Combination Chemotherapy in Treating Young Patients With Newly Diagnosed Acute Promyelocytic Leukemia

Study Overview
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Brief Summary
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This phase III trial is studying combination chemotherapy to see how well it works in treating young patients with newly diagnosed acute promyelocytic leukemia. Drugs used in chemotherapy work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. Giving more than one drug (combination chemotherapy) may kill more cancer cells.

Detailed Description
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PRIMARY OBJECTIVES: I. To decrease the total anthracycline dose from the best current published results in standard risk childhood acute promyelocytic leukemia (APL) while still maintaining a comparable event-free survival (EFS). SECONDARY OBJECTIVES: I. To assign treatment based on risk stratification by white blood cell count (WBC) at diagnosis. II. To estimate the induction failure rate, toxic death rate, disease-free survival rate and overall survival rate in both standard and high risk APL patients. III. To monitor for cardiotoxicity in an idarubicin/mitoxantrone based regimen. IV. To document the toxicity of a traditional chemotherapy/all-trans retinoic acid (ATRA) (tretinoin) based regimen combined with arsenic trioxide therapy. V. To study the relationship of Fms-like tyrosine kinase 3 (FLT3) mutations to clinical features and outcome in APL. VI. To study risk factors for pseudotumor cerebri in APL. VII. To study the relationship of early progenitor cell involvement to treatment failure in FLT3 positive APL. VIII. To compare the EFS of children enrolled on AAML0631 with the EFS of children enrolled on C9710 who were between the ages of 2 and 21 and did not receive arsenic trioxide. IX. To estimate the proportion of patients who carry a cryptic t(15;17), i.e., those who are positive for a promyelocytes.(PML)-retinoic acid receptor alpha (RARA) fusion transcript by polymerase chain reaction (PCR) analysis but have normal chromosomes. X. To estimate the proportion of patients with variant RARA partners. XI. To compare the outcome of patients with only a t(15;17) with that of patients who carry a t(15;17) and other chromosomal abnormalities. OUTLINE: This is a multicenter study. Patients are assigned to 1 of 2 arms based on risk factor (standard-risk [WBC less than 10,000/mm^3] or high-risk [WBC 10,000/mm^3 or higher]). ARM I (STANDARD-RISK): INDUCTION THERAPY: Patients receive tretinoin orally (PO) twice daily (BID) on days 1-30 and idarubicin intravenously (IV) over 15 minutes once on days 3, 5, and 7. CONSOLIDATION THERAPY: CONSOLIDATION 1: Patients receive arsenic trioxide IV over 2 hours on days 1-5, 8-12, 15-19, 22-26, and 29-33 and tretinoin PO BID on days 1-14. Treatment repeats every 5 weeks for 2 courses, followed by a 2-week break, and then treatment repeats for 2 more courses. Beginning 1 week later or when blood counts recover, patients proceed to consolidation 2. CONSOLIDATION 2: Patients receive cytarabine intrathecally (IT) on day 1, tretinoin PO BID on days 1-14, high-dose cytarabine IV over 3 hours every 12 hours on days 1-3, and mitoxantrone hydrochloride IV over 15-30 minutes once on days 3 and 4. Patients proceed to consolidation 3 1 week later or when blood counts recover. CONSOLIDATION 3: Patients receive cytarabine IT on day 1, tretinoin PO BID on days 1-14, and idarubicin IV over 15 minutes once daily on days 1, 3, and 5. High-risk patients and those standard-risk patients who are positive for minimal residual disease by real-time quantitative (RQ)-PCR receive consolidation 4 one week later or when blood counts recover. All other standard-risk patients proceed to maintenance therapy. MAINTENANCE THERAPY: Patients receive cytarabine IT on day 1 (course 1 only), tretinoin PO BID on days 1-14, mercaptopurine PO once daily (QD) on days 1-84, methotrexate PO once on days 1, 8, 15, 22, 29, 36, 43, 50, 57, 64, 71, and 78. Treatment repeats every 12 weeks for 9 courses. ARM II (HIGH-RISK): INDUCTION THERAPY: Patients receive tretinoin PO BID on days 1-30 and idarubicin IV over 15 minutes once on days 1, 3, and 5. Patients proceed to consolidation therapy one week later or when blood counts recover. CONSOLIDATION THERAPY: Patients receive consolidation 1, 2, and 3 as in Arm I. CONSOLIDATION 4: Patients receive cytarabine IT on day 1, tretinoin PO BID on days 1-14, high-dose cytarabine IV over 3 hours every 12 hours on days 1-3, and idarubicin IV over 15 minutes once on day 4. Patients who demonstrate molecular complete remission (CR) and remain in hematological CR proceed to maintenance therapy 1 week later or when blood counts recover. MAINTENANCE THERAPY: Patients receive maintenance therapy as in Arm I. After completion of study treatment, patients are followed every month for 1 year, every 3 months for 2 years, every 6 months for 2 years, and then annually for 5 years.

