Longer Follow-Up Of The Combination Of Clofarabine, Idarubicin, and Cytarabine (CIA) As Frontline Therapy For Patients Younger Than 61 Years With Newly Diagnosed Acute Myeloid Leukemia (AML)

Clofarabine is a second generation nucleoside analogue with activity in adults with AML. In a phase II trial of clofarabine in combination with idarubicin and cytarabine in newly diagnosed patients (pts) with acute myeloid leukemia (AML) </= 60 years old, the overall response rate (ORR) was 79%. The combination was well tolerated with low induction mortality. Compared to historical pts who were treated with idarubicin and cyarabine (IA), the overall survival (OS) and event-free survival (EFS) were significantly longer for CIA treated pts and mainly for pts </= 40 years old.

To report a longer follow up of this study.

Eligible were adults between 18-60 years old with newly diagnosed AML with adequate renal (creatinine </= 1.0 mg/dL) and hepatic (bilirubin </= 1.5 x upper limit of normal, [SGPT and/or SGOT] </= 2.5 x ULN) functions. Ptswere excluded for ECOG PS > 2, cardiac ejection fraction < 45%, or active and uncontrolled infection. For the first 30 pts, induction therapy consisted of Clofarabine 22.5 mg/m² iv daily (days 1-5), Idarubicin 6 mg/m² daily (days 1-3), and Cytarabine 0.75 g/m² daily (days 1-5). From pt 31 onward, induction doses were amended to Clofarabine 20 mg/m² x 5, Idarubicin 10 mg/m² x 3, and Cytarabine 1 g/m² x 5. Pts who did not achieve a complete remission (CR) following induction could receive one re-induction course. Pts in CR/CRp continued with up to 6 consolidation cycles with Clofarabine 22.5 mg/m² x 3, Idarubicin 6 mg/m² X 2, and Cytarabine 0.75 g/m² x 3, subsequently amended to Clofarabine 15 mg/m² x 3, Idarubicin 8 mg/m² x 2, and Cytarabine 0.75 g/m²x 3.

From April 2010 until February 2012, 57 pts were evaluable. With median follow up of 21.5 months (1.5-33.4), the median OS was 27.4 months, median relapse-free survival was not reached, and median EFS was 11.5 months. Patients </= 40 years who received CIA had a better OS (HR 0.43, CI 0.24-0.75, P = 0.007), and better EFS (HR 0.43, CI 0.24-0.75, P = 0.007) compared to pts > 40 years. Compared to a historical cohort of pts treated with IA, CIA continued to show superior OS (HR 0.8, CI 0.51-1.27, P = 0.043). In multivariate analysis, CIA retained its prognostic value on OS even when transplant was added as time dependent covariate (HR 0.84, CI 0.53-1.33, P = 0.04). Pts </= 40 years had superior OS (HR 0.15, CI 0.03-0.65, P= 0.039) when they were treated with CIA compared to IA.

A longer follow up of the CIA combination in newly diagnosed pts with AML </= 60 continues to show OS benefit compared to IA alone. Patients </=40 years continue to benefit the most from this combination regardless of transplant. A randomized trial to compare this combination to standard therapy in AML is needed to further investigate the role of this combination in AML.

Off Label Use: Clofarabine use in AML. Kantarjian:Sanofi-Aventis: Research Funding. Ravandi:Sanofi-Aventis: Research Funding. Faderl:Sanofi-Aventis: Membership on an entity’s Board of Directors or advisory committees, Research Funding.