Comparison of Different Combination Chemotherapy Regimens in Treating Children With Acute Lymphoblastic Leukemia

Escalating Dose Intravenous Methotrexate Without Leucovorin Rescue Versus Oral Methotrexate and Single Versus Double Delayed Intensification for Children With Standard Risk Acute Lymphoblastic Leukemia

RATIONALE: Drugs used in chemotherapy use different ways to stop cancer cells from dividing so they stop growing or die. Giving more than one drug may kill more cancer cells. It is not yet known which combination chemotherapy regimen is more effective in treating childhood acute lymphoblastic leukemia.

PURPOSE: This randomized phase III trial is comparing different combination chemotherapy regimens to see how well they work in treating children with acute lymphoblastic leukemia.

Study Overview

• Status: Completed
• Conditions: Leukemia
• Intervention / Treatment: Drug: cyclophosphamide; Drug: vincristine sulfate; Drug: cytarabine; Drug: pegaspargase; Drug: daunorubicin hydrochloride; Radiation: radiation therapy; Drug: dexamethasone; Drug: mercaptopurine; Drug: thioguanine; Drug: methotrexate; Drug: doxorubicin hydrochloride

Detailed Description

OBJECTIVES:

• Compare the event-free survival and overall survival of children with standard-risk acute lymphoblastic leukemia treated with escalating-dose IV methotrexate without leucovorin calcium versus oral methotrexate during the interim maintenance phase of therapy.
• Compare the event-free survival and overall survival of these patients after receiving treatment in two delayed intensification phases versus one delayed intensification phase.
• Compare the toxic effects of oral versus escalating-dose intravenous methotrexate in these patients.
• Determine the prognostic significance of the rate of disappearance of peripheral lymphoblasts and lymphocytes during the first week of treatment in these patients.
• Determine the prognostic significance of trisomies of chromosomes 4, 5, 10, and 17 and early treatment response in patients treated with these regimens.
• Determine the prognostic significance of the TEL-AML1 fusion transcript and early treatment response in patients treated with these regimens.
• Determine the minimal residual disease (MRD) by polymerase chain reaction in bone marrow and cerebrospinal fluid at various stages of therapy in these patients.
• Determine the prognostic significance of MRD during various stages of therapy in these patients.
• Determine whether a second delayed intensification therapy improves the prognosis of patients who have MRD at the end of induction therapy.

OUTLINE: This is a randomized, multicenter study. Patients without CNS disease at diagnosis, achieving a specified early marrow response profile and M1 marrow status of less than 5% blasts in the bone marrow (regardless of the proportion of mature lymphocytes) by day 28 of induction therapy, and remaining event free with favorable bone marrow status and cytogenetics between day 21 and 28 of consolidation therapy are randomized to one of four treatment arms. Patients with CNS disease at diagnosis are assigned to treatment arm II and undergo cranial irradiation. Patients with any of the following unfavorable bone marrow features and/or unfavorable cytogenetic features are assigned to the augmented treatment regimen by day 21 of induction chemotherapy or at the beginning of consolidation chemotherapy:

NOTE: All T-cell precursor patients that are not more than 4 months past completion of the delayed intensification phase of therapy should be switched to the augmented regimen as of 3/8/2004. These patients may be switched to the augmented regimen. The protocol gives specific instructions according to the phase of therapy the patients are actually in.

• Unfavorable marrow status:

  • M2: 5-25% blasts in bone marrow at day 28 of induction chemotherapy (or at day 14 of induction chemotherapy if day 7 status is M3) OR
  • M3: More than 25% blast cell in bone marrow, regardless of the proportion of mature lymphocytes at day 14 of induction chemotherapy

• Unfavorable cytogenetics: Must have 1 of the following:

  • t(9;22)(q34;q11)
  • t(4;11)(q21;q23)
  • Balanced t(1;19)(q23;p13)
  • Hypodiploidy with less than 45 chromosomes
  • Other 11q23 translocations involving MLL Patients receive standard induction chemotherapy comprising cytarabine (ARA-C) intrathecally (IT) on day 0 or up to 72 hours before day 0; oral dexamethasone (DM) twice daily on days 0-27; vincristine (VCR) IV on days 0, 7, 14, and 21; and pegaspargase (PEG-ASP) intramuscularly (IM) once between days 3-5. Patients without CNS disease at diagnosis receive methotrexate (MTX) IT on days 7 and 28. Patients with CNS disease at diagnosis receive MTX IT on days 7, 14, 21, and 28.

Patients who have achieved M1 marrow status by day 28 of induction therapy and have favorable early bone marrow response and cytogenetics proceed to standard consolidation therapy once blood counts have recovered. Patients with M3 bone marrow status at day 28 of induction therapy are taken off the protocol. All other patients are assigned to the augmented treatment regimen.

Beginning on day 28 of induction chemotherapy, patients receive standard consolidation chemotherapy comprising VCR IV on day 0 and oral mercaptopurine (MP) on days 0-27. Patients without CNS disease at diagnosis receive MTX IT on days 7, 14, 21, and 28. Patients with CNS disease at diagnosis receive MTX IT on day 7 and cranial irradiation 5 days a week for 2 weeks. Patients with testicular disease receive bilateral testicular radiotherapy 5 days a week for 1 week and then for 3 consecutive days during the next week.

NOTE: As of 3/8/2004, patients with T-cell disease who did not achieve M1 marrow status by day 14 of induction OR who did not receive augmented induction and/or consolidation (regardless of early marrow status) receive cranial irradiation.

