S0333 Combination Chemotherapy in Treating Patients With Newly Diagnosed Acute Lymphoblastic Leukemia

Study Overview
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Brief Summary
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RATIONALE: 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), and giving the drugs in different combinations may kill more cancer cells. PURPOSE: This phase II trial is studying how well combination chemotherapy works in treating patients with newly diagnosed acute lymphoblastic leukemia.

Detailed Description
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OBJECTIVES: Primary Determine the probability of 1-year continuous complete remission in patients with newly diagnosed acute lymphoblastic leukemia treated with first induction chemotherapy comprising daunorubicin, vincristine, prednisone, and pegaspargase; and second induction chemotherapy comprising high-dose cytarabine and mitoxantrone. Secondary Determine the frequency and severity of toxic effects of these induction regimens followed by consolidation therapy comprising cyclophosphamide, cytarabine, mercaptopurine, and methotrexate and maintenance chemotherapy comprising mercaptopurine, methotrexate, vincristine, doxorubicin, dexamethasone, cyclophosphamide, thioguanine, and cytarabine in these patients. Other objectives (if funding allows): To evaluate in a preliminary manner the significance of detecting minimal residual disease as a prognostic factor for survival and relapse-free survival of patients receiving chemotherapy To evaluate in a preliminary manner the pattern of gene expression of patients entered onto the trial and its relationship to cytogenetics/FISH risk classification, overall survival, and relapse-free survival OUTLINE: This is a multicenter study. First induction chemotherapy: Patients receive daunorubicin IV on days 1-3; vincristine IV on days 1, 8, 15, and 22; prednisone IV or orally on days 1-28, followed by a taper to day 35; and pegaspargase IV or subcutaneously (SC) on day 15. Patients with CNS leukemia also receive methotrexate intrathecally (IT) or intraventricularly twice weekly and oral leucovorin calcium four times daily for 4 doses after each administration of methotrexate. When blasts are no longer present in the spinal fluid, patients receive methotrexate IT or intraventricularly once weekly for 4 weeks and then once monthly for 1 year. Patients are reevaluated on day 28. Patients who achieve A1 bone marrow status and B1 peripheral blood status or those with resistant disease proceed to second induction therapy. Second induction chemotherapy: Patients receive high-dose cytarabine IV on days 1-5; mitoxantrone IV on day 3; and filgrastim (G-CSF) SC or IV beginning on day 7 and continuing until blood counts recover. Patients with CNS leukemia also receive methotrexate and leucovorin calcium as in first induction chemotherapy. Patients are reevaluated on day 28. Patients who achieve A1 bone marrow status and B1 peripheral blood status with no extramedullary disease (other than CNS involvement) proceed to consolidation chemotherapy. Patients with resistant disease OR Philadelphia chromosome- or BCR/ABL-positive disease are removed from the study after receiving double induction chemotherapy. Consolidation chemotherapy: Patients receive cyclophosphamide IV on days 1, 15, and 29; cytarabine IV on days 2-5 and 16-19; oral mercaptopurine on days 1-28; and methotrexate IT or intraventricularly on days 2, 9, 16, and 23. Patients with CNS leukemia also undergo cranial radiotherapy once daily, 5 days a week, for 2 weeks. Patients in complete remission proceed to maintenance chemotherapy. Maintenance chemotherapy: Course 1: Patients receive oral mercaptopurine on days 1-63 and oral methotrexate on days 1, 8, 15, 22, 29, 36, 43, 50, and 57. Patients proceed to course 2 after blood counts recover. Course 2: Patients receive vincristine IV and doxorubicin IV on days 1, 8, 15, and 22 and oral dexamethasone on days 1-28. Patients proceed to course 3 after blood counts recover. Course 3: Patients receive cyclophosphamide IV on day 1; oral thioguanine on days 1-14; and cytarabine IV on days 3-6 and 10-13. Patients proceed to course 4 after blood counts recover. Course 4: Patients receive oral mercaptopurine once daily for 2 years and oral methotrexate once weekly for 2 years. Treatment continues in the absence of disease relapse or unacceptable toxicity. After completion of study therapy, patients are followed every 3 months for 1 year, every 6 months for 1 year, and then annually for 3 years.

Official Title
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A Phase II Study of Double Induction Chemotherapy for Newly Diagnosed Non-L3 Adult Acute Lymphoblastic Leukemia With Investigation of Minimal Residual Disease and Risk of Relapse Following Maintenance Chemotherapy

Conditions
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Leukemia

Intervention / Treatment
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* Biological: filgrastim
* Drug: cyclophosphamide
* Drug: cytarabine
* Drug: daunorubicin
* Drug: dexamethasone
* Drug: doxorubicin
* Drug: leucovorin
* Drug: mercaptopurine
* Drug: methotrexate
* Drug: mitoxantrone
* Drug: Asparaginase
* Drug: prednisone
* Drug: thioguanine
* Drug: vincristine
* Radiation: radiation therapy
* Drug: allopurinol
* Drug: bactrim


