Trial Information

ALL-BFM 2000 Multi-Center Study for the Treatment of Children and Adolescents With Acute Lymphoblastic Leukemia

OBJECTIVES:

- Compare the relative efficacy of induction therapy comprising dexamethasone or
prednisone, in terms of a higher rate of event-free survival (EFS) and overall survival
and a reduced rate of relapse, in pediatric patients with intermediate-risk or
high-risk acute lymphoblastic leukemia (ALL).

- Compare the relative safety of a reduced-intensity reintensification regimen comprising
dexamethasone, vincristine, cyclophosphamide, and anthracyclines vs a standard
treatment regimen in pediatric patients with standard-risk ALL identified by fast
clearance of leukemic cells.

- Compare the efficacy of a second delayed reintensification regimen vs standard
reintensification therapy, in terms of improved EFS, in pediatric patients with
intermediate-risk ALL.

- Compare the efficacy of extended reintensification therapy (triple reinduction) vs
standard reintensification therapy (intensive pulses and one reintensification) in
pediatric patients with high-risk ALL.

OUTLINE: This is a randomized, multicenter study.

- Prednisone prephase therapy: Patients receive oral prednisone on days 1-7 and one dose
of methotrexate (MTX) intrathecally (IT) on day 1.

- Induction/consolidation therapy, protocol I: Patients are randomized to 1 of 2
treatment arms.

- Arm I (closed to accrual as of 6/30/2006): Patients receive prednisone (PRED) on
days 8-28.

- Arm II (closed to accrual as of 6/30/2006): Patients receive dexamethasone (DEXA)
on days 8-28.

Patients in both arms also receive vincristine (VCR) and daunorubicin hydrochloride (DNR)
once weekly in weeks 2-5; asparaginase (ASP) on days 12-33; cyclophosphamide (CPM) on days
36 and 64; cytarabine (ARA-C) in weeks 6-9; mercaptopurine (MP) on days 36-63; and MTX IT on
days 1, 12, 33, 45, and 59.*

NOTE: *Patients with CNS disease also receive MTX IT on days 18 and 27.

After completion of induction/consolidation therapy, patients are stratified according to
risk group based on disease response (standard-risk [SR] group [negative minimal residual
disease (MRD) on day 33 and before protocol M, day 78] vs high-risk [HR] group [MRD ≥ 10^-³
on day 78] vs intermediate-risk [IR] group [all nonSR/nonHR]).* Patients with SR and IR
disease proceed to extracompartment therapy. Patients with HR disease proceed to
reintensification therapy.

NOTE: *Patients meeting any of the following criteria are placed in the HR group regardless
of MRD response: Philadelphia chromosome-positive disease (BCR/ABL or t[9;22];
translocations [t4;11][q11;q23] or MLL/AF4); "prednisone-poor-response" (≥ 1,000 blasts/mm³
in the peripheral blood on day 8 after prednisone prephase therapy); or no response to study
induction therapy (M2/3 at day 33).

- Extracompartment therapy, protocol M: Patients receive MP on days 1-56 and MTX on days
8, 22, 36, and 50.

After completion of extracompartment therapy, SR and IR patients proceed to
reintensification therapy. SR patients are randomized to arms I or II. IR patients are
randomized to arms I or III. HR patients who have completed induction/consolidation therapy
are randomized to arms IV or V.

- Reintensification therapy:

- Arm I (standard reinduction therapy, protocol II [closed to accrual as of
6/30/2006]): SR and IR patients receive DEXA on days 1-22; VCR and doxorubicin
hydrochloride (DOX) in weeks 2-5; ASP on days 8, 11, 15, and 18; CPM on day 36;
ARA-C and thioguanine (TG) on days 36-49; and MTX IT on days 38 and 45.* Patients
then proceed to maintenance therapy.

NOTE: *Patients with CNS disease also receive MTX IT on days 1 and 18.

- Arm II (reduced-intensity reinduction therapy, protocol III [closed to accrual as of
6/30/2006]): SR patients receive DEXA on days 1-15; VCR and DOX on days 1 and 8; ASP on
days 1, 4, 8, and 11; CPM on day 15; ARA-C and TG on days 15-28; and MTX IT on days 17
and 24.* Patients then proceed to maintenance therapy.

NOTE: *Patients with CNS disease also receive MTX on day 1.

- Arm III (reduced-intensity reinduction/second delayed reinduction therapy [double
reintensification therapy] [closed to accrual as of 6/30/2006]): IR patients receive
reduced-intensity reintensification therapy as in arm II. After a 10-week interim
maintenance phase, treatment repeats once for a second delayed course of
reintensification therapy. Patients then proceed to maintenance therapy.

- Arm IV (standard reintensification therapy [closed to accrual as of 6/30/2006]): HR
patients receive two sequences of the following HR therapy elements (i.e., in this
order: 1, 2, 3, 1, 2, 3) following reintensification therapy as in arm I. Patients then
proceed to maintenance therapy.

- Element HR-1: Patients receive DEXA on days 1-5; VCR on days 1 and 6; ARA-C twice
on day 5; MTX and CPM every 12 hours on days 2-4 (5 doses); ASP on days 6 and 11;
and MTX/ARA-C/PRED IT on day 1.

- Element HR-2: Patients receive DEXA on days 1-5; vindesine on days 1 and 6; DNR on
day 5; MTX and ifosfamide every 12 hours on days 2-4 (5 doses); ASP on days 6 and
11; and MTX/ARA-C/PRED IT on day 1.* NOTE: *HR patients with CNS disease also
receive IT therapy on day 5.

- Element HR-3: Patients receive DEXA on days 1-5; ARA-C every 12 hours on days 1-2
(4 doses); etoposide five times daily on days 3-5; ASP on days 6 and 11; and
MTX/ARA-C/PRED IT on day 1.

- Arm V (extended reintensification therapy [triple protocol III] [closed to accrual as
of 6/30/2006]): HR patients receive HR therapy elements 3, 2, and 1 as in arm IV
following reintensification therapy as in arm II repeated the therapy element twice
with 4-week interim maintenance phases in between. Patients then proceed to maintenance
therapy.

- Interim maintenance/maintenance therapy: Patients receive MTX once weekly and MP
daily until week 104.

- Radiotherapy: HR patients or patients with T-cell acute lymphoblastic leukemia or
CNS disease undergo CNS radiotherapy.

PROJECTED ACCRUAL: A total of 2,000 patients will be accrued for this study.