Trial Information

EXTRAMEDULLARY RELAPSE AND OCCULT BONE MARROW INVOLVEMENT IN CHILDHOOD ACUTE LYMPHOBLASTIC LEUKEMIA: A PHASE III GROUP-WIDE STUDY

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.

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.