Azacitidine (AZA) Combination Therapy with Low-Dose AraC for Aggressive Type MDS, Overt AML, and AML Patients
Authors: Hirai Manabu , Inoue Atsushi , Hashimura Mitsuharu , Aimoto Mizuki , Sakamoto Erina 
Published: October 2019

Abstract
Introduction: Clinically we categorized myelodysplastic syndromes with progressing stages or with disease-related symptoms (fever, edema, pneumonia like shadow, etc) as an aggressive type MDS (aMDS). We hypothesized that these aggressive phases were induced by some malignant clones appeared in MDS patients. MDS overt leukemia could be also categorized in aMDS as a disease progression. From the basis of this stratification strategy, to terminate aggressive phase (to kill the malignant clones) low dose AraC based therapies were combined with azacitidine (AZA). Combination therapies (C+AZA) were retrospectively analyzed compared with AZA single therapy (sAZA) for aMDS patients. The benefit was observed in aMDS and even in overt AML patients with favorable karyotypes. In some relapsed or refractory AML cases, C+AZA therapy was tried as an induction and maintenance therapies resulted in complete remission. We present an over 3 years follow-up of C+AZA therapy for aMDS and overt AML patients.
Method: We evaluated a total of 73 patients with MDS (41), CMML (5), overt AML (23) and relapsed or refractory AML (4) between March 2011 and June 2015. Those patients with MDS and CMML who had disease-related symptoms or disease progression in the previous three months and overt AML were classified as aMDS. Thirty-five eligible patients with a median age of 74 years (55-87) 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 (AclacinonTM) 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.) was given in the morning, and 20 mg/m2 of AraC (s.c.) was administered 5-8 hours after 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 CA-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, 38 eligible patients with a median age of 76 years (62-86) were treated with CA-AZA (one or two cycles) as consolidation therapy, and maintained on sAZA therapy. Responses were evaluated according to IWG 2006 criteria for MDS.
Results: In those who received sAZA the diagnoses were RCMD (4), RAEB1 (8), RAEB2 (13), CMML (2), overt AML (7), relapsed AML (1); for CA-AZA the corresponding numbers were RCMD (3), RAEB1 (3), RAEB2 (10), CMML (3), overt AML (16), and relapsed or refractory AML (3). With sAZA, the IPSS-R risk category was intermediate in 6, high in 8, and very high in 11; for CA-AZA the numbers were respectively 2, 4 and 9, and low in one. The overall response rates for CA-AZA and sAZA were 65% and 17% respectively. In the sAZA group progressive disease was seen in nine (43%) and failure (death) in two (5.7%), after 1 to 3 courses. Failure was also observed in CA+AZA group (one case). Median overall survival (OS) in months was 11.1 vs. 7.9 for CA-AZA and sAZA respectively (P = 0.0167). In overt AML, CA-AZA also resulted in a significant improvement in OS (median OS: CA-AZA 23.9 mo vs. sAZA 7.6 mo; P = 0.0086). In all aggressive cases together, advantage of CA-AZA (median OS: CA-AZA 12.4 mo vs. sAZA 7.6 mo; P = 0.0086) was confirmed. Further, in cases with IPSS-R favorable karyotype (i.e. very good to intermediate), advantage of CA-AZA was more obvious. In this group, evident prolong of OS in CA-AZA arm was observed (median OS: CA-AZA not reached vs. sAZA 9.0 mo; P<0.000176). CA-AZA and favorable karyotype was extracted as significant risk factor by multivariate analysis (Hazard Ratio: 0.49 and 0.35, P = 0.036 and 0.0022, respectively).
Conclusions: After 3.3 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. Greater benefit was seen in aMDS and AML patients with favorable karyotype. Clinical stratification of MDS should be taken into consideration up on treatment selection.
Because of difficulties with planning a comparative clinical study in MDS patients, we now favor CA+AZA therapy for aMDS however CA+AZA worked well for relapsed or refractory AML patients. For elderly AML patients, CA-AZA therapy could be down for discussion. We have presented our retrospectively analyzed clinical experience and methodology for treating MDS patients with AZA.

Disclosures
Hirai: Nippon Shinyaku CO., LTD: Speakers Bureau.