• Arm I: Beginning on day 28 of consolidation chemotherapy, patients receive interim maintenance I chemotherapy comprising oral DM twice daily on days 0-4 and 28-32; VCR IV on days 0 and 28; oral MTX on days 0, 7, 14, 21, 28, 35, 42, and 49; oral MP on days 0-49; and MTX IT on day 28.

Beginning on day 56 of interim maintenance I chemotherapy, patients receive delayed intensification chemotherapy comprising oral DM twice daily on days 0-6 and 14-20; VCR IV and doxorubicin (DOX) IV over 15 minutes to 2 hours on days 0, 7, and 14; PEG-ASP IM on day 3; cyclophosphamide (CTX) IV over 20-30 minutes on day 28; oral thioguanine (TG) on days 28-41; ARA-C IV or subcutaneously (SC) daily on days 28-31 and 35-38; and MTX IT on days 0 and 28.

Beginning on day 56 of delayed intensification chemotherapy, patients receive interim maintenance II chemotherapy identical to interim maintenance I chemotherapy except patients receive MTX IT on days 0 and 28.

Beginning on day 56 of interim maintenance II chemotherapy, patients receive maintenance chemotherapy comprising oral DM twice daily on days 0-4, 28-32, and 56-60; VCR IV on days 0, 28, and 56; oral MP on days 0-83; oral MTX on days 7, 14, 21, 28, 35, 42, 49, 56, 63, 70, and 77; and MTX IT on day 0.

• Arm II: Patients receive interim maintenance I chemotherapy, delayed intensification chemotherapy, and interim maintenance II chemotherapy as in arm I. Beginning on day 56 of interim maintenance II chemotherapy, patients then receive a second course of delayed intensification chemotherapy followed by maintenance chemotherapy as in arm I.
• Arm III: Beginning on day 28 of consolidation chemotherapy, patients receive interim maintenance I chemotherapy comprising VCR IV; escalating doses of MTX IV on days 0, 10, 20, 30, and 40; and MTX IT on day 30. Patients then receive delayed intensification chemotherapy as in arm I. Patients receive interim maintenance II chemotherapy as in interim maintenance I chemotherapy, but with IV MTX starting at 2/3 of the maximum tolerated dose (MTD) attained in interim maintenance I chemotherapy. Patients then receive maintenance chemotherapy as in arm I.
• Arm IV: Patients receive interim maintenance I chemotherapy as in arm III, delayed intensification chemotherapy as in arm I, interim maintenance II chemotherapy as in arm III, delayed intensification II chemotherapy as in arm II, and maintenance chemotherapy as in arm I.
• Augmented Treatment: Patients receive induction chemotherapy comprising daunorubicin IV continuously for 48 hours beginning no later than day 21; oral DM twice daily on days 14-27; and VCR IV on days 14 and 21. Patients without CNS disease at diagnosis receive MTX IT on days 21 and 35. Patients with CNS disease at diagnosis receive MTX IT on days 21 and 28.

NOTE: Patients with T-cell disease should re-start with augmented consolidation and proceed as per the augmented regimen.

Beginning on day 35 of induction chemotherapy, patients receive consolidation therapy comprising CTX IV over 20-30 minutes on days 0 and 28; oral MP on days 0-13 and 28-41; ARA-C IV or SC daily on days 0-3, 7-10, 28-31, and 35-38; VCR IV on days 14, 21, 42, and 49; and PEG-ASP IM on days 14 and 42. Patients without CNS disease at diagnosis receive MTX IT on days 7, 14, and 21. Patients with CNS disease at diagnosis receive MTX IT on day 7 and cranial irradiation as in the randomized treatment section. Patients with testicular leukemia receive radiotherapy as in the randomized treatment section.

Beginning on day 63 of consolidation chemotherapy, patients receive interim maintenance I chemotherapy comprising VCR IV on days 0, 10, 20, 30, and 40; escalating doses of MTX IV on days 10, 20, 30, and 40; PEG-ASP IM on days 1 and 21; and MTX IT on days 0 and 30.

Beginning on day 56 of interim maintenance I chemotherapy, patients receive delayed intensification I chemotherapy comprising oral DM twice daily on days 0-6 and 14-20; VCR IV on days 0, 7, 14, 42, and 49; DOX IV over 15 minutes to 2 hours on days 0, 7, and 14; PEG-ASP IM on days 3 and 42; CTX IV over 20-30 minutes on day 28; oral TG on days 28-41; ARA-C IV or SC daily on days 28-31 and 35-38; and MTX IT on days 0 and 28.

NOTE: Patients with T-cell disease who are in interim maintenance I chemotherapy with escalating IV methotrexate should continue this phase and then proceed as per the augmented regimen. If these patients are receiving conventional interim maintenance chemotherapy with oral methotrexate, they should stop and restart the interim maintenance as per the augmented regimen. These patients receive cranial irradiation starting on day 28 of delayed intensification II chemotherapy.

Beginning on day 56 of delayed intensification I chemotherapy, patients receive interim maintenance II chemotherapy as in interim maintenance I chemotherapy, but with IV MTX starting at 2/3 of the MTD attained in interim maintenance I chemotherapy.

NOTE: Patients with T-cell disease who are in delayed intensification I chemotherapy proceed with this phase, with the addition of 2 vincristine doses on days 42 and 49 and PEG-ASP on day 42. These patients then proceed as per the augmented regimen with the addition of cranial irradiation starting on day 28 of delayed intensification II chemotherapy.

