Combination Chemotherapy in Treating Children With Acute Lymphoblastic Leukemia

Overview

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.

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

Study Type

  • Study Type: Interventional
  • Study Design
    • Allocation: Randomized
    • Intervention Model: Parallel Assignment
    • Primary Purpose: Treatment
    • Masking: None (Open Label)
  • Study Primary Completion Date: July 2007

Detailed Description

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.

Interventions

  • Drug: cyclophosphamide
    • Given IV
  • Drug: cytarabine
    • Deoxycytidine analogue which is metabolized to ARA-CTP, a substance which inhibits DNA polymerase.
  • Drug: daunorubicin hydrochloride
    • Given IV
  • Drug: dexamethasone
    • Dexamethasone is a synthetic fluorinated glucocorticoid devoid of mineralocorticoid effects.
  • Drug: leucovorin calcium
    • Synthetic d,l-5 CHO tetrahydrofolate, which is used to bypass the inhibition of dihydrofolate reductase by Methotrexate (MTX)
  • Drug: mercaptopurine
    • An analogue of the nucleic acid constituent adenine and the physiological purine base hypoxanthine
  • Drug: methotrexate
    • A folate analogue which inhibits the enzyme dihydrofolate reductase, haltin g DNA, RNA, and protein synthesis
  • Drug: pegaspargase
    • E-Coli asparaginase deaminates asparagine, thus, is lethal for cells which cannot synthesize asparagine.
  • Drug: thioguanine
    • Given orally
  • Drug: vincristine sulfate
    • Given IV

Arms, Groups and Cohorts

  • Experimental: Arm I: (combination chemotherapy)
    • 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.
  • Experimental: Arm II (combination chemotherapy)
    • 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.
  • Experimental: Arm III (combination chemotherapy)
    • 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.
  • Experimental: .Arm IV (combination chemotherapy)
    • 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.

Clinical Trial Outcome Measures

Primary Measures

  • Event-free survival
    • Time Frame: 4 years
    • The test statistic will compare Kaplan-Meier curves with sample size derived from a modification of the Makuch-Simon method for historical controls
  • Occurrence of anticipated failures
    • Time Frame: Up to 7 years
    • 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.
  • Grade 3 or greater CNS toxicity rates assessed using NCI CTC version 2.0
    • Time Frame: Up to 7 years

Secondary Measures

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

Participating in This Clinical Trial

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

Gender Eligibility: All

Minimum Age: 1 Year

Maximum Age: 9 Years

Are Healthy Volunteers Accepted: No

Investigator Details

  • Lead Sponsor
    • Children’s Oncology Group
  • Collaborator
    • National Cancer Institute (NCI)
  • Provider of Information About this Clinical Study
    • Sponsor
  • Overall Official(s)
    • Paul L. Martin, MD, Study Chair, Duke Cancer Institute

References

Rabin KR, Gramatges MM, Borowitz MJ, Palla SL, Shi X, Margolin JF, Zweidler-McKay PA. Absolute lymphocyte counts refine minimal residual disease-based risk stratification in childhood acute lymphoblastic leukemia. Pediatr Blood Cancer. 2012 Sep;59(3):468-74. doi: 10.1002/pbc.23395. Epub 2011 Nov 18.

Xu H, Cheng C, Devidas M, Pei D, Fan Y, Yang W, Neale G, Scheet P, Burchard EG, Torgerson DG, Eng C, Dean M, Antillon F, Winick NJ, Martin PL, Willman CL, Camitta BM, Reaman GH, Carroll WL, Loh M, Evans WE, Pui CH, Hunger SP, Relling MV, Yang JJ. ARID5B genetic polymorphisms contribute to racial disparities in the incidence and treatment outcome of childhood acute lymphoblastic leukemia. J Clin Oncol. 2012 Mar 1;30(7):751-7. doi: 10.1200/JCO.2011.38.0345. Epub 2012 Jan 30.

Borowitz MJ, Devidas M, Hunger SP, et al.: Prognostic signficance of end consolidation minimal residual disease (MRD) in childhood acute lymphoblastic leukemia (ALL): A report from the Children's Oncology Group (COG). [Abstract] J Clin Oncol 26 (Suppl 15): A-10000, 2008.

Borowitz MJ, Devidas M, Hunger SP, Bowman WP, Carroll AJ, Carroll WL, Linda S, Martin PL, Pullen DJ, Viswanatha D, Willman CL, Winick N, Camitta BM; Children's Oncology Group. Clinical significance of minimal residual disease in childhood acute lymphoblastic leukemia and its relationship to other prognostic factors: a Children's Oncology Group study. Blood. 2008 Jun 15;111(12):5477-85. doi: 10.1182/blood-2008-01-132837. Epub 2008 Apr 3.

Davies SM, Borowitz MJ, Rosner GL, Ritz K, Devidas M, Winick N, Martin PL, Bowman P, Elliott J, Willman C, Das S, Cook EH, Relling MV. Pharmacogenetics of minimal residual disease response in children with B-precursor acute lymphoblastic leukemia: a report from the Children's Oncology Group. Blood. 2008 Mar 15;111(6):2984-90. doi: 10.1182/blood-2007-09-114082. Epub 2008 Jan 8.

Hinds PS, Hockenberry MJ, Gattuso JS, Srivastava DK, Tong X, Jones H, West N, McCarthy KS, Sadeh A, Ash M, Fernandez C, Pui CH. Dexamethasone alters sleep and fatigue in pediatric patients with acute lymphoblastic leukemia. Cancer. 2007 Nov 15;110(10):2321-30. doi: 10.1002/cncr.23039.

Winick N, Martin PL, Devidas M, et al.: Delayed intensification (DI) enhances event-free survival (EFS) of children with B-precursor acute lymphoblastic leukemia (ALL) who received intensification therapy with six courses of intravenous methotrexate (MTX): POG 9904/9905: a Children's Oncology Group study (COG). [Abstract] Blood 110 (11): A-583, 2007.

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