Trial Information

TREATMENT OF PATIENTS WITH ACUTE LYMPHOBLASTIC LEUKEMIA WITH UNFAVORABLE FEATURES: A PHASE III GROUP-WIDE STUDY

OBJECTIVES: I. Compare the outcomes in children with higher risk acute lymphocytic leukemia
(ALL) treated with postinduction chemotherapy based on marrow response on day 7 of induction
therapy: for patients with rapid early response (M1/M2), standard vs intensified
consolidation chemotherapy and standard vs prolonged duration of intensification
chemotherapy; for patients with slow early response, addition of doxorubicin vs idarubicin
and cyclophosphamide to intensification chemotherapy. II. Decrease the incidence of
avascular necrosis by alternating dexamethasone dosing in patients undergoing 2 courses of
delayed intensification. III. Assess the impact of day 7 marrow status on outcome in these
patients. IV. Determine prognosis more precisely by supplementing presenting clinical
features, immunophenotype, ploidy, cytogenetics, and early marrow response with BAX/BCL-2
ratios, pattern of tyrosine kinase activation, leukemic burden following induction and
intensification therapy, and development of high antibody titer to E. coli asparaginase. V.
Correlate the traditional prognostic factors of day 7 marrow response, immunophenotype,
ploidy, cytogenetics, and early marrow response with BAX/BCL-2 ratios.

OUTLINE: This is a partially randomized, multicenter study. Patients are stratified by
center. Patients receive one course of the VPLD regimen comprised of vincristine IV and
daunorubicin IV over 15 minutes to 2 hours on days 0 and 7, oral prednisone daily on days
0-7, intrathecal cytarabine on day 0, and asparaginase or pegaspargase intramuscularly on
days 3, 5, and 7. Patients are assigned to 1 of 2 two postinduction chemotherapy groups
based on bone marrow response on day 7 of induction. Patients with M1/M2 marrow on day 7 are
considered rapid early responders. Patients with M3 marrow on day 7 are considered slow
early responders. Group 1: Rapid early responders Patients receive 2 additional courses of
VPLD induction chemotherapy. Patients are then randomized to 1 of 4 treatment arms: Arm I:
Beginning on day 35 of induction therapy, patients receive standard Berlin-Frankfurt-Munster
(BFM) regimen with standard delayed intensification. Standard BFM for patients in arm I
consists of the following: consolidation over 5 weeks with cyclophosphamide, cytarabine, and
mercaptopurine; interim maintenance over 8 weeks with oral methotrexate and mercaptopurine
(MTX/MP); and delayed intensification over 7 weeks consisting of reinduction with
vincristine, doxorubicin, oral dexamethasone, and asparaginase or pegaspargase followed by
reconsolidation with cyclophosphamide, thioguanine, and cytarabine. Arm II: Patients receive
standard BFM regimen with double delayed intensification. Patients receive therapy similar
to those in arm I, but dexamethasone is interrupted for 1 week during delayed
intensification and the intensification regimen is repeated, separated by an 8 week interim
maintenance course of oral MTX/MP. Arm III: Patients receive augmented BFM regimen with
standard delayed intensification. Patients receive 9 weeks of consolidation therapy with 2
courses of vincristine and pegaspargase alternating with the arm I consolidation therapy.
Vincristine, intravenous methotrexate, and pegaspargase (the Capizzi I regimen) are
substituted for oral MTX/MP in the interim maintenance regimen. Pegaspargase is substituted
for asparaginase and two additional doses of vincristine are administered during delayed
intensification. Arm IV: Patients receive augmented BFM regimen with double delayed
intensification. Patients receive intensified chemotherapy throughout, combining the
additional therapy given to patients in arms II and III. Patients receiving augmented BFM
regimen receive pegaspargase instead of asparaginase. Patients with CNS disease at diagnosis
are treated only on arm IV. Patients who are Philadelphia chromosome positive and do not
have a bone marrow donor are nonrandomly assigned to the treatment group for slow early
responders. All RER patients receive the same maintenance therapy with
vincristine/prednisone and oral MTX/MP. Intrathecal methotrexate is administered
periodically throughout protocol treatment. Group 2: Slow early responders Patients receive
augmented BFM consolidation therapy and Capizzi I interim maintenance identical to that
received by rapid early responders in arm IV. Patients are then randomized to receive double
delayed intensification with either idarubicin or doxorubicin and concurrent
cyclophosphamide. All patients receive the same maintenance therapy with
vincristine/prednisone and oral MTX/MP. Intrathecal MTX is administered periodically
throughout protocol treatment. Patients with CNS disease at entry receive craniospinal
irradiation daily for 5 consecutive days beginning on day 0 of consolidation therapy. All
slow early responders at diagnosis receive cranial irradiation daily for 5 consecutive days
during consolidation therapy. Patients with testicular leukemia at diagnosis receive
bilateral testicular irradiation daily for 5 consecutive days during consolidation
chemotherapy. Groups 1 and 2: Maintenance therapy continues for 2 years for girls or 3 years
for boys beyond completion of consolidation therapy. Patients are followed every 4-6 weeks
for 1 year, every 3 months for 1 year, every 6 months for 2 years, and then annually
thereafter.

PROJECTED ACCRUAL: Approximately 1,520 patients will be accrued for this study over 4 years.