Azacitidine (AZA) is a promising agent for higher risk myelodysplastic syndrome (MDS), but it does not prevent disease progression as a single agent in most cases of AML. MDS is a heterogeneous disease not only pathologically but also clinically. Some cases have progressive clinical stages and disease-related symptoms (fever, edema and effusion), so called aggressive MDS (aMDS). Since some aMDS cases failed single agent AZA treatment, we considered combination chemotherapy with AZA for aMDS. Here we report the use of low dose of AraC followed by AZA for aggressive MDS in a pilot study.


We evaluated eligible 37 MDS, CMML, overt AML and de novo AML patients from March, 2011 to June, 2013. All MDS and CMML patients had disease-related symptoms or disease progression in the previous 3 months. Twenty-two patients (median age 73 years, range 55-87) were treated with single agent AZA (sAZA) 75 mg/m2/day i.v. 1∼5, 8, 9 days every four weeks. For low dose AraC combination therapy, AraC 10mg/m2xtwice/day s.c. for 1∼5 days and Aclarubicin Hydrochloride (Aclacinon) 20 mg/m2/day i.v. for 1, 2days (CA therapy) was followed by AZA 75 mg/m2/day iv for 7 days (8∼12, 15, 16). Fifteen patients (median age 74 years, range 62∼85) received sAZA after 1 cycle of CA followed by AZA (CA-AZA). Responses were scored according to IWG 2006 criteria for MDS.


Diagnosis was RCMD n=3, RAEB1 n=4, RAEB2 n=10, CMML n=1, overt AML n=3, de novo AML n=1 for sAZA-treated group and RCMD n=1, RAEB1 n=2, RAEB2 n=6, CMML n=2, overt AML n=4 for CA-AZA-treated group. IPSS-R risk category was intermediate n=6, high n=2, very high n=8 for sAZA-treated group and intermediate n=1, high n=1, very high n=7 for CA-AZA-treated group. Overall response rate was 27.2% and 80% for sAZA- and CA-AZA-treated groups, respectively. 50% of progressive disease and 9% (n=2) of failure (death) were observed in sAZA group at 1 to 3 courses of AZA. One year overall survival (1yOS) was 38.1% and 90.9% in sAZA- and CA-AZA-treated groups, respectively, without significant difference (P=0.11). In overt AML, CA-AZA treatment resulted in a significant difference in 1yOS (0% vs. 100%, P=0.02). In the higher risk groups (High, Very high and overt AML) and the poor and very poor karyotype groups, CA-AZA treatment showed a trend towards improved 1yOS (P=0.07, P=0.11) compared with sAZA. Adverse events were similar between two treatment groups.


For aMDS, sAZA therapy was not sufficient to control disease progression. To suppress disease progression and to improve the efficacy of AZA, we used CA prior to AZA maintenance therapy. In one case with overt AML and in two cases of aggressive type CMML, CA with AZA maintenance successfully prevented disease progression for almost two years. These three cases are now being treated every two or three months with sAZA as maintenance therapy. AZA combination therapy with AraC have been examined in in vitro and in vivo studies (R.L. Momparler Cancer Res. 1975;35, G.L. Neil Cancer Res. 1976;36). Our low dose and short term chemotherapy (CA) was safely and effectively combined with AZA for older aMDS patients. We are planning a clinical study to further evaluate CA-AZA therapy in a larger cohort of patients.


Hirai:NIPPON SHINYAKU CO.,LTD: Speakers Bureau. Hino:NIPPON SHINYAKU CO.,LTD: Research Funding.

Author notes


Asterisk with author names denotes non-ASH members.