NOTE: Patients with T-cell disease who are within 4 months of completing delayed intensification I chemotherapy and have not received interim maintenance II chemotherapy with escalating IV methotrexate or delayed intensification II chemotherapy receive a course of interim maintenance chemotherapy and delayed intensification II chemotherapy according to the augmented regimen. If these patients have received interim maintenance II chemotherapy with escalating IV methotrexate, they receive delayed intensification II chemotherapy according to the augmented regimen. These patients also receive cranial irradiation starting on day 28 of delayed intensification II chemotherapy and then proceed to maintenance therapy.

Beginning on day 56 of interim maintenance II chemotherapy, patients receive delayed intensification II chemotherapy as in delayed intensification I chemotherapy.

Beginning on day 56 of delayed intensification II chemotherapy, patients receive maintenance chemotherapy comprising oral DM twice daily on days 0-4, 28-32, and 56-60; VCR IV on days 0, 28, and 56; oral MP on days 0-83; oral MTX on days 7, 14, 21, 28, 35, 42, 49, 56, 63, 70, and 77; and MTX IT on day 0.

Patients are followed every 4-8 weeks for one year, every 3 months for one year, every 6 months for one year, and then annually thereafter.

PROJECTED ACCRUAL: A total of 2,037 randomized patients will be accrued for this study within 3.75 years.

