Combination Chemotherapy in Treating Children With Acute Lymphoblastic Leukemia

Study Overview
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Brief Summary
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RATIONALE: Drugs used in chemotherapy use different ways to stop cancer cells from dividing so they stop growing or die. Combining more than one drug may kill more cancer cells. It is not yet known which regimen of combination chemotherapy is more effective for childhood acute lymphoblastic leukemia. PURPOSE: This randomized phase III trial is comparing different regimens of combination chemotherapy to see how well they work in treating children with acute lymphoblastic leukemia.

Detailed Description
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OBJECTIVES: Compare the efficacy and toxicity of short methotrexate infusion vs longer infusion in patients with low-risk acute lymphoblastic leukemia. Compare the efficacy of these regimens of methotrexate, with or without multidrug intensification, in these patients. OUTLINE: This is a randomized, multicenter study. Patients are stratified according to genetics (stratum 1: trisomy 4/10 but not TEL/AML1 vs stratum 2: TEL/AML1 with or without trisomy 4/10). All patients receive induction therapy (weeks 1-4) on another protocol (POG-9900). Stratum 1 Consolidation therapy begins on week 5. Patients are randomized to arm I or II. Arm I: Patients receive methotrexate (MTX) IV over 24 hours on day 1 and oral leucovorin calcium (CF) every 6 hours for 3 doses beginning 42 hours after initiation of MTX infusion during weeks 7, 10, 13, 16, and 19. Arm II: Patients receive MTX IV over 4 hours on day 1 and oral CF as in arm I during weeks 7, 10, 13, 16, and 19. Patients in arms I and II also receive MTX intrathecally (IT) on weeks 7, 10, 13, 16, 19, and 22; oral mercaptopurine (6-MP) daily on weeks 5-24; oral dexamethasone (DM) twice daily on days 1-7 of weeks 8 and 17; and vincristine (VCR) IV on day 1 of weeks 8, 9, 17, and 18. Stratum 2 Consolidation therapy begins on week 5 and delayed intensification therapy begins on week 16. Patients are randomized to delayed intensification or no delayed intensification. Patients randomized to no delayed intensification are then randomized to consolidation therapy on arm I or II. Patients randomized to delayed intensification are then randomized to arm III or IV. Patients with trisomy 4/10 are not randomized to arms III and IV. Arm III: Patients receive MTX IV and CF as in arm I on weeks 7, 10, 13, 24, 27, and 30. Arm IV: Patients receive MTX IV and CF as in arm II on weeks 7, 10, 13, 24, 27, and 30. Patients in arms III and IV also receive oral 6-MP daily on weeks 5-13 and then beginning on week 24 and continuing until the end of consolidation; MTX IT on weeks 7, 10, 13, 16, 20, 21, and 30; oral DM twice daily on days 1-7 of weeks 8, 16-18, and 28; VCR IV on day 1 of weeks 8, 9, 16-18, 28, and 29; pegaspargase intramuscularly on week 16; daunorubicin IV on day 1 of weeks 16-18; cyclophosphamide IV on day 1 of week 20; cytarabine IV or subcutaneously on days 2-5 of weeks 20 and 21; and oral thioguanine daily on days 1-14 of weeks 20 and 21. All patients then receive continuation therapy beginning on week 25 for arms I and II and week 33 for arms III and IV and continuing until week 130 for all arms. Continuation Arms I and II: Patients receive oral 6-MP daily on weeks 25-130; oral DM twice a day on days 1-7 and VCR IV on days 1 and 8 during weeks 25, 41, 57, 73, 89, and 105; oral MTX weekly on weeks 25-130 (except during weeks of IT MTX); and MTX IT on weeks 25, 37, 49, 61, 73, 85, 97, and 109. Arms III and IV: Patients receive oral 6-MP daily on weeks 33-130; oral DM twice a day on days 1-7 and VCR IV on days 1 and 8 during weeks 41, 57, 73, 89, and 105; oral MTX weekly on weeks 33-130 (except during weeks of IT MTX); and MTX IT on weeks 37, 49, 61, 73, 85, 97, and 109. Patients are followed every 2 months for 2 years, every 3 months for 1 year, every 6 months for 2 years, and then annually thereafter. PROJECTED ACCRUAL: A total 902 patients will be accrued for this study within 3.22 years.

