Clofarabine Plus Low-Dose Cytarabine Induction Followed By Clofarabine Plus Low-Dose Cytarabine Alternating With Decitabine Consolidation In Acute Myeloid Leukemia Frontline Therapy For Older Patients

The outcome of elderly patients (pts) with acute myeloid leukemia (AML) treated with currently available therapies remains unsatisfactory. Clofarabine has single agent activity in AML. The combination of clofarabine with low-dose cytarabine produced higher response rates with a comparable safety profile compared with single-agent clofarabine. We previously reported a phase II study of clofarabine + low dose cytarabine followed by prolonged consolidation with clorarabine + low dose cytarabine alternating with decitabine in elderly patients with newly diagnosed AML (Faderl, Cancer 2012). The complete remission (CR) rate was 58%. With median follow up of 31.2 months, the median overall survival (OS) was 12.7 months, and the median relapse free survival was 14.1months. The combination was well tolerated with induction mortality of 3% (Early Death <28 Days), 7% at 8-weeks. Here we report the result with a larger patient population and longer follow up.

Pts were eligible if they were >/= 60 years of age with newly diagnosed AML (based on World Health Organization [WHO] criteria) or high-risk myelodysplastic syndrome (MDS; >/=10% blasts or >/= intermediate-2 by the International Prognostic Scoring System) with Eastern Cooperative Oncology Group (ECOG) performance status of </= 2 and adequate organ function (serum total bilirubin </=2 mg/dL, alanine aminotransferase or aspartate aminotransferase </= 4 X the upper limit of normal, serum creatinine </= 2 mg/dL, and cardiac ejection fraction >40%). Induction therapy consisted of clofarabine 20 mg/m² IV daily X 5 days (1-5) plus cytarabine 20 mg subcutaneously (SC) twice daily (BID) X10 days (1-10). All responses were defined as per IWG criteria (2003). Pts who did not achieve a CR could receive 1 re-induction cycle at the same dose after at least 28 days from C #1. Pts could receive up to 17 cycles of consolidation therapy. Consolidation was administered in blocks of 3 cycles where clofarabine 20 mg/m² IV daily X 3 days (1-3) plus cytarabine 20 mg SC BID X 7 days (1-7) alternated with decitabine 20 mg/m²IV X5 days (1-5). Consolidation cycles were repeated every 4 to 7 weeks depending on hematopoietic recovery.

Between 10/21/08 and 10/17/2011, a total of 118 patients were enrolled. The clinical characteristics are summarized in Table 1. The overall response rate (ORR) was 68% (71 [60%] CR, 9 [8%] CRp/CRi). Twenty two (19%) pts required re-induction, 16 (73%) achieved a response (12 achieved CR, 2 CRp, and 2 CRi). Median number of cycles received was 3 (range, 1-19). With median follow up of 31.2 months (range, 9.5-53.9), the median OS was 11.1 (range, 0.2-53.9), EFS 7.7 (range, 0.2-49.5), and relapse-free survival (RFS) 15.9 months (range, 0.3-48.3). The median OS among the responders was 21.1 months (range, 1.3-53.9). Four-week mortality was 3% and 8-week mortality 8%. Adverse events were predominantly grade 2 or less and included (>/= 10%): elevated liver enzymes (53%), elevated bilirubin (42%), diarrhea (19%), nausea (81%), rash (54%), hand and foot syndrome (10%), and elevated creatinine (10%). Grade 3 or more toxicities included: elevated creatinine (3%), rash (2%), vomiting (1%), and hand and foot syndrome (1%). No unexpected toxicities were observed.

Clofarabine plus low-dose cytarabine followed by prolonged consolidation alternating with decitabine is an active regimen with an ORR of 73% in older patients with newly diagnosed AML and high risk MDS. The regimen was well tolerated with low induction mortality. A randomized trail to compare this combination to best available therapy is needed to further asses the role of this combination in the treatment paradigm of elderly patients with AML.

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