• Study Type: Interventional
• Enrollment (Actual): 3054
• Phase: Phase 3

Contacts and Locations

Study Locations

• Australia
  • New South Wales
    • Randwick, New South Wales, Australia, 2031
      • Sydney Children's Hospital
  • Queensland
    • Brisbane, Queensland, Australia, 4029
      • Royal Children's Hospital
  • Western Australia
    • Perth, Western Australia, Australia, 6001
      • Princess Margaret Hospital for Children
• Canada
  • British Columbia
    • Vancouver, British Columbia, Canada, V6H 3V4
      • British Columbia Children's Hospital
  • Manitoba
    • Winnipeg, Manitoba, Canada, R3E 0V9
      • CancerCare Manitoba
  • Newfoundland and Labrador
    • St. John's, Newfoundland and Labrador, Canada, A1B 3V6
      • Janeway Children's Health and Rehabilitation Centre
  • Nova Scotia
    • Halifax, Nova Scotia, Canada, B3J 3G9
      • IWK Health Centre
  • Ontario
    • London, Ontario, Canada, N6C 2V5
      • Children's Hospital of Western Ontario
  • Saskatchewan
    • Regina, Saskatchewan, Canada, S4T 7T1
      • Allan Blair Cancer Centre at Pasqua Hospital
    • Saskatoon, Saskatchewan, Canada, S7N 4H4
      • Saskatoon Cancer Centre
• New Zealand
  • Auckland, New Zealand
    • Starship Children's Health
• Switzerland
  • Bern, Switzerland, CH 3010
    • Swiss Pediatric Oncology Group Bern
  • Geneva, Switzerland, CH 1211
    • Swiss Pediatric Oncology Group Geneva
  • Lausanne, Switzerland, CH 1011
    • Swiss Pediatric Oncology Group Lausanne
• United States
  • Arizona
    • Phoenix, Arizona, United States, 85016
      • Phoenix Children's Hospital
  • California
    • Downey, California, United States, 90242
      • Southern California Permanente Medical Group
    • Duarte, California, United States, 91010-3000
      • City of Hope Comprehensive Cancer Center
    • Loma Linda, California, United States, 92354
      • Loma Linda University Cancer Institute at Loma Linda University Medical Center
    • Los Angeles, California, United States, 90095-1781
      • Jonsson Comprehensive Cancer Center, UCLA
    • Los Angeles, California, United States, 90027-0700
      • Children's Hospital Los Angeles
    • Los Angeles, California, United States, 90048
      • Samuel Oschin Comprehensive Cancer Institute at Cedars-Sinai Medical Center
    • Madera, California, United States, 93638-8762
      • Children's Hospital Central California
    • Oakland, California, United States, 94609-1809
      • Children's Hospital and Research Center at Oakland
    • Orange, California, United States, 92868
      • Children's Hospital of Orange County
    • Orange, California, United States, 92868
      • Chao Family Comprehensive Cancer Center at University of California Irvine Medical Center
    • Sacramento, California, United States, 95825
      • Kaiser Permanente Medical Center - Sacramento
    • San Diego, California, United States, 92120
      • Kaiser Permanente Medical Center/Kaiser Foundation Hospital - San Diego
    • San Francisco, California, United States, 94143
      • UCSF Comprehensive Cancer Center
    • Santa Barbara, California, United States, 93102
      • Santa Barbara Cottage Hospital
    • Santa Clara, California, United States, 95051-5386
      • Kaiser Permanente Medical Center - Santa Clara
    • Travis Air Force Base, California, United States, 94535
      • General Robert Huyser Cancer Center at David Grant Medical Center
  • Colorado
    • Denver, Colorado, United States, 80218
      • Presbyterian - St. Luke's Medical Center
    • Denver, Colorado, United States, 80218
      • Children's Hospital Cancer Center
  • Connecticut
    • Farmington, Connecticut, United States, 06360-7106
      • Carole and Ray Neag Comprehensive Cancer Center at the University of Connecticut Health Center
    • New Haven, Connecticut, United States, 06520-8064
      • Yale Comprehensive Cancer Center
  • Delaware
    • Wilmington, Delaware, United States, 19899
      • Alfred I. DuPont Hospital for Children
  • District of Columbia
    • Washington, District of Columbia, United States, 20007
      • Lombardi Cancer Center at Georgetown University Medical Center
    • Washington, District of Columbia, United States, 20010-2970
      • Children's National Medical center
  • Georgia
    • Atlanta, Georgia, United States, 30342
      • AFLAC Cancer Center and Blood Disorders Service of Children's Healthcare of Atlanta - Scottish Rite Campus
    • Macon, Georgia, United States, 31201
      • Medical Center of Central Georgia
    • Savannah, Georgia, United States, 31405
      • Curtis & Elizabeth Anderson Cancer Institute at Memorial Health University Medical Center
  • Idaho
    • Boise, Idaho, United States, 83712
      • Mountain States Tumor Institute - Boise
  • Illinois
    • Chicago, Illinois, United States, 60601
      • University of Chicago Cancer Research Center
    • Chicago, Illinois, United States, 60612
      • University of Illinois Medical Center
    • Park Ridge, Illinois, United States, 60068-1174
      • Lutheran General Cancer Care Center
    • Springfield, Illinois, United States, 62794-9658
      • Southern Illinois University School of Medicine
  • Indiana
    • Indianapolis, Indiana, United States, 46202-5225
      • Riley Children Cancer Center at Riley Hospital for Children
  • Iowa
    • Des Moines, Iowa, United States, 50308
      • Blank Children's Hospital
    • Iowa City, Iowa, United States, 52242-1009
      • Holden Comprehensive Cancer Center at University of Iowa
  • Kentucky
    • Lexington, Kentucky, United States, 40536-0284
      • Markey Cancer Center at University of Kentucky Chandler Medical Center
    • Louisville, Kentucky, United States, 40202-3830
      • Kosair Children's Hospital
  • Louisiana
    • New Orleans, Louisiana, United States, 70112
      • MBCCOP - LSU Health Sciences Center
  • Maryland
    • Baltimore, Maryland, United States, 21215
      • Alvin and Lois Lapidus Cancer Institute at Sinai Hospital
  • Massachusetts
    • Springfield, Massachusetts, United States, 01107
      • Baystate Regional Cancer Program at D'Amour Center for Cancer Care
  • Michigan
    • Ann Arbor, Michigan, United States, 48109-0914
      • University of Michigan Comprehensive Cancer Center
    • Detroit, Michigan, United States, 48202
      • Josephine Ford Cancer Center at Henry Ford Health System
    • Grand Rapids, Michigan, United States, 49503
      • DeVos Children's Hospital
    • Kalamazoo, Michigan, United States, 49007-5364
      • Bronson Methodist Hospital
    • Lansing, Michigan, United States, 48910
      • Breslin Cancer Center at Ingham Regional Medical Center
    • Royal Oak, Michigan, United States, 48073-6769
      • CCOP - Beaumont
    • Royal Oak, Michigan, United States, 48073-6769
      • William Beaumont Hospital - Royal Oak
  • Minnesota
    • Duluth, Minnesota, United States, 55805
      • St. Mary's - Duluth Clinic Cancer Center
    • Minneapolis, Minnesota, United States, 55455
      • University of Minnesota Cancer Center
    • Minneapolis, Minnesota, United States, 55404
      • Children's Hospitals and Clinics - Minneapolis/St. Paul
