Atovaquone (Mepron®) Combined With Conventional Chemotherapy for de Novo Acute Myeloid Leukemia (AML)

Standard cytotoxic chemotherapy is based on the Medical Research Council (MRC) backbone of
cytarabine, and daunorubicin. This combination of chemotherapy is highly myelosuppressive and
can lead to oral aversions, dietary intolerance, and gastrointestinal infections
necessitating holding of oral drugs. Because of the toxicity of the best currently available
therapy, new drugs that are considered for incorporation into existing treatment regimens
will ideally have a tolerable side effect profile. This study will evaluate the tolerability
of incorporating the orally bioavailable drug atovaquone in combination with standard
cytotoxic induction chemotherapy for newly diagnosed pediatric AML patients. Therefore,
quantifying the frequency with which atovaquone is held due to a side effect of therapy is
crucial information to gather in this population.

Inclusion Criteria:

1. Age: Children ≥1 month and children and young adults < 21 years of age

2. Diagnosis: Patients must be newly diagnosed with acute myelogenous leukemia

2.1 Patients with previously untreated primary AML who meet the customary criteria for
AML with ≥ 20% bone marrow blasts as set out in the 2008 World Health Organization
(WHO) Myeloid Neoplasm Classification are eligible.

Attempts to obtain bone marrow either by aspirate or biopsy must be made unless
clinically prohibitive. In cases where it is clinically prohibitive, peripheral blood
with an excess of 20% blasts and in which adequate flow cytometric and
cytogenetics/Fluorescent in situ hybridization (FISH) testing is feasible can be
substituted for the marrow exam at diagnosis

2.2 Patients with < 20% bone marrow or peripheral blood blasts are eligible if they
have:

- A karyotypic abnormality characteristic of de novo AML (t(8;21)(q22;q22),
inv(16)(p13q22) or t(16;16)(p13;q22) or 11q23 abnormalities,

- The unequivocal presence of megakaryoblasts, or

- Biopsy proven isolated myeloid sarcoma (myeloblastoma; chloroma, including
leukemia cutis).

3. Pre-existing myelodysplastic syndrome:

Patients with a history of myelodysplastic syndrome that has progressed to AML which
meets the criteria above are eligible.

4. Therapy-related or secondary AML Patients with AML which is thought to be therapy
related but meet the criteria above are eligible.

5. Prior Therapy:

Prior therapy with hydroxyurea, all-trans retinoic acid (ATRA), corticosteroids (any
route), and IT cytarabine given at diagnosis is allowed. Hydroxyurea and ATRA cannot
be given concurrently with protocol therapy. There is no specific amount of time
mandated between the last dose of hydroxyurea or ATRA and the start of protocol
therapy.

With the exception of infants who had previously received low dose cytarabine to
control disease, patients who have previously received any other antileukemic therapy
(i.e. chemotherapy or radiation therapy) are not eligible for this protocol.

6. Organ Function Requirement:

Adequate Liver Function Defined as:

- Direct Bilirubin ≤2x upper limit of normal (ULN) for age and institution (unless
related to leukemic involvement), and

- serum glutamate-pyruvate transaminase (SGPT) (ALT) ≤2.5x ULN for age and
institution (unless it is related to leukemic involvement)

7. Ability to receive enteral medication:

Eligible patients should have no contraindication to enteral administration of medication
(e.g. oral, Nasogastric (NG), G-tube, etc) as determined by the evaluating physician.

Exclusion Criteria:

1. Excluded Constitutional Conditions

Patients with a history of any of the following constitutional conditions are not
eligible:

- Fanconi anemia

- Shwachman syndrome

- Any other known constitutional bone marrow failure syndrome

- Patients with constitutional trisomy 21 or with constitutional mosaicism of
trisomy 21 who are eligible to receive treatment for Down Syndrome (DS) related
AML Note: Enrollment and initiation of therapy may occur pending results of
clinically indicated studies to exclude these conditions. If a patient is found
to have any of these conditions they should be removed from the study once
results are received. Patients who are removed due to ineligibility after results
are received will be replaced.

2. Other Excluded Conditions

Patients with any of the following oncologic diagnoses are not eligible:

- Any concurrent malignancy

- Juvenile myelomonocytic leukemia (JMML)

- Philadelphia chromosome positive AML

- Biphenotypic or bilineal acute leukemia

- Acute promyelocytic leukemia Note: Enrollment and initiation of therapy may occur
pending results of clinically indicated studies to exclude these conditions. If a
patient is found to have any of these conditions they should be removed from the
study once results are received. Patients who are removed due to ineligibility
after results are received will be replaced.

3. Prior receipt of anthracyclines Patients with treatment-related AML who have received
more than 250mg/m2 of anthracyclines (in daunorubicin equivalents) are not eligible.

4. Known Allergy or Intolerance to Atovaquone Patients with a known allergy or
intolerance to atovaquone are not eligible.

5. Enrollment on another ongoing treatment study Patients who are enrolled on a treatment
study are not eligible

6. Pregnancy or Breast-Feeding 6.1 Female patients who are pregnant are ineligible since
fetal toxicities and teratogenic effects have been noted for several of the study
drugs.

5.2 Lactating females are not eligible unless they have agreed not to breastfeed their
infants.

5.3 Female patients of childbearing potential are not eligible unless a negative pregnancy
test result has been obtained.

6. Informed Consent: All patients and/or their parents or legally authorized
representatives must sign a written informed consent. Assent, when appropriate, will be
obtained according to institutional guidelines.