RATIONALE: Drugs used in chemotherapy use different ways to stop cancer cells from dividing so they stop growing or die.

PURPOSE: Phase III trial to compare the effectiveness of combination chemotherapy in treating children who have relapsed acute lymphoblastic leukemia.

Condition	Treatment or Intervention	Phase
Quality of Life recurrent childhood acute lymphoblastic leukemia	Drug: cytarabine  Drug: dexamethasone  Drug: etoposide  Drug: hydrocortisone  Drug: idarubicin  Drug: ifosfamide  Drug: leucovorin calcium  Drug: mesna  Drug: methotrexate  Drug: pegaspargase  Drug: thioguanine  Drug: vincristine	Phase III

Further Study Details: 

OBJECTIVES: I. Improve the outcome in children with first isolated central nervous system (CNS), testicular, or ocular relapse of acute lymphoblastic lymphoma (ALL), and increase the knowledge of the characteristics of extramedullary and subsequent relapses of ALL.

II. Quantitate, by current molecular biologic techniques, occult systemic leukemia in cases of conventional isolated extramedullary relapse, and examine the relationship between this assessment and subsequent clinical outcome, particularly overt marrow relapse.

III. Quantitate occult systemic leukemia in subsets of extramedullary relapse that include site (CNS, testis, or eye), time of relapse (early or late), initial risk group, immunophenotype, DNA index and karyotype, gender (for CNS and eye), and ethnicity, and assess the response to therapy in patients entered on companion protocol CCG-B958.

IV. Compare the relative sensitivities of two quantitative in vitro assays for occult systemic leukemia (fluorescence-activated cell sorter/leukemic progenitor cell clonogenic assay vs. polymerase chain reaction-based clonospecific assay), correlate the assays with clinical outcome, and assess other biologic studies of leukemic cells (e.g., neurotropic potential in the SCID mouse xenograft model and methotrexate sensitivity).

V. Determine the event-free survival (EFS) and pattern of failure in children with first isolated CNS, testicular, or ocular relapse after treatment that includes intensive systemic chemotherapy.

VI. Correlate EFS in patients with CNS and ocular relapse with sex, and in patients with relapse at all three sites with ethnicity.

VII. Evaluate the impact of combined chemotherapy and radiotherapy on health status in survivors at two and four years after extramedullary relapse and study entry.

PROTOCOL OUTLINE: All patients receive induction chemotherapy over 5 weeks with: etoposide, ifosfamide/mesna, dexamethasone, vincristine, and pegaspargase (if pegaspargase is not available, E. coli asparaginase may be substituted throughout study); then dexamethasone, vincristine, pegaspargase (or E. coli asparaginase), and high-dose methotrexate with leucovorin rescue; and triple intrathecal chemotherapy (TIT). Following induction chemotherapy, all patients receive two 6-week courses of intensification therapy with intermittent TIT; each course consists of dexamethasone, vincristine, high-dose methotrexate/leucovorin, thioguanine, cytarabine, etoposide, and pegaspargase (or E. coli asparaginase) followed by dexamethasone, vincristine, high-dose methotrexate/leucovorin, thioguanine, ifosfamide/mesna, and idarubicin.

Patients receive 2 additional courses of intensification chemotherapy followed by four 12-week courses of maintenance chemotherapy with vincristine and methotrexate every 2 weeks and daily oral thioguanine. Total duration of therapy is 78 weeks.

Patients with isolated ocular relapse receive local radiotherapy prior to initiation of induction chemotherapy; those who also have CNS leukemia begin TIT with the radiotherapy. Patients with CNS relapse receive craniospinal irradiation during the first month of maintenance therapy, with the dose and fields based on whether they will receive TBI and whether they have had CNS irradiation previously. Patients with testicular relapse receive bilateral testicular irradiation during the first 3 weeks of intensification therapy.

Patients are followed every 3 months for 3 years, every 6 months for 3 years, and yearly thereafter, or upon relapse, second malignancy, loss to follow up, or death. All patients undergo quality-of-life assessment at entry and 2 and 4 years after entry.

PROJECTED ACCRUAL: Approximately 120 patients will be accrued for this study.

