Combined Tretinoin and Arsenic Trioxide for Patients With Newly Diagnosed Acute Promyelocytic Leukemia Followed by Risk-Adapted Postremission Therapy

Induction will consist of tretinoin 45 mg/m2 po daily (rounded up to the nearest 10mg) in two
divided doses (25 mg/m2 in patients <20 years of age) for 35 days and ATO 0.15 mg/kg IV daily
for 35 doses given 5-7 days per week. The drugs will then be discontinued, and the patient
will be followed until a clinical complete remission is achieved. Idarubicin 12 mg/m2 IV for
4 doses will be added during induction on day 2 if the presenting WBC is >10,000/μl, or if
the WBC increases to 5,000/μl on day 5, 10,000/μl on day 10, or 15,000/μl on day 15, because
of the increased risk of the APL differentiation syndrome and relapse in these patients.
Dexamethasone 10 mg twice daily with be given on days 1-14 of induction as prophylaxis for
the APL differentiation syndrome. All patients will then receive four courses of
consolidation with tretinoin 45 mg/m2 po daily (rounded up to the nearest 10mg) (25 mg/m2 in
patients <20 years of age) for 15 days and ATO 0.15 mg/kg IV for 25 doses.

Patients with high-risk disease or who received Idarubicin during Induction may receive
intrathecal cytarabine as CNS prophylaxis given by the treating physician during
consolidation, at the discretion of the site PI. High-risk patients will also receive
maintenance therapy with additional courses of tretinoin and ATO every 3 months for 2 years.
Each maintenance course will consist of tretinoin 45 mg/m2 po daily (25 mg/m2 in patients <20
years of age) for 15 days and ATO 0.15 mg/kg IV for 10 doses. Disease status will be
monitored with serial analyses of peripheral blood samples using RT-PCR for PML-RARα mRNA.
Patients will be followed until relapse, death, loss to follow-up, or removal from study.

Induction therapy can be given as an inpatient or outpatient. Consolidation and maintenance
treatments will be given as an outpatient. Consolidation may also be given at the patient's
local institution. Intrathecal cytarabine treatments will be administered as an outpatient.

Inclusion Criteria:

- Previously untreated patients with a morphologic diagnosis of APL, confirmed by
demonstration of t(15;17) using conventional cytogenetics OR florescence in situ
hybridization (FISH), OR a positive RT-PCR assay for PML-RAR at the subject's local
institution.

- Age ≥18 years. Karnofsky performance status of ≥ 60%.

- Adequate renal function as demonstrated by a serum creatinine ≤ 2.0 mg/dl or a
creatinine clearance of > 60 ml/min.

- Adequate hepatic function as demonstrated by a bilirubin < 2.0 mg/dl (unless
attributable to Gilbert's disease) and an alkaline phosphatase, AST, and ALT ≤ 2.5
times the upper limit of normal.

- Normal cardiac function as demonstrated by a left ventricular ejection fraction ≥ 50%
on echocardiogram or MUGA scan.

- QTc ≤ 500 msec on baseline ECG.

- Negative serum pregnancy test in women of childbearing potential.

- Ability to swallow oral medication.

- Men and women of child-bearing potential must be willing to practice an effective
method of birth control during treatment and at least 4 months after treatment is
finished.

- Patients with central nervous system involvement by APL are eligible and may receive
concomitant treatment with radiation therapy and/or intrathecal chemotherapy in
accordance with standard medical practice.

Exclusion Criteria:

- Previous treatment for APL, except tretinoin, which may be given for up to 7 days
prior to study entry.

- Active serious infections not controlled by antibiotics.

- Pregnant women or women who are breast-feeding.

- Concurrent active malignancy requiring immediate therapy.

- Clinically significant cardiac disease (NY Heart Association Class III or IV),
including chronic arrhythmias, or pulmonary disease.

- Other serious or life-threatening conditions deemed unacceptable by the principal
investigator.