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

Study Overview
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Brief Summary
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The purpose of this study is to find what effects, good and/or bad, treatment with two drugs has on leukemia. The first medicine is tretinoin (also called all-trans retinoic acid, ATRA, or Vesanoid). It is an approved medicine that causes the leukemia cells in APL to mature. It is related to vitamin A. The second is arsenic trioxide (Trisenox). It is an approved medicine for APL that comes back after earlier treatment. APL is most often treated with tretinoin and standard chemotherapy drugs. These chemotherapy drugs can cause infection and bleeding. They can also damage the heart and normal bone marrow cells. This can lead to a second leukemia years later. In this study, the investigators are using tretinoin and arsenic trioxide together. Both drugs work to treat APL. They have been used together in only a limited number of people. The investigators want to use these drugs together to reduce the amount of standard chemotherapy and decrease side effects. The patient will receive standard chemotherapy with a drug called idarubicin only if they have a higher chance of the leukemia coming back or a higher risk of side effects.

Detailed Description
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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.

Official Title
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Phase II Study of Combined Tretinoin and Arsenic Trioxide for Patients With Newly Diagnosed Acute Promyelocytic Leukemia Followed by Risk-Adapted Postremission Therapy

Conditions
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Acute Promyelocytic Leukemia

Intervention / Treatment
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* Drug: Tretinoin and Arsenic Trioxide


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Tretinoin and Arsenic Trioxide<br>This is a multicenter, phase II trial to study the efficacy of combined tretinoin and ATO in the treatment of newly diagnosed APL in an effort to reduce or eliminate the amount of standard chemotherapy required for long-term remission. | Drug: Tretinoin and Arsenic Trioxide<br>* See Detailed Description<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To Determine the Rate of Molecular Remission | after induction with combined tretinoin and ATO (along with idarubicin in patients with high-risk disease or who develop leukocytosis) in APL. | 4 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Participants Who Experienced a Complete Remission | after induction with tretinoin and ATO (with idarubicin in patients with high-risk disease or who develop leukocytosis). | 4 years | 
| To Determine the Proportion of Patients in Molecular Remission | after each course of postremission therapy. | 4 years | 
| To Determine the Disease-free and Event-free Survival of Patients | treated with this program. | 4 years | 
| To 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) Frequencies of toxicities based on the NCI Common Terminology Criteria for Adverse Events (CTCAE), version 4.0 will be tabulated. | 4 years | 
| To Characterize the Differentiation of APL Cells During Treatment | with combined tretinoin and ATO using serial immunophenotyping studies of peripheral blood | 4 years | 
| Explore the in Vivo Induction of Telomerase-dependent Cell Death | by ATRA (Tretinoin) and ATO (Arsenic Trioxide). Bone marrow samples will be analyzed at baseline and at the time of clinical CR for telomerase activity, telomere length and TERT expression | 4 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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ATO, Tretinoin, all-trans retinoic acid, ATRA, Vesanoid, Arsenic Trioxide, Trisenox, 11-040