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. A recent randomized phase III study in AML relapse showed higher response rates and better event-free survival with the combination of clofarabine and cytarabine (CA) compared to cytarabine alone. We have also reported the feasibility and safety of the addition of idarubicin to CA (CIA) in a previous phase I and II study. To explore this combination further, we conducted a phase II study of CIA in pts</= 60 years with previously untreated AML.

Patients (Pts) were eligible if they were </=60 yrs of age with newly diagnosed AML. Pts were 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 × 5, Idarubicin 10 mg/m² × 3, and Cytarabine 1 g/m² × 5. Pts who have not achieved a complete remission following the induction could receive one re-induction course. Pts in CR or CRp continued with up to 6 consolidation cycles with Clofarabine 22.5 mg/m² × 3, Idarubicin 6 mg/m² (days 1–2), and Cytarabine 0.75 g/m² × 3, subsequently amended to Clofarabine 15 mg/m² × 3, Idarubicin 8 mg/m² × 2, and Cytarabine 0.75 g/m² × 3. Supportive care was standard. Pts ≥ 50 yrs were admitted to a laminar air flow room for the duration of the induction.

From April 2010 until August 2011, 51 pts have been accrued with a median age of 49 yrs (range 19–59): 33 pts (65%) with de novo AML and 18 pts (35%) with secondary AML (18 related to MDS, 7 related to therapy). Three pts (5%) had a PS of 2. Median WBC at diagnosis was 3.4 × 10⁹/L (0.6-92.3). Thirty-three (65%) pts had abnormal cytogenetics (21/33[64%] poor risk and 5/33 [15%] intermediate risk). Molecular profile: 6 pts (11%) had FLT3/ITD, 3 pts (6%) CEBPA, and 8 pts (16%) NPM1 mutations. Thirty-five pts (69%) achieved CR and 1 (2%) CRp for an overall response rate (ORR) of 71%. 61% pts (31/51) achieved CR following one induction cycle. 18% (9/51) pts required a re-induction and 44% (4/9) of them responded after the re-induction. Responding pts received a median of 2 courses (1–8) courses. With a median follow-up of 23 weeks (3–36+) median remission duration has not been reached with a 1-yr remission probability of 85%. Ten pts (19%) died on study including 2 (4%) who died < 28 days from treatment start (one from septic shock and multi-organ failure, and one from Steven Johnson syndrome). Median overall survival (OS) for responding pts has not been reached (2–36 weeks). One-yr survival probability is 65%. Sixteen pts (31%) proceeded with an allogenic stem cell transplant in CR1. Most toxicities were </= grade 2 and included rash (41 %), nausea (29%), diarrhea (23%), elevated transaminases (21%), and elevated bilirubin (17%). Toxicities > grade 2 included elevated bilirubin (4%), hypokalemia (4%), cellulitis (4%) and seizure (1%). Myelosuppression was ubiquitous but prolonged myelosuppression > 42 days was infrequent. 76 % (39/51) pts had neutropenic fever.

Clofarabine, Idarubicin and Cytarabine achieve a response rate of 71% in patients </=60 yrs with previously untreated AML. Induction mortality was low and the toxicity profile was expected and manageable. Longer follow up and comparisons with standard induction therapy will be needed to further assess the role of this combination in AML therapy.

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