Participation Criteria
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Eligibility Criteria
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DISEASE CHARACTERISTICS: Morphologically confirmed acute lymphoblastic leukemia (ALL), meeting any of the following criteria: FAB class L1 or L2 disease Mixed lineage ALL Ph-negative/BCR/ABL-negative Newly diagnosed disease Patients with the following diagnoses are not eligible: FAB class L3 ALL Non-Hodgkin's lymphoma Chronic myelogenous leukemia in lymphoid blast crisis Mixed lineage acute myeloid leukemia Acute minimally differentiated myeloid leukemia (M0) Must be registered on protocols SWOG-9007 AND SWOG-S9910 PATIENT CHARACTERISTICS: Age 18 to 64 Performance status Zubrod 0-3 Life expectancy Not specified Hematopoietic Not specified Hepatic No chronic liver disease Hepatitis panel, including hepatitis B and C, negative History of hepatitis A with positive antibody allowed Renal Creatinine ≤ 1.5 times upper limit of normal OR Creatinine clearance > 60 mL/min Cardiovascular Left ventricular function normal Ejection fraction ≥ 50% by MUGA or 2-dimensional echocardiogram No symptomatic congestive heart failure No coronary artery disease No cardiomyopathy No uncontrolled arrhythmia Other Not pregnant or nursing Fertile patients must use effective contraception HIV negative No other malignancy within the past 5 years except adequately treated basal cell or squamous cell skin cancer, carcinoma in situ of the cervix, or adequately treated stage I or II cancer in complete remission PRIOR CONCURRENT THERAPY: Biologic therapy Not specified Chemotherapy No prior remission induction chemotherapy for ALL Prior hydroxyurea to control WBC count allowed Endocrine therapy Not specified Radiotherapy Not specified Surgery Not specified Other No other prior treatment for ALL

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 64 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: Induc x2, Consol, Maint<br>Induc 1: Allopurinol; Daunorubicin; Vincristine; Prednisone; asparaginase; Bactrim Induc 2: Allopurinol; cytarabine; Dexamethasone; filgrastim; mitoxantrone; Methotrexate; leucovorin Consol: Cyclophosphamide; cytarabine; 6-mercaptopurine; Methotrexate; filgrastim Maint:Course 1: 6-mercaptopurine; Methotrexate Course 2: Vincristine; doxorubicin; Dexamethasone Course 3: Cyclophosphamidee; thioguanine; cytarabine Course 4: 6-mercaptopurine; methotrexate | Biological: filgrastim<br>* As needed per physician discretion<br>Drug: cyclophosphamide<br>* Cyclophosphamide Consolidation: 650 mg/m2; IV; days 1, 15, 29 Post-consolidation course 3: 650 mg/m2; IV; day 1<br>Drug: cytarabine<br>* Induction 2: 3 g/m2; IV over 3 hrs; days 1-5 Consolidation: 75 mg/m2/d; IV push; days 2-5 and 16-19 Post-consolidation course 3: 75 mg/m2/d; IV push; days 3-6 and 10-13<br>Drug: daunorubicin<br>* Induction: 60 mg/m2/d; IV; days 1, 2, and 3<br>Drug: dexamethasone<br>* Induction 2: 0.1% QID; eye drops; days 1-6 Post consolidation course 2: 10 mg/m2/d; PO; days 1-28<br>Drug: doxorubicin<br>* Post consolidation: 25 mg/m2; IV; days 1, 8, 15, and 22<br>Drug: leucovorin<br>* For CNS during induction: 5 mg every 6 hrs for 4 doses; PO; days 1, 4, 8, 11, etx.; after methotrexate if WBC < 3,000<br>Drug: mercaptopurine<br>* Consolidation: 60 mg/m2; PO; days 1-28 Post-consolidation course 1: 60 mg/m2/d; PO; days 1-63 Post-consolidation course 4: 60 mg/m2/d; PO; daily for 2 yrs<br>Drug: methotrexate<br>* Consolidation: 12 mg; intrathecal or intraventricularly; days 2, 9, 16, and 23 Post-consolidation course 1: 20 mg/m2/wk; PO; days 1, 8 15, 22, 29, 36, 43, 50, 57 Post-consolidation course 4: 20 mg/m2; PO; weekly for 2 yrs<br>Drug: mitoxantrone<br>* Induction 2: 80 mg/m2; IV; day 3<br>Drug: Asparaginase<br>* Induction: 2,000 IU/m2; IM or IV; day 15<br>Drug: prednisone<br>* Induction: 60 mg/m2/d; PO or IV; days 1-35<br>Drug: thioguanine<br>* Post-consolidation course 3: 60 mg/m2/d; PO; days 1-14<br>Drug: vincristine<br>* Induction: 1.4 mg/m2/d (2 mg max); IV; days 1, 8, 15, 22<br>Radiation: radiation therapy<br>* For CNS during consolidation: cranial radiation after blasts are no longer present in spinal fluid. Total dose of 1800 cGy over 2 wks in 10 fractions of 180 cGy 5 days/wk.<br>Drug: allopurinol<br>* 300 mg/d PO Days 1-7<br>Drug: bactrim<br>* 1 double strenth tablet 2x/d, 2x/wk, PO, begin with prednisone<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Continuous Complete Remission at 1 Year | A patient has a continuous complete remission at 1 year if they achieve a CR and are alive 365 days after registering to the study. | After induction, after consolidation, every 3 months during maintenance, and every three months after off treatment for up to a year | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Toxicity | Number of patients with Grade 3-5 adverse events that are related to study drug by given type of adverse event | Patients were assessed for adverse events after the induction cycle | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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L1 adult acute lymphoblastic leukemia, L2 adult acute lymphoblastic leukemia, untreated adult acute lymphoblastic leukemia