Official Title
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ALINC #17 Treatment for Patients With Low Risk Acute Lymphoblastic Leukemia: A Pediatric Oncology Group Phase III Study

Conditions
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Leukemia

Intervention / Treatment
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* Drug: cyclophosphamide
* Drug: cytarabine
* Drug: daunorubicin hydrochloride
* Drug: dexamethasone
* Drug: leucovorin calcium
* Drug: mercaptopurine
* Drug: methotrexate
* Drug: pegaspargase
* Drug: thioguanine
* Drug: vincristine sulfate


Participation Criteria
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Eligibility Criteria
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DISEASE CHARACTERISTICS: Diagnosis of B-cell precursor acute lymphoblastic leukemia Registered on POG-9900 Classification Study Registered within 7 days of documenting complete response (CR) after induction therapy on day 29 or, if 2 more weeks of induction are required, within 7 days of CR determination Classified as low-risk: WBC less than 50,000/mm^3 Age 1 to 9 No adverse translocations [E2A-PBX1, t(1;19) or BCR/ABL, t(9;22); and MLL rearrangements] No CNS 3 disease (CSF WBC at least 5/mm^3 with blasts present) No testicular disease At least one of the following present: TEL/AML1, t(12;21) Simultaneous trisomy of chromosomes 4 and 10 PATIENT CHARACTERISTICS: Age: 1 to 9 Performance status: Not specified Life expectancy: Not specified Hematopoietic: See Disease Characteristics Hepatic: Not specified Renal: Not specified Other: Not pregnant or nursing Fertile patients must use effective contraception PRIOR CONCURRENT THERAPY: Biologic therapy Not specified Chemotherapy Not specified Endocrine therapy Not specified Radiotherapy Not specified Surgery Not specified