Ages Eligible for Study:  up to  20 Years

Criteria

PROTOCOL ENTRY CRITERIA:

--Disease Characteristics--

• Acute lymphoblastic leukemia (ALL) with isolated extramedullary relapse; Relapse occurred during or following front-line therapy for ALL; Initial diagnosis of more than 25% blasts of L1 or L2 morphology; No leukemic marrow (M1) by conventional assessment
• Patients with B precursor ALL must also be enrolled on study CCG-B958
• Relapse occurred in the CNS, testis, or eye; Ocular relapse confirmed by an ophthalmologist and by cytology or iris biopsy; Combined CNS and ocular relapse eligible
• Down Syndrome patients not eligible
• No prior bone marrow transplantation in first remission
• No prior toxicity from any study drugs
• Patient age: Under 21

California
      Children's Hospital Los Angeles, Los Angeles,  California,  90027-0700,  United States
      Children's Hospital of Orange County, Orange,  California,  92668,  United States
      Jonsson Comprehensive Cancer Center, UCLA, Los Angeles,  California,  90095-1781,  United States
      Long Beach Memorial Medical Center, Long Beach,  California,  90806,  United States
      UCSF Cancer Center and Cancer Research Institute, San Francisco,  California,  94115-0128,  United States
Colorado
      Children's Hospital of Denver, Denver,  Colorado,  80218,  United States
District of Columbia
      Children's National Medical Center, Washington,  District of Columbia,  20010-2970,  United States
Illinois
      University of Chicago Cancer Research Center, Chicago,  Illinois,  60637,  United States
Indiana
      Indiana University Cancer Center, Indianapolis,  Indiana,  46202-5265,  United States
Iowa
      University of Iowa Hospitals and Clinics, Iowa City,  Iowa,  52242,  United States
Michigan
      University of Michigan Comprehensive Cancer Center, Ann Arbor,  Michigan,  48109-0752,  United States
Minnesota
      Mayo Clinic Cancer Center, Rochester,  Minnesota,  55905,  United States
      University of Minnesota Cancer Center, Minneapolis,  Minnesota,  55455,  United States
Missouri
      Children's Mercy Hospital - Kansas City, Kansas City,  Missouri,  64108,  United States
Nebraska
      University of Nebraska Medical Center, Omaha,  Nebraska,  68198-3330,  United States
New York
      Herbert Irving Comprehensive Cancer Center, New York,  New York,  10032,  United States
      Kaplan Cancer Center, New York,  New York,  10016,  United States
      Memorial Sloan-Kettering Cancer Center, New York,  New York,  10021,  United States
North Carolina
      Lineberger Comprehensive Cancer Center, UNC, Chapel Hill,  North Carolina,  27599-7295,  United States
Ohio
      Children's Hospital Medical Center - Cincinnati, Cincinnati,  Ohio,  45229-3039,  United States
      Children's Hospital of Columbus, Columbus,  Ohio,  43205-2696,  United States
      Ireland Cancer Center, Cleveland,  Ohio,  44106-5065,  United States
Oregon
      Doernbecher Children's Hospital, Portland,  Oregon,  97201-3098,  United States
Pennsylvania
      Children's Hospital of Philadelphia, Philadelphia,  Pennsylvania,  19104,  United States
      Children's Hospital of Pittsburgh, Pittsburgh,  Pennsylvania,  15213,  United States
Tennessee
      Vanderbilt Cancer Center, Nashville,  Tennessee,  37232-6838,  United States
Utah
      Huntsman Cancer Institute, Salt Lake City,  Utah,  84132,  United States
Washington
      Children's Hospital and Regional Medical Center - Seattle, Seattle,  Washington,  98105,  United States
      Fred Hutchinson Cancer Research Center, Seattle,  Washington,  98109,  United States
Wisconsin
      University of Wisconsin Comprehensive Cancer Center, Madison,  Wisconsin,  53792,  United States
Australia, Western Australia
      Princess Margaret Hospital for Children, Perth,  Western Australia,  6001,  Australia
Canada, British Columbia
      British Columbia Children's Hospital, Vancouver,  British Columbia,  V6H 3V4,  Canada
Canada, Nova Scotia
      IWK Grace Health Centre, Halifax,  Nova Scotia,  B3J 3G9,  Canada

Study chairs or principal investigators

Michael L.N. Willoughby,  Study Chair,  Children's Cancer Group   

Study ID Numbers:  CDR0000064968; CCG-1951
Record last reviewed:  June 2004
Last Updated:  October 13, 2004
Record first received:  November 1, 1999
ClinicalTrials.gov Identifier:  NCT00002816
Health Authority: United States: Federal Government
ClinicalTrials.gov processed this record on 2005-04-08