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

Study Overview
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Brief Summary
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This phase III trial studies tretinoin and arsenic trioxide in treating patients with newly diagnosed acute promyelocytic leukemia. Standard treatment for acute promyelocytic leukemia involves high doses of a common class of chemotherapy drugs called anthracyclines, which are known to cause long-term side effects, especially to the heart. Tretinoin may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Arsenic trioxide may stop the growth of cancer cells by either killing the cells, by stopping them from dividing, or by stopping them from spreading. Completely removing or reducing the amount of anthracycline chemotherapy and giving tretinoin together with arsenic trioxide may be an effective treatment for acute promyelocytic leukemia and may reduce some of the long-term side effects.

Detailed Description
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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. EXPLORATORY 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.

Official Title
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A Phase III Study for Patients With Newly Diagnosed Acute Promyelocytic Leukemia (APL) Using Arsenic Trioxide and All-Trans Retinoic Acid

Conditions
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Acute Promyelocytic Leukemia With t(15;17)(q24.1;q21.2); PML-RARA

Intervention / Treatment
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* Drug: Arsenic Trioxide
* Drug: Cytarabine
* Drug: Dexamethasone
* Drug: Idarubicin
* Other: Laboratory Biomarker Analysis
* Drug: Mitoxantrone Hydrochloride
* Other: Quality-of-Life Assessment
* Other: Questionnaire Administration
* Drug: Tretinoin


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 12 Months
Maximum Age: 21 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: Treatment (tretinoin, arsenic trioxide, chemotherapy)<br>See Detailed Description | Drug: Arsenic Trioxide<br>* Given IV<br>* Other names: White Arsenic;Drug: Cytarabine<br>* Given IV<br>* Other names: WR-28453;Drug: Dexamethasone<br>* Given PO or IV<br>* Other names: ZoDex;Drug: Idarubicin<br>* Given IV<br>* Other names: 4-DMDR;Other: Laboratory Biomarker Analysis<br>* Correlative studies<br>Drug: Mitoxantrone Hydrochloride<br>* Given IV<br>* Other names: Pralifan;Other: Quality-of-Life Assessment<br>* Ancillary studies<br>* Other names: Quality of Life Assessment;Other: Questionnaire Administration<br>* Ancillary studies<br>Drug: Tretinoin<br>* Given PO<br>* Other names: Vitinoin;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Event-free Survival (EFS) in Standard Risk Acute Promyelocytic Leukemia (APL) Patients | EFS is defined as the time from on study to failure to achieve hematological complete response (CR) prior to start of consolidation, persistence of molecular positive disease after minimal residual disease (MRD) positive consolidation course, relapse (molecular, morphologic or extramedullary), or death. The Kaplan-Meier method will be used to estimate 2-year EFS along with 90% log-minus-log transformed confidence limits. | Up to 24 months | 
| EFS in High Risk APL Patients | EFS is defined as the time from on study to failure to achieve hematological CR prior to start of consolidation, persistence of molecular positive disease after MRD positive consolidation course, relapse (molecular, morphologic or extramedullary), or death. The Kaplan-Meier method will be used to estimate 2-year EFS along with 90% log-minus-log transformed confidence limits. | Up to 24 months |