Ages Eligible for Study
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Minimum Age: 1 Year
Maximum Age: 9 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: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm I: (combination chemotherapy)<br>CONSOLIDATION: Pts receive Methotrexate(MTX) IV over 24 hrs on day 1 and oral leucovorin calcium (CF) every 6 hrs for 3 doses at 42 hours after initiation of MTX infusion during weeks 7, 10, 13, 16, and 19. Pts also receive MTX IT on wks 7, 10, 13, 16, 19, and 22; oral mercaptopurine(6-MP) daily wks 5-24; oral dexamethasone (DM) 2x on days 1-7 of wks 8 and 17; and vincristine sulfate (VCR) IV on day 1 of wks 8, 9, 17, and 18. CONTINUATION: Pts receive oral 6-MP daily on wks 25-130; oral DM twice a day on days 1-7 and vincristine sulfate (VCR) IV on days 1 and 8 during wks 25, 41, 57, 73, 89, and 105; oral MTX on wks 25-130 (except during wks of IT MTX); and MTX IT on wks 25, 37, 49, 61, 73, 85, 97, and 109. | Drug: dexamethasone<br>* Dexamethasone is a synthetic fluorinated glucocorticoid devoid of mineralocorticoid effects.<br>* Other names: NSC#034521;Drug: leucovorin calcium<br>* Synthetic d,l-5 CHO tetrahydrofolate, which is used to bypass the inhibition of dihydrofolate reductase by Methotrexate (MTX)<br>* Other names: NSC#003590;Drug: mercaptopurine<br>* An analogue of the nucleic acid constituent adenine and the physiological purine base hypoxanthine<br>* Other names: NSC #00075;Drug: methotrexate<br>* A folate analogue which inhibits the enzyme dihydrofolate reductase, haltin g DNA, RNA, and protein synthesis<br>* Other names: IND#4291;Drug: vincristine sulfate<br>* Given IV<br>* Other names: NSC #67574;|
| Experimental: Arm II (combination chemotherapy)<br>CONSOLIDATION: Pts receive methotrexate (MTX) IV over 4 hrs on day 1 and oral leucovorin calcium (CF) during wks 7, 10, 13, 16, and 19. Pts also receive MTX IT on wks 7, 10, 13, 16, 19, and 22; oral mercaptopurine (6-MP) daily on wks 5-24; oral dexamethasone (DM) 2x on days 1-7 of wks 8 and 17; and vincristine sulfate (VCR) IV on day 1 of wks 8, 9, 17, and 18. CONTINUATION: Pts receive oral 6-MP daily on wks 25-130; oral DM 2x on days 1-7 and vincristine sulfate (VCR) IV on days 1 and 8 during wks 25, 41, 57, 73, 89, and 105; oral MTX weekly on wks 25-130 (except during wks of IT MTX); and MTX IT on wks 25, 37, 49, 61, 73, 85, 97, and 109. | Drug: dexamethasone<br>* Dexamethasone is a synthetic fluorinated glucocorticoid devoid of mineralocorticoid effects.<br>* Other names: NSC#034521;Drug: leucovorin calcium<br>* Synthetic d,l-5 CHO tetrahydrofolate, which is used to bypass the inhibition of dihydrofolate reductase by Methotrexate (MTX)<br>* Other names: NSC#003590;Drug: mercaptopurine<br>* An analogue of the nucleic acid constituent adenine and the physiological purine base hypoxanthine<br>* Other names: NSC #00075;Drug: methotrexate<br>* A folate analogue which inhibits the enzyme dihydrofolate reductase, haltin g DNA, RNA, and protein synthesis<br>* Other names: IND#4291;Drug: vincristine sulfate<br>* Given IV<br>* Other names: NSC #67574;|
| Experimental: Arm III (combination chemotherapy)<br>CONSOLIDATION: Pts receive methotrexate (MTX) IV and leucovorin calcium (CF) as in arm I on wks 7, 10, 13, 24, 27, and 30. Pts also receive oral mercaptopurine (6-MP) daily on wks 5-13 and then on wk 24 and continuing until the end of consolidation; MTX IT on wks 7, 10, 13, 16, 20, 21, and 30; oral dexamethasone (DM) twice daily on days 1-7 of wks 8, 16-18, and 28; vincristine sulfate (VCR) IV on day 1 of wks 8, 9, 16-18, 28, and 29; pegaspargase intramuscularly on wk 16; daunorubicin hydrochloride IV on day 1 of wks 16-18; cyclophosphamide IV on day 1 of wk 20; cytarabine IV or subcutaneously on days 2-5 of wks 20 and 21; and oral thioguanine daily on days 1-14 of wks 20 and 21. CONTINUATION: Pts receive oral 6-MP daily on wks 33-130; oral dexamethasone (DM) twice a day on days 1-7 and VCR IV on days 1 and 8 during wks 41, 57, 73, 89, and 105; oral MTX weekly on wks 33-130 (except during wks of IT MTX); and MTX IT on wks 37, 49, 61, 73, 85, 97, and 109. | Drug: cyclophosphamide<br>* Given IV<br>* Other names: NSC #26271;Drug: cytarabine<br>* Deoxycytidine analogue which is metabolized to ARA-CTP, a substance which inhibits DNA polymerase.