Tretinoin and Arsenic Trioxide in Treating Patients With Untreated Acute Promyelocytic Leukemia

PRIMARY OBJECTIVES:

I. To eliminate exposure to conventional chemotherapy (including anthracyclines), for
patients with standard risk acute promyelocytic leukemia (APL), through use of arsenic
trioxide (ATO) and all-trans retinoic acid (ATRA) (tretinoin) based therapy while achieving
an event free survival (EFS) that is not inferior compared to historical controls.

II. To significantly reduce exposure to conventional chemotherapy, and in particular,
anthracycline exposure, for patients with high risk APL, through use of ATO and ATRA based
therapy while achieving an event free survival that is not inferior compared to historical
controls.

SECONDARY OBJECTIVES:

I. To analyze the clinical impact of FMS-like tyrosine kinase 3 (FLT3) mutations in pediatric
APL.

II. To correlate clinical outcomes with the kinetics of reduction in promyelocytic leukemia
(PML)/retinoic acid receptor alpha (RARalpha) transcript level by quantitative real-time
(RT)-polymerase chain reaction (PCR) (RQ-PCR) in bone marrow and peripheral blood samples
from diagnosis to time points during therapy.

III. To monitor incidence of coagulopathy complications, utilizing standardized conventional
supportive care, and correlate with a battery of coagulation testing.

IV. To evaluate the neurocognitive outcomes of patients treated on this protocol using
patient-completed, performance-based measures of neuropsychological functioning and parent
questionnaire report.

OUTLINE:

INDUCTION THERAPY: Patients with standard and high risk APL receive tretinoin orally (PO)
twice daily (BID) and arsenic trioxide intravenously (IV) over 2-4 hours on days 1-28. High
risk APL patients also receive dexamethasone PO or IV BID on days 1-14 and idarubicin IV over
15 minutes on days 1, 3, 5, and 7. Patients achieving hematologic complete remission
(hCR)/hematologic complete remission with incomplete blood count recovery (hCRi) may go on to
consolidation therapy. Patients who do not achieve hCR/hCRi may continue treatment with
tretinoin and arsenic trioxide for up to 70 days.

CONSOLIDATION THERAPY: Patients receive tretinoin PO BID on days 1-14 and 29-42 and arsenic
trioxide IV over 2-4 hours on days 1-5, 8-12, 15-19, and 22-26. Treatment repeats every 56
days for up to 3 courses in the absence of disease progression or unacceptable toxicity.
Patients then receive tretinoin PO BID on days 1-14 and arsenic trioxide IV over 2-4 hours on
days 1-5, 8-12, 15-19, and 22-26.

MINIMAL RESIDUAL DISEASE (MRD) CONSOLIDATION THERAPY: Patients who have APL in the bone
marrow after 2 courses of consolidation therapy receive MRD consolidation therapy prior to
continuing onto consolidation course 3. Patients receive cytarabine IV over 1-3 hours every
12 hours on days 1-4; mitoxantrone hydrochloride IV over 15-30 minutes on days 3-6; and
tretinoin PO BID on days 1-14. If there are no APL cells in the bone marrow after completion
of MRD consolidation therapy, patients continue on to consolidation course 3.

After completion of study treatment, patients are followed up monthly for 12 months, every 3
months for 36 months, every 6 months for 48 months, and then annually for 2 years.

Inclusion Criteria:

- Patients must be newly diagnosed with a clinical diagnosis of APL (initially by
morphology of bone marrow or peripheral blood)

- Bone marrow is highly preferred but in cases where marrow cannot be obtained at
diagnosis, peripheral blood will be accepted

- If the RQ-PCR results are known at the time of study enrollment, the patient must
demonstrate the PML-RARalpha transcript by RQ-PCR to be eligible

- NOTE: A lumbar puncture is not required in order to be enrolled on study nor are
lumbar punctures recommended at the time of diagnosis; if the diagnosis of APL is
known or suspected, diagnostic lumbar punctures in patients with neurologic symptoms
should be deferred until any coagulopathy is corrected; if central nervous system
(CNS) disease is suspected or proven, a computed tomography (CT) or magnetic resonance
imaging (MRI) should be considered to rule out the possibility of an associated
chloroma; if CNS disease is documented, patients are still eligible and will receive
protocol directed intrathecal treatments

- Patients may receive up to a maximum of 5 days of pre-treatment with ATRA prior to
administration of protocol therapy

- Treatment with hydroxyurea, corticosteroids (any route) and intrathecal cytarabine
prior to beginning protocol directed therapy is allowed; however, it should be noted
that lumbar puncture and intrathecal therapy at initial diagnosis of APL is not
recommended

- All patients and/or their parents or legal guardians must sign a written informed
consent

- All institutional, Food and Drug Administration (FDA), and National Cancer Institute
(NCI) requirements for human studies must be met

Exclusion Criteria:

- Patients with secondary APL are excluded; this includes all patients with APL that may
have resulted from prior treatment (chemotherapy or radiation)

- Patients with isolated myeloid sarcoma (myeloblastoma, chloroma, including leukemia
cutis) but without evidence of APL by bone marrow or peripheral blood morphology are
excluded

- Patients with a pre-existing diagnosis of a prolonged QT syndrome (even if corrected
QT interval [QTc] is normal at the time of APL diagnosis) are excluded

- Patients with a baseline QTc of > 450 msec are excluded; Bazett?s formula is to be
used for measurement of the corrected QT interval: the QT interval (msec) divided by
the square root of the RR interval (msec)

- Patients with a history or presence of significant ventricular or atrial
tachyarrhythmia are excluded

- Patients with right bundle branch block plus left anterior hemiblock, bifascicular
block are excluded

- Patients with serum creatinine > 3.0 mg/dL and patients on active dialysis for renal
dysfunction are excluded

- Patients who have received treatment with any other cytotoxic chemotherapy prior to
beginning protocol therapy (other than allowed in above criteria) are excluded

- Female patients who are pregnant are excluded; patients should not be pregnant or plan
to become pregnant while on treatment; a pregnancy test prior to enrollment is
required for female patients of childbearing potential

- Lactating females who plan to breastfeed their infants are excluded

- Sexually active patients of reproductive potential who have not agreed to be abstinent
or use 2 forms of effective contraception during treatment through 1 month off therapy
are excluded