Clofarabine Plus Cytarabine (ARA-C) Combination Is Active in Newly Diagnosed Patients (PTS) ≥ Age 50 with Acute Myeloid Leukemia (AML) and Myelodysplastic Syndrome (MDS).

Clofarabine is a next-generation deoxynucleoside analog with activity in acute leukemias. As clofarabine effectively inhibits ribonucleotide reductase, it is also suited for biochemical modulation strategies with other nucleoside analogs. In a previous study of clofarabine plus ara-C in pts with relapsed/refractory AML/MDS, we reported a CR rate of 24% (41% OR) (Blood 102:615a, 2003). Cellular pharmacology studies suggested that accumulation of intracellular clofarabine triphosphate resulted in higher ara-CTP accumulation of the leukemia blasts. We conducted a phase II study to investigate the efficacy and safety of clofarabine plus ara-C in pts ≥ 50 yrs with newly diagnosed AML and MDS (≥ 10% marrow blasts). Pts were excluded for ECOG PS > 2, age ≥ 75, and good prognosis karyotypes [t(8;21), inv(16), t(15;17)]. Clofarabine was given at 40mg/m²/d over 1-hour (hr) i.v. daily for 5 days (d2-6) followed 4 hrs later by ara-C at 1g/m²/d over 2-hrs i.v. daily for 5 days (d1-5). Sixty pts (53 AML, 7 RAEB-2 incl. 1 CMML-2) were enrolled and are evaluable. Median age: 61 yrs (range 50–74). Twenty-eight pts (47%) had secondary AML (17 AHD, 11 other malignancies) and 30 pts (50%) had abnormal cytogenetics (−5/−7 in 15, +8 in 10, del(11)(q23) in 3). 31 pts (52%) achieved CR; another 5 pts (8%) achieved CRp. Of 11 pts who received a second induction course, 4 pts (36%) responded (2 CR, 2 CRp). The CR rate was 60% (18/30 pts) in the diploid and 43% (13/30) in the abnormal karyotype group. Median time to CR: 29 days (20–98). 9 deaths (15%) occurred on study of which 4 pts (7%) died during the first course (d10 to d42). Adverse events included transient facial flushing and headaches (< gr. 3) during the infusion, and hyperbilirubinemia (gr. 3 in 3 pts), skin rashes, ↑ SGPT/SGOT, palmoplantar dyserysthesias, pancreatitis (1 pt) and renal failure (1 pt). Our data suggest that clofarabine + ara-C is active in older pts with newly diagnosed AML/high-risk MDS. The toxicity profile is acceptable. An update of time-to-event parameters will be presented.