    • Rochester, Minnesota, United States, 55905
      • Mayo Clinic Cancer Center
  • Missouri
    • Kansas City, Missouri, United States, 64108
      • Children's Mercy Hospital
  • Nebraska
    • Omaha, Nebraska, United States, 68114
      • Children's Hospital of Omaha
    • Omaha, Nebraska, United States, 68198-2168
      • UNMC Eppley Cancer Center at the University of Nebraska Medical Center
  • Nevada
    • Las Vegas, Nevada, United States, 89109
      • Sunrise Hospital and Medical Center
  • New Jersey
    • Livingston, New Jersey, United States, 07039
      • St. Barnabas Medical Center
    • New Brunswick, New Jersey, United States, 08903
      • Cancer Institute of New Jersey at UMDNJ - Robert Wood Johnson Medical School
    • Newark, New Jersey, United States, 07112-2094
      • Newark Beth Israel Medical Center
    • Paterson, New Jersey, United States, 07503
      • St. Joseph's Hospital and Medical Center
    • Summit, New Jersey, United States, 07901
      • Valerie Fund Children's Center at Atlantic Health
  • New York
    • Albany, New York, United States, 12208
      • Cancer Center of Albany Medical Center
    • Bronx, New York, United States, 10461
      • Albert Einstein Cancer Center at Albert Einstein College of Medicine
    • Brooklyn, New York, United States, 11203
      • SUNY Downstate Medical Center
    • Brooklyn, New York, United States, 11212
      • Brookdale University Hospital and Medical Center
    • Brooklyn, New York, United States, 11201-5493
      • Brooklyn Hospital Center
    • Brooklyn, New York, United States, 11219
      • Comprehensive Cancer Center at Maimonides Medical Center
    • New Hyde Park, New York, United States, 11042
      • Schneider Children's Hospital
    • New York, New York, United States, 10021
      • Memorial Sloan-Kettering Cancer Center
    • New York, New York, United States, 10021
      • New York Weill Cornell Cancer Center at Cornell University
    • New York, New York, United States, 10032
      • Herbert Irving Comprehensive Cancer Center at Columbia University
    • Stony Brook, New York, United States, 11794
      • Long Island Cancer Center at Stony Brook University Hospital
    • Syracuse, New York, United States, 13210
      • SUNY Upstate Medical University Hospital
    • Valhalla, New York, United States, 10595
      • New York Medical College
  • North Carolina
    • Chapel Hill, North Carolina, United States, 27599
      • Lineberger Comprehensive Cancer Center at University of North Carolina - Chapel Hill
    • Charlotte, North Carolina, United States, 28232-2861
      • Blumenthal Cancer Center at Carolinas Medical Center
    • Charlotte, North Carolina, United States, 28233
      • Presbyterian Cancer Center at Presbyterian Hospital
  • North Dakota
    • Fargo, North Dakota, United States, 58122
      • Meritcare Roger Maris Cancer Center
    • Fargo, North Dakota, United States, 58103-4940
      • Dakota Cancer Institute at Innovis Health - Dakota Clinic
  • Ohio
    • Akron, Ohio, United States, 44308-1062
      • Children's Hospital Medical Center of Akron
    • Cincinnati, Ohio, United States, 45229-3039
      • Cincinnati Children's Hospital Medical Center
    • Cleveland, Ohio, United States, 44106-5065
      • Ireland Cancer Center at University Hospitals of Cleveland and Case Western Reserve University
    • Columbus, Ohio, United States, 43205-2696
      • Columbus Children's Hospital
    • Dayton, Ohio, United States, 45404
      • Children's Medical Center - Dayton
    • Toledo, Ohio, United States, 43601
      • Toledo Children's Hospital
    • Toledo, Ohio, United States, 43608
      • St. Vincent Mercy Medical Center
  • Oregon
    • Portland, Oregon, United States, 97225
      • CCOP - Columbia River Oncology Program
    • Portland, Oregon, United States, 97239-3098
      • Doernbecher Children's Hospital at Oregon Health & Science University
  • Pennsylvania
    • Danville, Pennsylvania, United States, 17822-1320
      • Geisinger Medical Center
    • Hershey, Pennsylvania, United States, 17033
      • Children's Hospital at Milton S. Hershey Medical Center
    • Philadelphia, Pennsylvania, United States, 19104
      • Children's Hospital of Philadelphia
    • Pittsburgh, Pennsylvania, United States, 15213
      • Children's Hospital of Pittsburgh
  • Rhode Island
    • Providence, Rhode Island, United States, 02903
      • Rhode Island Hospital
  • South Dakota
    • Sioux Falls, South Dakota, United States, 57117-5039
      • Sioux Valley Hospital and University of South Dakota Medical Center
  • Tennessee
    • Johnson City, Tennessee, United States, 37614-0622
      • East Tennessee State University Cancer Center at Johnson City Medical Center
    • Knoxville, Tennessee, United States, 37901
      • East Tennessee Children's Hospital
    • Nashville, Tennessee, United States, 37232-6310
      • Vanderbilt Children's Hospital
  • Texas
    • Amarillo, Texas, United States, 79106
      • Texas Tech University Health Sciences Center School of Medicine
    • Austin, Texas, United States, 78701
      • Children's Hospital of Austin
    • Dallas, Texas, United States, 75230
      • Medical City Dallas Hospital
    • Houston, Texas, United States, 77030-4009
      • MD Anderson Cancer Center at University of Texas
    • Lubbock, Texas, United States, 79410
      • Covenant Children's Hospital
    • San Antonio, Texas, United States, 78229-3900
      • MBCCOP - South Texas Pediatrics
    • San Antonio, Texas, United States, 78229-3902
      • Methodist Cancer Center at Methodist Specialty and Transplant Hospital
    • Temple, Texas, United States, 76508
      • CCOP - Scott and White Hospital
  • Virginia
    • Norfolk, Virginia, United States, 23507
      • Children's Hospital of The King's Daughters
  • Washington
    • Seattle, Washington, United States, 98105
      • Children's Hospital and Regional Medical Center - Seattle
    • Seattle, Washington, United States, 98112
      • Group Health Central Hospital
    • Spokane, Washington, United States, 99210-0248
      • Deaconess Medical Center
    • Tacoma, Washington, United States, 98415-0299
      • Mary Bridge Children's Hospital and Health Center
  • West Virginia
    • Charleston, West Virginia, United States, 25302
      • West Virginia University - Robert C. Byrd Health Sciences Center - Charleston Division
    • Huntington, West Virginia, United States, 25701
      • Cabell Huntington Hospital
  • Wisconsin
    • Green Bay, Wisconsin, United States, 54301
      • Bellin Memorial Hospital
    • La Crosse, Wisconsin, United States, 54601
      • Gundersen Lutheran Cancer Center at Gundersen Lutheran Medical Center
    • Madison, Wisconsin, United States, 53792-6164
      • University of Wisconsin Comprehensive Cancer Center
    • Marshfield, Wisconsin, United States, 54449
      • CCOP - Marshfield Clinic Research Foundation
    • Marshfield, Wisconsin, United States, 54449-5772
      • Marshfield Clinic - Marshfield Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 1 year to 9 years (Child)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

