ALBERT

Description: Introduction 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. Method 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. Results 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. Conclusions 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. Disclosures: Hirai: NIPPON SHINYAKU CO.,LTD: Speakers Bureau. Hino:NIPPON SHINYAKU CO.,LTD: Research Funding.

Description: Abstract 1187 It has been shown that serum ferritin (SF) levels are associated with mortality in transfusion-dependent patients with MDS. Optimal dosing with deferasirox has been shown to decrease SF level even in transfusion-dependent patients and to be able to decrease the adverse effects of repeated transfusion. Previous studies have however shown that about 50% of patients withdraw from treatment because of side effects in the early phase of treatment. Low-dose deferasirox (mean 6.3 mg/kg, range 1.6∼25.6) was administered to 53 patients (MDS 34, AA 13, ALL 2, MF 2, AML 1,ML 1) with dose escalation up to the maximum dose tolerated (mean 9.8 mg/kg, range 1.6∼31.0). In 47 eligible cases, a mean SF of 1579 ng/ml (range 320∼4477) decreased to 1101 ng/ml (range 233∼1680) at 18 months with 71% of continuous rate. Just six cases had treatment stopped, solely because of renal dysfunction. In three cases with transfusion-dependent aplastic anemia, deferasirox (6.25∼10.8 mg/kg) was given with G-CSF, cyclosporin A, and metenolone with the successful abreaction from transfusion dependency and even with elevation of the platelet count (from 10 to 30∼50×109/L). Continuous administration of low-dose deferasirox, as tolerated, was thought to be sufficient to prevent a rise in SF in transfusion-dependent patients. A prospective study that will examine OS in such MDS patients has been started. Disclosures: No relevant conflicts of interest to declare.

Description: 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.