Safety of Zileuton (Zyflo) in Combination With Imatinib Mesylate (Gleevec) in CML.

More than twenty two thousand people live with chronic myelogenous leukemia in the United
States and more than five thousand people are expected to be diagnosed this year. The
majority of patients with this disease are diagnosed in what is called the chronic phase.
The standard treatment for this phase of the disease is therapy with a medication called
imatinib. This treatment can diminish the amount of disease to very low levels that only
very sensitive and specialized techniques can measure; it does not, however, provide a cure.

Dr. Shaoguang Li and colleagues at University of Massachusetts have published a unique
discovery that the arachidonate 5-lipoxygenase (5-LO) gene (Alox5) is a critical regulator
for LSCs in BCR-ABL-induced CML (Chen Y et al. Loss of the Alox5 gene impairs leukemia stem
cells and prevents chronic myeloid leukemia. Nature Genetics 41:783-792, 2009). In the
absence of Alox5, BCR-ABL failed to induce CML in preclinical studies. While deficiency in
Alox5 had no effect on normal hematopoiesis, impairment of the LSCs function through
differentiation and cell division of CML LSCs was observed. This defect led to a depletion
of LSCs and a failure of CML development. Treatment with a 5-LO inhibitor (zileuton) also
impaired the function of LSCs and prolonged survival. These results demonstrate that a
specific target gene can be found in cancer stem cells and its inhibition can completely
inhibit the function of these stem cells. These findings provide an exciting opportunity to
develop the first anti-cancer stem cell therapy for treating CML.

Inclusion Criteria:

- Patients with CML in chronic phase (patients already on imatinib)

- Presence of Philadelphia chromosome or bcr-abl rearrangement

- Age ≥ 18 years

- ECOG performance status ≤ 2

- Written informed consent

Exclusion Criteria:

- Hepatic dysfunction (serum bilirubin ≥ 2 x ULN, and/or ALT ≥ 3 x ULN, and/or AST ≥ 3
x ULN)

- Renal dysfunction (creatinine ≥ 200 μmol/l or 2.3 mg/dl)

- Severe cardiac dysfunction (NYHA classification III-IV)

- Severe pulmonary or neurologic disease

- Pregnant or lactating females

- Patients with a history of active malignancy during the past 5 years with the
exception of nonmetastatic skin cancer (e.g. treated squamous or basal cell
carcinoma) or stage 0 cervical carcinoma

- Patients known to be HIV-positive

- Patients with active, uncontrolled infections

- Male and female patients of reproductive potential who are not practicing effective
means of contraception

- Patients with known allergic reaction or intolerance to either imatinib or zileuton

- Patients requiring anticoagulation therapy with coumadin