DISEASE CHARACTERISTICS:

• Diagnosis of previously untreated B-cell precursor acute lymphoblastic leukemia

  • More than 25% L1 or L2 lymphoblasts
  • No more than 25% L3 lymphoblasts
  • WBC < 50,000/mm^3
• No T-cell precursor acute lymphoblastic leukemia by immunophenotyping
• Massive lymphadenopathy, massive splenomegaly, or large mediastinal mass allowed
• CNS or testicular leukemia allowed
• No patients found to have t(8;14)(q24;q32), t(8;22)(q24;q11), and t(2;8)(p11-p12;q24) (characteristic of Burkitt's lymphoma)

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
• Fertile patients must use effective contraception

PRIOR CONCURRENT THERAPY:

Biologic therapy:

• Not specified

Chemotherapy:

• No more than 72 hours since prior intrathecal cytarabine

Endocrine therapy:

• At least 30 days since prior systemic corticosteroids given for more than 48 hours
• Prior corticosteroids for mediastinal mass causing superior mediastinal syndrome allowed
• Prior or concurrent inhaled corticosteroids allowed

Radiotherapy:

• Prior radiotherapy for mediastinal mass causing superior mediastinal syndrome allowed
• No concurrent spinal radiotherapy

Surgery:

• Not specified

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

7

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Induction Not Randomized; Standard Induction (28 Days). M3 Marrow at Day 28 and Off Protocol Therapy.	Drug: cyclophosphamide; Given IV; Other Names: Cytoxan; NSC-26271; Drug: vincristine sulfate; Given IV; Other Names: VCR; Oncovin; NSC-67574; Drug: pegaspargase; Given IM; Other Names: Oncaspar; L-asparaginase with polyethylene glycol; PEG-asparaginase; Drug: dexamethasone; Given PO; Other Names: Decadron; DM; NSC-34521; Drug: methotrexate; Given PO and IT; Other Names: MTX
Experimental: Induction and Oral MTX, Double Delayed Intensification CNS; Patients with CNS disease at diagnosis, without other unfavorable characteristics. Standard Induction (28 Days). Consolidation (28 days) and in remission Day 21 and at time of randomization, Interim maintenance I (2 months), Delayed intensification I (2 months), Interim maintenance II (2 months), Delayed intensification II (2 months), then Maintenance (12 week cycles). Cranial radiation therapy during the Consolidation phase.	Drug: cyclophosphamide; Given IV; Other Names: Cytoxan; NSC-26271; Drug: vincristine sulfate; Given IV; Other Names: VCR; Oncovin; NSC-67574; Drug: cytarabine; Given IT; Other Names: Cytosar-U; Cytosine Arabinoside; NSC-63878; Ara_C; Drug: pegaspargase; Given IM; Other Names: Oncaspar; L-asparaginase with polyethylene glycol; PEG-asparaginase; Radiation: radiation therapy; Undergo radiation therapy; Other Names: irradiation; radiation; radiotherapy; therapy; Drug: dexamethasone; Given PO; Other Names: Decadron; DM; NSC-34521; Drug: mercaptopurine; Given PO; Other Names: 6-MP; Drug: thioguanine; Given PO; Other Names: NSC-752; 6 TG; Drug: methotrexate; Given PO and IT; Other Names: MTX; Drug: doxorubicin hydrochloride; Dose 25 g/m² IV Days 0, 7, 14, given over a period of 15 minutes to 2 hours; Other Names: Adriamycin; NSC-123127
Experimental: Induction and Augmented regimen (IV MTX, Double DI); Patients with unfavorable characteristics. Standard Induction (14 Days), Augmented Induction (Days 14-35), Consolidation (9 weeks), Interim Maintenance I (56 Days), Delayed Intensification I (2 months), Interim Maintenance II (2 months), Delayed Intensification II (2 months), then Maintenance (84 day courses).	Drug: cyclophosphamide; Given IV; Other Names: Cytoxan; NSC-26271; Drug: vincristine sulfate; Given IV; Other Names: VCR; Oncovin; NSC-67574; Drug: cytarabine; Given IT; Other Names: Cytosar-U; Cytosine Arabinoside; NSC-63878; Ara_C; Drug: pegaspargase; Given IM; Other Names: Oncaspar; L-asparaginase with polyethylene glycol; PEG-asparaginase; Drug: daunorubicin hydrochloride; Given IV; Other Names: Cerubidine; NSC-82151; Radiation: radiation therapy; Undergo radiation therapy; Other Names: irradiation; radiation; radiotherapy; therapy; Drug: dexamethasone; Given PO; Other Names: Decadron; DM; NSC-34521; Drug: mercaptopurine; Given PO; Other Names: 6-MP; Drug: thioguanine; Given PO; Other Names: NSC-752; 6 TG; Drug: methotrexate; Given PO and IT; Other Names: MTX; Drug: doxorubicin hydrochloride; Dose 25 g/m² IV Days 0, 7, 14, given over a period of 15 minutes to 2 hours; Other Names: Adriamycin; NSC-123127
Experimental: Induction and Oral MTX, Single Delayed Intensification; Patients without CNS disease at diagnosis, with favorable cytogenetics. Standard Induction (28 Days). Consolidation (28 days) and in remission Day 21 and at time of randomization, Interim maintenance I (2 months), Delayed intensification I (2 months), Interim maintenance II (2 months) then Maintenance (12 week cycles). Biopsy-proven testicular leukemia pts at diagnosis will receive testicular radiation therapy during the consolidation phase.	Drug: cyclophosphamide; Given IV; Other Names: Cytoxan; NSC-26271; Drug: vincristine sulfate; Given IV; Other Names: VCR; Oncovin; NSC-67574; Drug: cytarabine; Given IT; Other Names: Cytosar-U; Cytosine Arabinoside; NSC-63878; Ara_C; Drug: pegaspargase; Given IM; Other Names: Oncaspar; L-asparaginase with polyethylene glycol; PEG-asparaginase; Radiation: radiation therapy; Undergo radiation therapy; Other Names: irradiation; radiation; radiotherapy; therapy; Drug: dexamethasone; Given PO; Other Names: Decadron; DM; NSC-34521; Drug: mercaptopurine; Given PO; Other Names: 6-MP; Drug: thioguanine; Given PO; Other Names: NSC-752; 6 TG; Drug: methotrexate; Given PO and IT; Other Names: MTX; Drug: doxorubicin hydrochloride; Dose 25 g/m² IV Days 0, 7, 14, given over a period of 15 minutes to 2 hours; Other Names: Adriamycin; NSC-123127
