Azacitidine (AZA) Combination Therapy with Low-Dose AraC Is Well Tolerated and Highly Effective for MDS with Overt Leukemia
Authors: Hirai Manabu , Aimoto Mizuki , Inoue Atsushi , Hashimura Mitsuharu , Sakamoto Erina , Nakamae Hirohisa , Hino Masayuki 
Published: October 2019

Abstract
Introduction: Conversion to overt leukemia is the final, progressive and most aggressive stage in myelodysplastic syndromes (MDS). Azacitidine (AZA) is a promising agent for improving prognosis in higher-risk MDS, but inadequate as a single agent for progressive disease, for example with AML and the aggressive stage of MDS (aMDS), defined by clinical progression with the presence of disease-related symptoms such as fever, edema and effusions. For disease control in aMDS we have used low-dose AraC prior to AZA therapy (AraC→AZA), which was well tolerated by elderly patients. Significant benefits were observed not only in aMDS but also in MDS patients with overt leukemia, compared with single agent AZA therapy (sAZA). However two-week duration of the cyclic AraC and AZA therapy (AraC→AZA) was inconvenient for patients. We therefore combined AraC with AZA (AraC+AZA) for seven days. Five to eight hours after administration of 75 mg/m2 of AZA, 20 mg/m2 of AraC (s.c.) was given. Six of ten (60%) patients with overt AML achieved complete remission after single course of AraC+AZA therapy. We present a clinic-based pilot study of very simple, convenient, and effective combination therapy with AZA and AraC that can be used in older patients with MDS and overt AML.
Method: We evaluated a total of 50 patients with MDS (29), CMML (4), overt AML (14) and relapsed AML (3) between March 2011 and July 2014. Those patients with MDS and CMML all had disease-related symptoms or disease progression in the previous three months (the so-called aggressive stage of MDS: aMDS). Twenty-two eligible patients with a median age of 73 years (55–87 years) were treated with single AZA (sAZA) 75 mg/m2/day i.v. on days 1–5, 8 and 9, every four weeks. With AraC→AZA (CA→AZA) therapy, AraC 10 mg/m2 was given twice daily on days 1–5 and Aclarubicin hydrochloride (Aclacinon) 14 mg/m2/day on days 1 and 2, followed by AZA 75 mg/m2/day i.v. for seven days (on days 8–12, 15 and 16). With AraC+AZA therapy (CA+AZA), 75 mg/m2 of AZA (i.v. / s.c.) was given in the morning, and 20 mg/m2 of AraC (s.c.) was administered 5–8 hours after the AZA on days 1–5, 8 and 9, every four weeks. Aclarubicin hydrochloride 14 mg/m2/day was given i.v. on days 1 and 2. With a persistently high WBC count after AraC+AZA therapy, 20 mg/m2 of AraC (s.c.) daily was continued until WBC decreased to 1–2x109 /L. After one cycle of (CA→/+AZA) as an induction therapy, 27 eligible patients with a median age of 74 years (62–86 years) were treated with AraC+AZA (one or two cycles) as consolidation therapy, and maintained on sAZA therapy. Responses were scored according to IWG 2006 criteria for MDS.
Results: In those who received sAZA the diagnoses were RCMD n=3, RAEB1 n=5, RAEB2 n=9, CMML n=1, overt AML n=3, relapsed AML n=1; for CA→/+AZA (CA-AZA) the corresponding numbers were RCMD n=1, RAEB1 n=2, RAEB2 n=9, CMML n=3, overt AML n=10, and relapsed AML n=2. With sAZA, the IPSS-R risk category was intermediate in six, high in two, and very high in eight; for CA-AZA the numbers were respectively one, three and eight. The overall response rates for sAZA vs. CA-AZA were 27% and 74%. In the sAZA group progressive disease was seen in nine (40.9%) and failure (death) in two (9.1%), after one to three courses. Median overall survival (OS) in months was 5.8 vs. 19.0 for sAZA and CA-AZA respectively (P=0.002). In overt AML, CA-AZA also resulted in a significant improvement in OS (P=0.012) (median OS: sAZA 7.7 mo vs. CA-AZA 24.2 mo), with 60% CR rates after CA-AZA. In the CA-AZA group with favorable karyotypes, there was a significant difference in OS compared with sAZA (median OS in months: 9.0 vs. 24.2, P=0.005). The observed rate of adverse events in the CA-AZA group was no higher than the sAZA group.
Conclusions: CA+AZA therapy was established based on both in vitro and in vivo studies (R.L. Momparler Cancer Res. 1975;35, G.L. Neil Cancer Res. 1976;3). After 2.5 years of observation of sAZA vs. CA-AZA therapy for aMDS, we found CA-AZA to be of significant benefit, even in patients with overt AML. Effects were observed after just one or two courses of CA+AZA. Greater benefit was seen in MDS patients with favorable karyotypes. AZA may work as a hypomethylating drug for epigenetic disorders and act in synergy with AraC. Because of failures (deaths) with sAZA and difficulties with planning a comparative clinical study in MDS patients, we now favor CA+AZA therapy for aMDS. We have presented our clinical evidence and methodology for treating MDS patients with AZA.

Disclosures
Hirai: Nippon shinyaku CO.,LTD: Speakers Bureau. Nakamae:Nippon Shinyaku CO.,LTD: Research Funding. Hino:Nippon Shinyaku CO.,LTD: Research Funding; astellas CO.,LTD: Research Funding.