<br>* Other names: NSC #063878;Drug: daunorubicin hydrochloride<br>* Given IV<br>* Other names: NSC #82151;Drug: dexamethasone<br>* Dexamethasone is a synthetic fluorinated glucocorticoid devoid of mineralocorticoid effects.<br>* Other names: NSC#034521;Drug: leucovorin calcium<br>* Synthetic d,l-5 CHO tetrahydrofolate, which is used to bypass the inhibition of dihydrofolate reductase by Methotrexate (MTX)<br>* Other names: NSC#003590;Drug: mercaptopurine<br>* An analogue of the nucleic acid constituent adenine and the physiological purine base hypoxanthine<br>* Other names: NSC #00075;Drug: methotrexate<br>* A folate analogue which inhibits the enzyme dihydrofolate reductase, haltin g DNA, RNA, and protein synthesis<br>* Other names: IND#4291;Drug: pegaspargase<br>* E-Coli asparaginase deaminates asparagine, thus, is lethal for cells which cannot synthesize asparagine.<br>* Other names: NSC#109229;Drug: thioguanine<br>* Given orally<br>* Other names: NSC # 752;Drug: vincristine sulfate<br>* Given IV<br>* Other names: NSC #67574;|
| Experimental: .Arm IV (combination chemotherapy)<br>CONSOLIDATION: Pts receive methotrexate (MTX) and leucovorin calcium (CF) on wks 7, 10, 13, 24, 27, and 30. Pts receive mercaptopurine(6-MP) daily weeks 5-13 then beginning wk 24 and continuing until end of consolidation; MTX on wks 7, 10, 13, 16, 20, 21, and 30; dexamethasone (DM) 2x daily on days 1-7 of wks 8, 16-18, and 28; vincristine sulfate (VCR) day 1 of wks 8, 9, 16-18, 28, and 29; pegaspargase on wk 16; daunorubicin hydrochloride on day 1 of wks 16-18; cyclophosphamide on day 1 of wk 20; cytarabine on days 2-5 of wks 20 and 21; thioguanine daily on days 1-14 of wks 20 and 21. CONTINUATION: Pts receive mercaptopurine(6-MP) daily on weeks 33-130; oral dexamethasone (DM) twice a day on days 1-7 and VCR IV on days 1 and 8 during weeks 41, 57, 73, 89, and 105; oral MTX weekly on weeks 33-130 (except during weeks of IV MTX); and IV MTX on weeks 37, 49, 61, 73, 85, 97, and 109. | Drug: cyclophosphamide<br>* Given IV<br>* Other names: NSC #26271;Drug: cytarabine<br>* Deoxycytidine analogue which is metabolized to ARA-CTP, a substance which inhibits DNA polymerase.<br>* Other names: NSC #063878;Drug: daunorubicin hydrochloride<br>* Given IV<br>* Other names: NSC #82151;Drug: dexamethasone<br>* Dexamethasone is a synthetic fluorinated glucocorticoid devoid of mineralocorticoid effects.<br>* Other names: NSC#034521;Drug: leucovorin calcium<br>* Synthetic d,l-5 CHO tetrahydrofolate, which is used to bypass the inhibition of dihydrofolate reductase by Methotrexate (MTX)<br>* Other names: NSC#003590;Drug: mercaptopurine<br>* An analogue of the nucleic acid constituent adenine and the physiological purine base hypoxanthine<br>* Other names: NSC #00075;Drug: methotrexate<br>* A folate analogue which inhibits the enzyme dihydrofolate reductase, haltin g DNA, RNA, and protein synthesis<br>* Other names: IND#4291;Drug: pegaspargase<br>* E-Coli asparaginase deaminates asparagine, thus, is lethal for cells which cannot synthesize asparagine.<br>* Other names: NSC#109229;Drug: thioguanine<br>* Given orally<br>* Other names: NSC # 752;Drug: vincristine sulfate<br>* Given IV<br>* Other names: NSC #67574;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Event-free survival | The test statistic will compare Kaplan-Meier curves with sample size derived from a modification of the Makuch-Simon method for historical controls | 4 years | 
| Occurrence of anticipated failures | An O'Brien-Fleming analysis will be conducted, with significance declared if the observed logrank Z-statistic exceeds the z/sqrt(IF), where IF=fraction of anticipated failures that have occurred and z=critical value of the final analysis. | Up to 7 years | 
| Grade 3 or greater CNS toxicity rates assessed using NCI CTC version 2.0 |  | Up to 7 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Measures of laboratory factors (other than MRD) | Cox multiple regression will be utilized. | Up to 7 years | 
| Homocysteine levels | Will be correlated to acute neurotoxicity by Cox regression. | Up to 7 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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childhood acute lymphoblastic leukemia in remission, B-cell childhood acute lymphoblastic leukemia