Clofarabine Plus Cytarabine in Patients With Previously Untreated Acute Myeloid Leukemia and High-risk Myelodysplastic Syndrome

The treatment of acute myeloid leukemia (AML) in older patients has not improved
significantly in recent years when compared with the considerable progress that has been made
in younger patients. Hence, new drugs and approaches are needed in this poor-prognosis group
of patients with AML.

Nucleoside analogs are among the most active antileukemic agents available. Clofarabine was
synthesized as a rational extension of the experience with other deoxyadenosine analogs.
Clofarabine is converted to the monophosphate form by the enzyme deoxycytidine kinase which
represents the major metabolite of clofarabine. Phosphorylation of clofarabine is
substantially more efficient than that of other nucleosides such as fludarabine and so is
intracellular retention of the triphosphate form of clofarabine. Mechanisms of action include
inhibition of DNA synthesis, inhibition of DNA polymerases, and potent inhibition of
ribonucleotide reductase (RNR) resulting in depletion of normal nucleotides and increased DNA
uptake of the analog. Single agent clofarabine has shown activity in phase I studies in AML
and ALL. As a potent inhibitor of RNR, however, clofarabine is ideal to be incorporated into
biochemical modulation strategies such as have been tested and validated with fludarabine and
ara-C in AML. By combining clofarabine with ara-C, inhibition of RNR by clofarabine will
result in a drop of deoxynucleotides causing a decrease in the feedback inhibition of
deoxycytidine kinase which is the rate-limiting step in the synthesis of ara-CTP leading to
increased retention of ara-CTP. Therefore, the activity of clofarabine and ara-C in leukemic
cells would be complemented by a biochemical synergism between these agents that should
result in better clinical efficacy. We have established the safety of the combination in
salvage patients with acute leukemias.

Inclusion Criteria:

- Previously untreated acute myeloid leukemia (AML) or high-risk myelodysplastic
syndrome (MDS) (> 10% blasts). Prior therapy with hydroxyurea, single agent
chemotherapy (e.g. decitabine), hematopoietic growth factors, biological or "targeted"
therapies are allowed.

- Age > 50 years to < 74 years (diploid cytogenetics) and < 69 years (abnormal
cytogenetics).

- ECOG performance status
- 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).

- Male and female patients who are fertile agree to use an effective barrier method of
birth control (ie, latex condom, diaphragm, cervical cap, etc) to avoid pregnancy.
Female patients need a negative serum or urine pregnancy test within 7 days of study
enrollment (applies only if patient is of childbearing potential. Non-childbearing is
defined as >= 1 year postmenopausal or surgically sterilized).

- Patients who are considered to require immediate induction (rapidly rising WBC >/=
50,000 and/or organ involvement as per the assessment of the treating physician) can
be treated without final cytogenetic results and pretreatment assessment of cardiac
ejection fraction (MUGA or echocardiogram) if by history and physical examination
patients have
Exclusion Criteria:

- AML with the following cytogenetic abnormalities: t(15;17), t(8;21), inv(16).
Cytogenetic results do not need to be available if immediate induction is required
(see inclusion #7).

- Cardiac ejection fraction < 30%. Pretreatment assessment of ejection fraction is not
necessary if immediate induction is required as long as by history and physical
examination patients have
- Active and uncontrolled infection or any other severe concurrent disease considered
life-threatening, or which, in the judgement of the investigator and after discussion
with the Principal Investigator, would make the patient inappropriate for entry into
the study.