28 July 1998; accepted 7 September 1998

Table 1 Peripheral blood data before and after treatment with VK2 in an MDS patient with myelofibrosis

WBC (/␮l) Hb (g/dl) PLT (×109/l) Differential WBC (%) Blast Myelo Meta Stab Seg Eo Ba Mo Ly Erythroblasts (/100 WBC)

Before treatment

After 6 weeks of VK2 therapy

4400 6.2 31

7100 7.5 133

34 12 8 16 14 2 0 2 12 6

8 16 6 30 16 0 0 0 24 0

formance status for over 10 months without any myeloablative therapy, although a few percent of blast cells are still detectable in the peripheral blood. No side-effects of MK4, including myelosuppression have been detected. It is still not clear whether his hematological improvement was achieved because of the induction of apoptosis or differentiation of blast cells in response to VK2 therapy. However, our observation strongly suggests the clinical benefit of using non-toxic VK2 for the treatment of MDS, especially in elderly patients. A formal clinical trial also seems to be warranted.

M Yaguchi K Miyazawa M Otawa Y Ito Y Kawanishi K Toyama

1st Department of Internal Medicine (Hematology/Oncology), Tokyo Medical College, Shinjuku-ku, Tokyo, Japan

References 1 De Witte T, Suciu S, Peetermans M, Fenaux P, Strijckmans P, Hayat M, Jaksic B, Selleslag D, Zittoun R, Dardenne M, Solbou G, Zwierzina H, Muus P. Intensive chemotherapy for poor prognosis myelodysplasia (MDS) and secondary acute leukemia following MDS of more than 6 months duration. A pilot study by the Leukemia Cooperative Group of European Organization for Research and Treatment in Cancer (EORTC-LCG). Leukemia 1995; 9: 1805–1811. 2 Gassmann W, Schmitz N, Loffler H, De Witte T. Intensive chemotherapy and bone marrow transplantation for myelodysplastic syndromes. Semin Hematol 1996; 33: 196–205. 3 Yaguchi M, Miyazawa K, Katagiri T, Nishimaki J, Kizaki M, Tohyama K, Toyama K. Vitamin K2 and its derivatives induce apoptosis in leukemia cells and enhance the effect of all-trans retinoic acid. Leukemia 1997; 11: 779–787. 4 Yaguchi M, Miyazawa K, Otawa M, Katagiri T, Nishimaki J, Uchida Y, Iwase O, Gotoh A, Kawanishi Y, Toyama K. Vitamin K2 selectively induces apoptosis of blastic cells in myelodysplastic syndrome: flow cytometric detection of apoptotic cells using APO2.7 monoclonal antibody. Leukemia 1998; 12: 1392–1397.

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Figure 1 VK2 selectively eliminates the MDS blastic population in vitro and in vivo. Upper panel: Mononuclear cells separated from the patient’s peripheral blood were cultured in RPMI 1640 containing 10% fetal bovine serum in the presence or absence of 3 or 10 ␮m MK4 for 72 h. Then the cells were analyzed by flow cytometry after staining with phycoerythrin-conjugated CD34 and fluorescein isothiocyanateconjugated CD33 monoclonal antibodies. Leukemic blast cells were separated as the CD34++/CD33dull+ fraction. Lower panel: After administration of MK4 (90 mg/day) for 6 weeks, the peripheral white blood cells were isolated by red blood cell lysis and analyzed as described above. The flow cytogram was compared with that obtained before treatment. Each number represents the percentage of blast cells in the whole gated area.

5 Sasaki I, Hashimoto S, Yoda M, Hida T, Ohsawa S, Nakajo S, Nakayama K. Novel role of vitamin K2: a potent inducer of differentiation of various human myeloid leukemia cell lines. Biochem Biophys Res Commun 1994; 205: 1305–1310.

6 Shino M, Yamashiro T, Yamada K, Mori Y, Sato T, Kawabe K, Okada K. Determination of menaquinone-4 in plasma and administration of menaquinone-4 dosage forms in healthy human subjects. Yakugaku Zasshi 1982; 102: 651–658.

COMMENTS ON A PUBLISHED PAPER A more precise diagnosis of AML M0, a part of which exhibits a near-tetraploid karyotype

TO THE EDITOR Villamor et al1 described characteristics of nine cases of acute myeloblastic leukemia with minimal myeloid differentiation (AML M0). An abnormal karyotype was diagnosed only in two of six patients examined, ie in case No. 6 with 79–88 chromosomes (near-tetraploidy) in 20 metaphases and in case No. 8 with a complex karyotype. These results extend our finding of near-tetraploid karyotypes in two patients with AML M0.2 Later, from 1992 to August 1995 we diagnosed two other patients with AML M0 among 71 consecutive new AML cases. The first AML M0 was

Correspondence: P Lemezˇ; Fax: 420 66 285 12 Received 16 September 1998; accepted 9 October 1998

a 58-year-old male with a complex karyotype: 46, XY, −5, −8, +M, +M [14], 47, XY, −5, −8, +19, +M, +M [4]. The second patient was a 63-year-old woman with a secondary AML M0 after a prior myelodysplasia and a near-tetraploid karyotype 71–94, XXXX, +M, +M[20]. Both patients died of pancytopenia after induction treatments on the 24th and 52nd day of therapy, respectively. Recently we have shown3 that at least six of 17 patients with near-tetraploid AML were classified as AML M0, often with erythroid and/or megakaryocytic dysplasia pointing to their origin in myeloid pluripotent progenitors. Near-tetraploid karyotype is easily morphologically recognized by the large blast size.2,3 Thus, AML M0 in a proportion of cases may be a subtype of near-tetraploid AML and in a further proportion a subtype of AML with a complex karyotype in the morphologic, immunologic, and cytogenetic (MIC) classification.