Background and Rationale
Although all-trans retinoic acid (ATRA) and anthracycline-based therapy produces long-term remissions in most patients with acute promyelocytic leukemia (APL), significant morbidity and late complications, such as cardiomyopathy, myelodysplastic syndrome (MDS), and acute myeloid leukemia (AML), have been reported more commonly. Previous studies indicate that combined ATRA and arsenic trioxide (ATO) produce high clinical and molecular remission rates when used as induction. Additionally, we and others have shown that ATO has activity against minimal residual disease (MRD), thereby reducing the number of anthracycline-based consolidation courses required for long-term remission. Building on these findings, we are conducting a multicenter, phase II trial to study the efficacy of combined ATRA and ATO in an effort to reduce or eliminate the amount of standard chemotherapy required for long-term remission.
Key Eligibility 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-RARα
- Age ≥18 years
- Serum creatinine ≤ 2.0 mg/dl or a creatinine clearance of > 60 ml/min
- Serum bilirubin < 2.0 mg/dl (unless attributable to Gilbert's disease) and alkaline phosphatase, AST, and ALT ≤ 2.5 times the upper limit of normal
- Left ventricular ejection fraction ≥ 50% on echocardiogram or MUGA scan
- QTc ≤ 500 msec on baseline ECG
Study Objectives
- Determine the rate of clinical and molecular remission after induction with combined ATRA and ATO (along with idarubicin in patients with high-risk disease or who develop leukocytosis) in APL
- Determine the proportion of patients in molecular remission after each course of postremission therapy
- Determine the disease-free, event-free, and overall survival of patients treated with this program
- Determine the toxicity of this treatment program, including the early death rate (within 30 days), the incidence of APL differentiation syndrome, the number and length of hospitalizations, the incidence of secondary myelodysplastic syndrome (MDS)/acute myeloid leukemia (AML), and the effects of treatment on left ventricular ejection fraction (LVEF)
- Characterize the differentiation of APL cells during treatment with combined ATRA and ATO using serial immunophenotyping studies of peripheral blood
- Explore the in vivo induction of telomerase-dependent cell death by ATRA and ATO
Study Design
Patients may receive ATRA for up to seven days prior to study entry. Upon patient presentation, risk groups will be assigned according to established criteria: low- and intermediate-risk patients with a presenting WBC ≤10,000/µL; high-risk patients with a presenting WBC >10,000/µL. Induction for all patients will consist of ATRA and ATO daily for 35 days. The drugs will then be discontinued, and the patient will be followed until a clinical complete remission is achieved. Idarubicin will be added during induction only for patients with high-risk disease or who develop leukocytosis during therapy, because of the increased risk of APL differentiation syndrome and relapse. Dexamethasone will be given on days one through 14 of induction as prophylaxis for the APL differentiation syndrome.
All patients will then receive four courses of consolidation with ATRA for 15 days and ATO for 25 doses. During consolidation, high-risk patients will receive central nervous system prophylaxis with six doses of intrathecal cytarabine. Following consolidation, high-risk patients will receive eight cycles of maintenance therapy consisting of ATRA for 15 days and ATO for ten doses every three months. Low- and intermediate-risk patients will not receive maintenance therapy.
The differentiating effects of therapy will be characterized by serial flow cytometric analyses of peripheral blood. Effects of combined ATRA and ATO on telomerase activity, telomere length, and TERT expression will be assessed by analyses of blood and bone marrow samples. Disease status will be monitored with serial analyses of blood samples using RT-PCR for PML-RARα.
Contact
For more information and to see if your patient is eligible for this study, please contact Dr. Jae Park at 212-639-4048.
