• Objectives:
• 1) To determine the complete remission (CR) rate and remission duration in patients > 60 years with previously untreated AML and high-risk MDS following induction treatment with clofarabine versus clofarabine and ara-C.
• 2) To determine the safety profile and tolerability of clofarabine versus clofarabine when given in combination with ara-C in patients > 60 years of age with previously untreated AML and high-risk MDS.

Clofarabine is a chemotherapy drug that is designed to interfere with the growth and development of cancer cells. Ara-C is a chemotherapy drug which is approved for the treatment of AML and MDS. Although there is experience with the combination of both drugs, there have not been any phase 1 trials that explored the particular doses and schedule of clofarabine plus ara-C that a patient may receive.

Ara-C is one of the most active antileukemic agents and is the backbone of many combination regimens for patients with acute leukemias. Clofarabine is a novel nucleoside analogue that was found to be active as a single agent in patients with advanced leukemias, especially AML. Thus, a combination of ara-C and clofarabine in older patients with newly diagnosed, previously untreated AML may achieve even better results and is worth exploring in a phase II study.

Ara-C requires intracellular phosphorylation to the triphosphate compound ara-CTP to become biologically active. Cellular pharmacology studies have shown accumulation of ara-CTP to several hundred mM/L using high doses of ara-C. Furthermore, correlations have been demonstrated between the accumulation of ara-CTP and clinical responses in patients with relapsed AML. However, high doses of ara-C are associated with substantial toxicities especially in older patients. Studies by Plunkett et al. (Semin Oncol 1987; 14: 159-166) have demonstrated that accumulation of ara-CTP by human leukemia cells in vivo is saturated at ara-C plasma concentrations that are achieved by intermediate doses of ara-C (dose range of 1 to 2 g/m2/day) thus obviating the need for high-dose ara-C regimens and associated complications at least in some patients.

Clofarabine acts through inhibition of DNA synthesis and repair. Importantly, clofarabine is also a potent inhibitor of ribonucleotide reductase (RnR) and thus ideally suited for biochemical modulation strategies with other nucleoside analogs such as ara-C. RnR inhibitors can be used successfully to modulate ara-CTP accumulation in leukemic cells. Inhibition of RnR by clofarabine will result in a decrease in the levels of deoxynucleotides causing a subsequent decrease in the feedback inhibition of deoxycytidine kinase, the rate-limiting step in the synthesis of ara-CTP. The combination of clofarabine with ara-C would thus lead to increased retention of ara-CTP in leukemic cells so that the antileukemic activity of clofarabine is complemented by a biochemical synergy between these agents that should result in greater clinical efficacy.

Based on the observations made in the phase I clinical trial, the maximum (MTD) of clofarabine for acute leukemias is 40mg/m2/day i.v. daily for 5 days. Hepatotoxicity was defined as the dose limiting toxicity (DLT). In an ongoing phase I/II study of the identical combination in patients for relapsed and refractory acute leukemias, ara-C was given at the dose of 1g/m2/day i.v. over 2 hours from days 1-5, and the clofarabine dose was escalated over 15, 22.5, 30, to 40mg/m2/day i.v. on days 2-6 in combination with ara-C. No DLTs occurred including the 40mg/m2/day dose level of clofarabine and the combination at these dose levels is considered as feasible and safe.

However, especially older patients have reduced tolerance for chemotherapy necessitating interruptions, delays, and dose modifications with on-going therapy. As the optimal induction of older patients with AML has not been defined, and as encouraging results have been reported with clofarabine, we propose to randomize patients with AML and high-risk MDS older than 60 years to either receive clofarabine alone or clofarabine in combination with ara-C. In order to investigate novel doses and schedules of these drugs alone or in combination we propose a dose of clofarabine of 30mg/m2 with ara-C at a low dose schedule of 20mg/m2 subcutaneously (s.c.).

The MRC group randomized patients age 60 years to low dose ara-C 20mg/m2 s.c. daily x 4 versus hydroxyurea (the standard of care in England). They show low-dose ara-C to be significantly better in relation to CR rate (15% versus 1%; p<0.001) and survival (12-month survival 20% versus < 10%) (Alan Burnett, personal communication). The current design will answer several questions: 1) what is the single agent activity of clofarabine in this group of patients; 2) is clofarabine better than low dose ara-C?; 3) is the combination of clofarabine plus ara-C better than clofarabine alone and is it well tolerated? This will then prepare us for potential FDA pivotal trials of either single agent clofarabine, or clofarabine versus low dose ara-C, or clofarabine plus ara-c versus low-dose ara-C.

• Acute Myeloid Leukemia
• Myelodysplastic Syndrome

• Drug: Clofarabine
• Drug: Clofarabine plus Ara-C

Inclusion Criteria:

• Previously untreated AML and high-risk MDS ( > 10% blasts, or IPSS intermediate-2). Prior therapy with hydroxyurea, single agent chemotherapy (e.g. decitabine), hematopoietic growth factors, biological or "targeted" therapies are allowed.
• Age > 60 years.
• ECOG performance status </= 2.
• Sign a written informed consent form.
• Adequate liver function (total bilirubin < 2mg/dL, SGPT or SGOT < x 4 ULN) and renal function (serum creatinine < 2mg/dL).

Exclusion Criteria:

• Patients with >= NYHA grade 3 heart disease as assessed by history and/or physical examination.