Official Title
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Risk Adapted Treatment of Newly Diagnosed Childhood Acute Promyelocytic Leukemia (APL) Using Arsenic Trioxide (Trisenox® ) During Consolidation

Conditions
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Childhood Acute Promyelocytic Leukemia With PML-RARA, Myeloid Neoplasm

Intervention / Treatment
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* Drug: Arsenic Trioxide
* Drug: Cytarabine
* Other: Diagnostic Laboratory Biomarker Analysis
* Drug: Idarubicin
* Drug: Mercaptopurine
* Drug: Methotrexate
* Drug: Mitoxantrone Hydrochloride
* 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 acute promyelocytic leukemia initially by morphology (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; APL is considered a hematological emergency and treatment should be initiated as quickly as possible without waiting for molecular or cytogenetic/fluorescence in situ hybridization (FISH) confirmation; for patients who are unable to begin receiving ATRA in a timely manner following a presumed diagnosis of APL, consideration should be given to initiating ATRA and proceeding with treatment outside of the AAML0631 protocol; if the RQ-PCR results are known at the time of study enrollment, the patient must demonstrate PML-RARA and/or RARA-PML transcripts by RQ-PCR to be eligible; patients without evidence of APL by bone marrow or peripheral blood morphology but with isolated myeloid sarcoma (myeloblastoma; chloroma, including leukemia cutis) are eligible provided that the t(15;17) translocation is documented on either marrow or tumor tissue by cytogenetics, FISH, or PCR prior to study enrollment; in this situation, touch preps from the tumor site can be evaluated by FISH with PML-RARA probes; NOTE: A lumbar puncture is not required to be enrolled on study; if the diagnosis of APL is known or suspected, extreme caution must be exercised in performing a lumbar puncture during active coagulopathy; in addition a computed tomography (CT) or magnetic resonance imaging (MRI) should be considered to rule out the possibility of an associated chloroma if central nervous system (CNS) disease is suspected or proven; if CNS disease is documented, patients are still eligible No minimal performance status criteria The patient must not have received systemic definitive treatment for APL or other suspected leukemia, including cytotoxic chemotherapy, retinoids, or arsenic; prior therapy with corticosteroids, hydroxyurea, or leukopheresis will not exclude the patient; if a patient received intrathecal cytarabine prior to the diagnosis of APL being known, the patient will still be eligible as long as they meet all other eligibility requirements Exclusion Criteria: Pregnant women or nursing mothers are excluded; treatment under this protocol would expose an unborn child to significant risks; patients should not be pregnant or plan to become pregnant while on treatment; women and men of reproductive potential should agree to use an effective means of birth control; there is an extremely high risk of fetal malformation if pregnancy occurs while on ATRA in any amount even for short periods Patients with a pre-existing prolonged QT Syndrome will not be eligible for this protocol due to the use of arsenic trioxide which can prolong the QT interval

Ages Eligible for Study
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Minimum Age: 2 Years
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
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm I (standard risk, combination chemotherapy)<br>See Detailed Description | Drug: Arsenic Trioxide<br>* Given IV<br>* Other names: White Arsenic;Drug: Cytarabine<br>* Given IT or IV<br>* Other names: WR-28453;Other: Diagnostic Laboratory Biomarker Analysis<br>* Correlative studies<br>Drug: Idarubicin<br>* Given IV<br>* Other names: 4-DMDR;Drug: Mercaptopurine<br>* Given orally<br>* Other names: WR-2785;Drug: Methotrexate<br>* Given orally<br>* Other names: WR-19039;Drug: Mitoxantrone Hydrochloride<br>* Given IV<br>* Other names: Pralifan;Drug: Tretinoin<br>* Given orally<br>* Other names: Vitinoin;|
| Experimental: Arm II (high risk, combination chemotherapy)<br>See Detailed Description. | Drug: Arsenic Trioxide<br>* Given IV<br>* Other names: White Arsenic;Drug: Cytarabine<br>* Given IT or IV<br>* Other names: WR-28453;Other: Diagnostic Laboratory Biomarker Analysis<br>* Correlative studies<br>Drug: Idarubicin<br>* Given IV<br>* Other names: 4-DMDR;Drug: Mercaptopurine<br>* Given orally<br>* Other names: WR-2785;Drug: Methotrexate<br>* Given orally<br>* Other names: WR-19039;Drug: Mitoxantrone Hydrochloride<br>* Given IV<br>* Other names: Pralifan;Drug: Tretinoin<br>* Given orally<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) | EFS - time from study entry until failure to achieve complete remission during consolidation, relapse, or death. For further clarification see definitions provided in the protocol. | At 3 years from study entry | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Hematologic Remission Rate | Proportion of patients in hematologic remission at end of consolidation, course 1 are reported. | End of consolidation, course 1: up to 5 months | 
| Hematologic, Molecular, and Cytogenetic Remission Rate | Proportion of patients in hematologic, molecular, and cytogenetic remission at end of consolidation, course 3 and 4 are reported. Patients were determined to be in remission by all three criteria. | End of consolidation, course 3; up to 7 months (for Standard Risk) or end of consolidation, course 4; up to 9 months (for High Risk) | 
| Overall Survival (OS) | OS - time from study entry to death. | At 3 years from study entry |