Experimental: Induction and Oral MTX, Double Delayed Intensification; Patients without CNS disease at diagnosis, with favorable cytogenetics. Standard Induction (28 Days). Consolidation (28 days) and in remission Day 21 and at time of randomization, Interim maintenance I (2 months), Delayed intensification I (2 months), Interim maintenance II (2 months), Delayed intensification II (2 months), then Maintenance (12 week cycles). Biopsy-proven testicular leukemia pts at diagnosis will receive testicular radiation therapy during the consolidation phase.	Drug: cyclophosphamide; Given IV; Other Names: Cytoxan; NSC-26271; Drug: vincristine sulfate; Given IV; Other Names: VCR; Oncovin; NSC-67574; Drug: cytarabine; Given IT; Other Names: Cytosar-U; Cytosine Arabinoside; NSC-63878; Ara_C; Drug: pegaspargase; Given IM; Other Names: Oncaspar; L-asparaginase with polyethylene glycol; PEG-asparaginase; Radiation: radiation therapy; Undergo radiation therapy; Other Names: irradiation; radiation; radiotherapy; therapy; Drug: dexamethasone; Given PO; Other Names: Decadron; DM; NSC-34521; Drug: mercaptopurine; Given PO; Other Names: 6-MP; Drug: thioguanine; Given PO; Other Names: NSC-752; 6 TG; Drug: methotrexate; Given PO and IT; Other Names: MTX; Drug: doxorubicin hydrochloride; Dose 25 g/m² IV Days 0, 7, 14, given over a period of 15 minutes to 2 hours; Other Names: Adriamycin; NSC-123127
Experimental: Induction and IV MTX, Single Delayed Intensification; Patients without CNS disease at diagnosis, with favorable cytogenetics. Standard Induction (28 Days). Consolidation (28 days) and in remission Day 21 and at time of randomization, Interim maintenance I (2 months), Delayed intensification I (2 months), Interim maintenance II (2 months) then Maintenance (12 week cycles). Biopsy-proven testicular leukemia pts at diagnosis will receive testicular radiation therapy during the consolidation phase.	Drug: cyclophosphamide; Given IV; Other Names: Cytoxan; NSC-26271; Drug: vincristine sulfate; Given IV; Other Names: VCR; Oncovin; NSC-67574; Drug: cytarabine; Given IT; Other Names: Cytosar-U; Cytosine Arabinoside; NSC-63878; Ara_C; Drug: pegaspargase; Given IM; Other Names: Oncaspar; L-asparaginase with polyethylene glycol; PEG-asparaginase; Radiation: radiation therapy; Undergo radiation therapy; Other Names: irradiation; radiation; radiotherapy; therapy; Drug: dexamethasone; Given PO; Other Names: Decadron; DM; NSC-34521; Drug: mercaptopurine; Given PO; Other Names: 6-MP; Drug: thioguanine; Given PO; Other Names: NSC-752; 6 TG; Drug: methotrexate; Given PO and IT; Other Names: MTX; Drug: doxorubicin hydrochloride; Dose 25 g/m² IV Days 0, 7, 14, given over a period of 15 minutes to 2 hours; Other Names: Adriamycin; NSC-123127
Experimental: Induction and IV MTX, Double Delayed Intensification; Patients without CNS disease at diagnosis, with favorable cytogenetics. Standard Induction (28 Days). Consolidation (28 days) and in event free remission Day 21 and at time of randomization, Interim maintenance I (2 months), Delayed intensification I (2 months), Interim maintenance II (2 months), Delayed intensification II (2 months), then Maintenance (12 week cycles). Biopsy-proven testicular leukemia pts at diagnosis will receive testicular radiation therapy during the consolidation phase.	Drug: cyclophosphamide; Given IV; Other Names: Cytoxan; NSC-26271; Drug: vincristine sulfate; Given IV; Other Names: VCR; Oncovin; NSC-67574; Drug: cytarabine; Given IT; Other Names: Cytosar-U; Cytosine Arabinoside; NSC-63878; Ara_C; Drug: pegaspargase; Given IM; Other Names: Oncaspar; L-asparaginase with polyethylene glycol; PEG-asparaginase; Radiation: radiation therapy; Undergo radiation therapy; Other Names: irradiation; radiation; radiotherapy; therapy; Drug: dexamethasone; Given PO; Other Names: Decadron; DM; NSC-34521; Drug: mercaptopurine; Given PO; Other Names: 6-MP; Drug: thioguanine; Given PO; Other Names: NSC-752; 6 TG; Drug: methotrexate; Given PO and IT; Other Names: MTX; Drug: doxorubicin hydrochloride; Dose 25 g/m² IV Days 0, 7, 14, given over a period of 15 minutes to 2 hours; Other Names: Adriamycin; NSC-123127

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Event Free Survival	The primary outcome index used in examining the randomized treatment groups will be event free survival (EFS) from the time of randomization (i.e., end of Consolidation), where the life table events will consist of the first occurrence of leukemic relapse at any site, death, or occurrence of a second malignancy.	Time of randomization

Collaborators and Investigators

• Sponsor: Children's Oncology Group
• Collaborators: National Cancer Institute (NCI)
• Investigators: Study Chair: Yousif H. Matloub, MD, University of Wisconsin, Madison

