Multivariate and Subgroup Analyses of a Multinational Phase III Trial of Decitabine in Older Patients with Newly Diagnosed Acute Myeloid Leukemia
Authors: Mayer Jiri , Arthur Christopher , Delaunay Jacques , Mazur Grzegorz , Thomas Xavier , Wierzbowska Agnieszka , Jones Mark M , Berrak Erhan , Kantarjian Hagop M. 
Published: October 2019

Abstract
Abstract 3618

Introduction:
A recent phase III trial compared efficacy and safety of decitabine with those of patient's treatment choice (TC) of supportive care or low-dose cytarabine in older patients with newly diagnosed acute myeloid leukemia (AML) and poor- or intermediate-risk cytogenetics (Kantarjian et al. J Clin Oncol 2012;30:2760; NCT00260832). At the planned clinical cutoff date in 2009 (396 deaths), a nonsignificant trend toward increased median overall survival (OS) was seen with decitabine (7.7 months; 95% confidence interval [CI] 6.2, 9.2 months) vs TC (5.0 months; 95% CI: 4.3, 6.3 months); estimated hazard ratio (HR) 0.85 (P=.108). A 2010 post hoc analysis of mature data (446 deaths) from this study showed that the median OS had not changed but HR had improved (0.82; 95% CI 0.68, 0.99; nominal P=.037) and favored decitabine versus TC. At the 2009 cutoff, remission rates (complete response [CR] or CR with incomplete platelet recovery [CRp] were significantly improved with decitabine (17.8%) vs TC (7.8%; P=.001). Decitabine was generally well tolerated. A multivariate analysis was conducted using the mature (2010) data to identify potential predictors of OS in this older population with AML.

Methods:
Eligible patients were aged ≥65 years with newly diagnosed de novo or secondary AML (≥20% blasts), poor- or intermediate-risk cytogenetics, and Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0–2. Patients were randomized 1:1 to receive decitabine (20 mg/m2 intravenously once daily for 5 consecutive days every 4 weeks) or TC (supportive care or cytarabine 20 mg/m2 subcutaneously once daily for 10 days every 4 weeks), stratified by age, cytogenetic risk, and ECOG PS. A multivariate Cox proportional hazards model was used to investigate the effects of the following demographic and baseline characteristics on OS in addition to treatment effect: sex, age (<70, 70–<75, or ≥75 years), baseline cytogenetic risk (intermediate vs poor), AML type (de novo vs secondary), baseline ECOG PS (0/1 vs 2), geographic region (North America/Australia, Western Europe, Eastern Europe, Asia), baseline bone marrow blasts (>50% vs ≤50%), baseline platelet count (analyzed at each unit of 100 × 109/L) and baseline white blood cell (WBC) count (analyzed at each unit of 25 × 109/L). These potential prognostic factors were evaluated simultaneously, and values were not adjusted for multiple testing.

Results:
Of 485 randomized patients, 242 received decitabine and 243 received TC (cytarabine, n=215; supportive care, n=28). Baseline patient demographics and clinical characteristics were similar between groups and indicated a high-risk population: 71% of patients were aged ≥70 years, 35.3% had secondary AML, 36.0% had poor-risk cytogenetics, and 25.8% had ECOG PS 2 or higher; median baseline proportion of blasts in bone marrow was 46.0%. Patient characteristics that appeared to adversely affect OS at the 0.05 level included more advanced age, poorer baseline ECOG PS, poor cytogenetics, higher bone marrow blast count, low baseline platelet count, high WBC count, and geographic region (Western vs Eastern Europe) (Table).

Conclusions:
In older patients with AML, OS was associated with prognostic factors of age, ECOG PS, cytogenetic risk, baseline bone marrow blasts, baseline platelet counts, and baseline WBC in addition to responding differently to decitabine vs TC (supportive care or cytarabine). Treatment response is related both to patient and disease status in older patients with AML.

Disclosures:
Mayer: Eisai: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Off Label Use: Decitabine is a nucleoside metabolic inhibitor indicated for treatment of patients with myelodysplastic syndromes (MDS) including previously treated and untreated, de novo and secondary MDS of all French-American-British subtypes (refractory anemia, refractory anemia with ringed sideroblasts, refractory anemia with excess blasts, refractory anemia with excess blasts in transformation, and chronic myelomonocytic leukemia) and intermediate-1, intermediate-2, and high-risk International Prognostic Scoring System groups. Delaunay:Novartis, Genzyme: Consultancy. Jones:Eisai Inc: Employment. Berrak:Eisai Inc: Employment. Kantarjian:Eisai: Research Funding.