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We performed an open-labeled single-arm prospective phase II clinical trial of vitamin K(2) (menatetrenone: VK2) monotherapy and VK2 plus 1alpha-hydroxyvitamin D(3) (alfacalcidol: VD3) combination therapy for myelodysplastic syndromes (MDS) with refractory anemia and refractory cytopenia with multilineage dysplasia, having either low or intermediate-1 risks of the IPSS. The overall response rate to VK2 monotherapy (45mg/day) after 16 weeks was 13% (5/38) including 4 cases with improvement of both anemia and thrombocytopenia and 1 case with thrombocytopenia. We then enrolled and evaluated 20 out of 33 VK2-monotherapy non-responders for VK2 plus VD3 (0.75microg/day) combination therapy. The overall response rate at 16 weeks after initiation of VK2 plus VD3 was 30% (6/20). HI for hemoglobin (Hb) was observed in 6 out of 11 patients (55%) and for thrombocytopenia in 3 out of 11 patients (27%), respectively. No HI was observed for neutropenia in VK2 monotherapy and VK2 plus VD3 combination therapy. It was suggested that IPSS scores and absolute neutrophil counts positively correlated, and Hb levels inversely correlated with the response to VK2 plus VD3 combination therapy. Our study demonstrated that VK2 plus VD3 combination therapy appears to be promising for improvement of anemia and thrombocytopenia with low/intermediate-1 MDS., (Copyright 2010 Elsevier Ltd. All rights reserved.)

An acute promyelocytic leukemia (APL) cell line with natural resistance to all-trans retinoic acid (ATRA), UF-1, was induced to differentiate into mature granulocyte when treated with the combination of ATRA and granulocyte colony-stimulating factor (G-CSF), while neither of them alone was capable of inducing the differentiation effectively. Continuous presence of both agents was required for the maximal differentiation-inductive effect. Neither proliferation arrest nor induction of apoptosis preceded the differentiation. Differentiated phenotype was accompanied by growth arrest, however, not by increased apoptosis. It was assumed that cellular events at the downstream of the signaling pathways of ATRA and G-CSF cooperatively played pivotal roles in the differentiation-induction.

We examined the efficacy of cyclosporin A (CsA) in 50 patients with myelodysplastic syndrome (MDS) consisting from 47 of RA, 1 of RARS, and 2 of RAEB. These patients showed various marrow cell types including hypo-, normo-, and hypercellularity. Patients belonged to the following International Prognostic Scoring System (IPSS) risk groups: 4 of low, 41 of intermediate-1, and 5 of intermediate-2. The median CsA dose was 4.58mg/kg, and treatment responses were classified according to the International Working Group (IWG) criteria. Hematological improvement (HI) was observed in 30 (60%) patients, and all of them were belonged to RA. In the patients with RARS or RAEB, no efficacy was observed. Four (8%) of the responders achieved partial remission (PR) with granulocytes > or = 1500microl(-1), Hb>11g/dl and platelets > or = 100,000microl(-1). Higher response rate (53%) was shown in erythroid lineage (HI-E) compared to platelet (HI-P, 36%) or neutrophil lineage (HI-N, 35%). When we analyzed the correlation between the response to CsA therapy and the karyotype or HLA type, there were significantly more responders with good karyotype or DRB1*1501 than with intermediate/poor karyotypes or with other HLA types. These results indicate the usefulness of CsA therapy for MDS patients with any marrow cellularity, especially for erythroid lineage and patients with good karyotype or DRB1*1501.

To evaluate the long-term effectiveness of interferon-alpha (IFN-alpha) therapy in patients with chronic myelogenous leukemia (CML) in chronic phase, we examined the updated outcomes of 159 patients who had been enrolled between 1988 and 1991 into a randomized trial comparing IFN-alpha with busulfan. At a median follow-up of 73 months, the median survival was 71 months in the IFN-alpha group and 55 months in the busulfan group (P=0.0563), and the median time of remaining in chronic phase was 58 months in the IFN-alpha group and 39 months in the busulfan group (P=0.4676). Landmark analysis showed a significant advantage in survival (P=0.009) and duration of chronic phase (P=0.0001) in patients with any cytogenetic response among the IFN-alpha group. About half patients were discontinued IFN-alpha administration in spite of cytogenetic response in this study. It appears that continuation of IFN-alpha might possibly confer a survival advantage. Pretreatment factors associated with cytogenetic response included high hemoglobin level, low percentage of peripheral basophils and low leukocyte counts. Multivariate analysis identified lower percentage of bone marrow basophilia (P=0.007) for survival advantage. If a group with a very good prognosis is predicted by a new prognostic model, it might be an option to wait for bone marrow transplantation.

Double minute chromosomes (dmin) are relatively rare in leukemias. Cytogenetic analysis of blood cells from a woman with blastic phase chronic myelogenous leukemia (BC-CML) showed numerous dmin chromosomes and complex abnormalities including a Philadelphia (ph(1))-chromosome. Oncogene amplification in hematopoietic malignancies is also rare. Using PCR, we retrospectively investigated the extent of c-myc gene amplification in DNA extracted from stored blood smears from the patient. To qualify the PCR products, the beta-globin gene was used as the internal reference gene and it was co-amplified with the c-myc gene. The extent of amplified c-myc was about 6.8-fold. This finding suggests that the c-myc gene was amplified in dmin and that the gene amplification contributes to the progression to acute leukemia or rapid growth of leukemic cells.

A mouse monoclonal antibody (MA-10) was raised using cells of a patient with AML (M2). MA-10 reacted with leukemic cells in 44 out of 60 AML cases. Intense reaction was observed especially in 32/38 cases with M1 and M2, as well as 9/9 with common ALL and 2/2 with T-ALL. No appreciable reaction was observed with mature blood cells with only exception of T cells. In-vitro addition of MA-10 did not affect the growth of GM-CFC and BFU-e from two patients with CML in chronic phase. MA-10 identified three polypeptides of approximate mol. wt of 74,000, 50,000 and 30,000.