Publications and helpful links

General Publications

• Matloub Y, Asselin BL, Stork LC, et al.: Outcome of children with T-Cell acute lymphoblastic leukemia (T-ALL) and standard risk (SR) features: results of CCG-1952, CCG-1991 and POG 9404. [Abstract] Blood 104 (11): A-680, 195a, 2004.
• Bruggers CS, Moyer-Mileur LJ, Ransdall L: Body composition, bone mineral acquisition, and cardiovascular fitness in children with standard risk acute lymphoblastic leukemia: response to a home-based exercise and nutrition education program. [Abstract] 2006 Pediatric Academic Societies' Annual Meeting, April 29 - May 2, San Francisco, CA. A-3505.46, 2006.
• Fernandez CV, Kodish E, Taweel S, Shurin S, Weijer C; Children's Oncology Group. Disclosure of the right of research participants to receive research results: an analysis of consent forms in the Children's Oncology Group. Cancer. 2003 Jun 1;97(11):2904-9. doi: 10.1002/cncr.11391.
• Matloub Y, Bostrom BC, Hunger SP, Stork LC, Angiolillo A, Sather H, La M, Gastier-Foster JM, Heerema NA, Sailer S, Buckley PJ, Thomson B, Cole C, Nachman JB, Reaman G, Winick N, Carroll WL, Devidas M, Gaynon PS. Escalating intravenous methotrexate improves event-free survival in children with standard-risk acute lymphoblastic leukemia: a report from the Children's Oncology Group. Blood. 2011 Jul 14;118(2):243-51. doi: 10.1182/blood-2010-12-322909. Epub 2011 May 11.
• Matloub Y, Bostrom BC, Angiolillo AL, et al.: Children with NCI standard risk acute lymphoblastic leukemia (ALL) and TEL-AML1 or favorable chromosome trisomies are almost certain to be cured with graduated intensity therapy: results of the CCG - 1991 study. [Abstract] Blood 114 (22): A-320, 2009.
• Matloub Y, Bostrom BC, Hunger SP, et al.: Escalating dose intravenous methotrexate without leucovorin rescue during interim maintenance is superior to oral methotrexate for children with standard risk acute lymphoblastic leukemia (SR-ALL): Children's Oncology Group study 1991. [Abstract] Blood 112 (11): A-9, 2008.
• Matloub Y, Angiolillo A, Bostrom B, et al.: Double delayed intensification (DDI) is equivalent to single DI (SDI) in children with National Cancer Institute (NCI) standard-risk acute lymphoblastic leukemia (SR-ALL) treated on Children's Cancer Group (CCG) clinical trial 1991 (CCG-1991). [Abstract] Blood 108 (11): A-146, 2006.
• Matloub Y, Rabin KR, Ji L, Devidas M, Hitzler J, Xu X, Bostrom BC, Stork LC, Winick N, Gastier-Foster JM, Heerema NA, Stonerock E, Carroll WL, Hunger SP, Gaynon PS. Excellent long-term survival of children with Down syndrome and standard-risk ALL: a report from the Children's Oncology Group. Blood Adv. 2019 Jun 11;3(11):1647-1656. doi: 10.1182/bloodadvances.2019032094.

Study record dates

Study Major Dates

• Study Start: June 1, 2000
• Primary Completion (Actual): November 1, 2007
• Study Completion (Actual): June 1, 2008

Study Registration Dates

• First Submitted: July 5, 2000
• First Submitted That Met QC Criteria: January 26, 2003
• First Posted (Estimate): January 27, 2003

Study Record Updates

• Last Update Posted (Estimate): February 23, 2016
• Last Update Submitted That Met QC Criteria: February 19, 2016
• Last Verified: February 1, 2016

More Information

Terms related to this study

• Keywords: L3 childhood acute lymphoblastic leukemia; untreated childhood acute lymphoblastic leukemia; L1 childhood acute lymphoblastic leukemia; L2 childhood acute lymphoblastic leukemia
• Additional Relevant MeSH Terms: Immune System Diseases; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Leukemia; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Leukemia, Lymphoid; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Autonomic Agents; Peripheral Nervous System Agents; Antiviral Agents; Nucleic Acid Synthesis Inhibitors; Enzyme Inhibitors; Anti-Inflammatory Agents; Antirheumatic Agents; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Tubulin Modulators; Antimitotic Agents; Mitosis Modulators; Antiemetics; Gastrointestinal Agents; Glucocorticoids; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Antineoplastic Agents, Hormonal; Antineoplastic Agents, Alkylating; Alkylating Agents; Myeloablative Agonists; Antineoplastic Agents, Phytogenic; Topoisomerase II Inhibitors; Topoisomerase Inhibitors; Dermatologic Agents; Antibiotics, Antineoplastic; Reproductive Control Agents; Abortifacient Agents, Nonsteroidal; Abortifacient Agents; Folic Acid Antagonists; Dexamethasone; Cyclophosphamide; Doxorubicin; Liposomal doxorubicin; Cytarabine; Methotrexate; Vincristine; Daunorubicin; Asparaginase; Mercaptopurine; Thioguanine; Pegaspargase
• Other Study ID Numbers: 1991; U10CA098543 (U.S. NIH Grant/Contract); CCG-1991 (Other Identifier: Children's Cancer Group); CDR0000067855 (Other Identifier: Clinical Trials.gov); NCT00005945 (Other Identifier: NCI); NCI-2012-02333 (Other Identifier: NCI)