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RATIONALE: Drugs used in chemotherapy use different ways to stop tumor cells from dividing so they stop growing or die. Combining more than one drug may kill more tumor cells. It is not yet known which regimen of combination chemotherapy plus steroid therapy is more effective for acute lymphoblastic leukemia or lymphoblastic non-Hodgkin's lymphoma.
PURPOSE: Randomized phase III trial to compare the effectiveness of different regimens of combination chemotherapy plus steroid therapy in treating children who have acute lymphoblastic leukemia or lymphoblastic non-Hodgkin's lymphoma.
Full description
OBJECTIVES:
OUTLINE: This is a randomized, multicenter study. Patients are stratified for prephase therapy according to center, disease (acute lymphoblastic leukemia [ALL] vs non-Hodgkin's lymphoma [NHL]), WBC for ALL patients (less than 10,000/mm^3 vs 10,000/mm^3 to less than 100,000/mm^3 vs greater than 100,000/mm^3), stage for NHL patients (I or II vs III or IV), and whether prephase already started (yes vs no). Patients are stratified for protocol II therapy according to center, risk group (very low risk [VLR] vs average risk 1 [AR1] vs average risk 2 [AR2]), and treatment arm at first randomization.
Prephase: Patients are randomized to 1 of 2 treatment arms
Patients in both arms also receive methotrexate (MTX) intrathecally (IT) on day 1.
Protocol IA (days 8-35):
Patients with VLR, AR1, or AR2 disease after protocol IA proceed to protocol IB, interval therapy, and then protocol II. Patients with VHR disease after protocol IA proceed to the VHR patient protocol.
Protocol IB (for VLR, AR1, or AR2 patients): Patients with precursor B-cell ALL must be in complete remission (CR) and patients with NHL must be in CR or good partial remission.
VLR patients: Patients receive oral mercaptopurine (MP) on days 36-63; ARA-C IV on days 38-41, 45-48, 52-55, and 59-62; and MTX IT on days 38 and 52.
AR1 and AR2 patients: Patients receive oral MP and ARA-C in the same manner as VLR patients; CTX IV over 1 hour on days 36 and 63; and TIT on days 38 and 52.
VLR, AR1, and AR2 patients are also randomized to 1 of 2 treatment arms.
Interval therapy for VLR, AR1, or AR2 patients (begins 14 days after completion of protocol I): Patients receive oral MP daily on days 1-56; HD-MTX IV over 24 hours on days 8, 22, 36, and 50; leucovorin calcium (CF) (or levofolinic acid) orally or IV beginning 36 hours after initiation of MTX infusion and repeating every 6 hours until hour 72 or until serum MTX level is adequate; and TIT on days 9, 23, 37, and 51.
Protocol II (reinduction therapy IIA and reconsolidation therapy IIB):
VLR patients: Patients receive oral DM twice daily on days 1-21; VCR IV on days 8, 15, 22, and 29; doxorubicin (DOX) IV over 1-4 hours on days 8 and 15; ARA-C IV on days 38-41 and 45-48; oral thioguanine (TG) once daily on days 36-49; and MTX IT on day 38.
AR patients: Patients receive DM, VCR, ARA-C, and TG in the same manner as VLR patients; DOX IV over 1-4 hours on days 8, 15, 22, and 29; CTX IV over 30-60 minutes on day 36; and TIT on day 38.
VLR and AR patients are also randomized to 1 of 2 treatment arms.
Maintenance therapy for VLR and AR patients (begins 14 days after completion of protocol II):
After course 6, AR1 and AR2 patients receive further maintenance therapy comprising oral MP once daily and oral MTX once a week.
VHR patient protocol (recommended treatment): Patients with VHR disease after protocol IA receive reinforced consolidation (protocol IB') and VANDA regimens.
After protocol IB' and VANDA, VHR patients who are eligible for stem cell transplantation (SCT) and have an HLA-compatible familial donor undergo transplantation. Patients who are ineligible for SCT receive interval therapy, followed by 2 sequences of blocks R1, R2, and R3 (2 courses of each block for a total of 6 courses), and then maintenance therapy for a total treatment duration of 2 years.
Interval therapy: Patients receive oral MP once daily on days 1-42; HD-MTX IV over 24 hours on days 8, 22, and 36; CF as in interval therapy (described above); and TIT on days 9, 23, and 37.
Blocks R1, R2, and R3 (this sequential regimen is repeated once):
Maintenance therapy: (begins 14 days after the second course of block R3 and ends 2 years after initiation of study therapy): Patients receive treatment as in maintenance therapy for AR1 patients. Treatment repeats every 10 weeks for 5 courses.
Patients are followed every 3 months for 5 years and then annually thereafter.
PROJECTED ACCRUAL: A total of 1,400-1,500 patients will be accrued for this study within 5.5 years.
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Inclusion and exclusion criteria
DISEASE CHARACTERISTICS:
Histologically confirmed acute lymphoblastic leukemia (ALL) of FAB L1 or L2 morphology
Histologically confirmed precursor B or precursor T lymphoblastic non-Hodgkin's lymphoma (NHL)
Very low-risk (VLR) patients meeting 1 of the following criteria:
ALL of B-cell lineage
WBC less than 10,000/mm^3
Must meet 1 of the following conditions:
Good response to prephase therapy
Absence of t(9;22) or BCR/ABL, t(4;11)/MLL-AF4, or 11q23/MLL rearrangement
No acute undifferentiated leukemia (AUL)
No CNS or gonadal involvement
Precursor B-lymphoblastic NHL stage I or II OR
Average risk (AR) patients:
Must meet 1 of the following criteria:
AR patients substratified in:
AR1: B-cell lineage ALL with WBC less than 100,000/mm^3
AR2: B-cell lineage ALL with WBC at least 100,000/mm^3
Newborn Down syndrome patients with AR2 features are assigned to the AR1 group OR
VHR patients:
Must meet 1 of the following criteria:
ALL patients meeting 1 of the following conditions:
NHL patients who failed to achieve CR or GPR after completion of protocol IA
All VHR patients are eligible for stem cell transplantation except those whose sole VHR criterion is a poor response to prephase therapy and who have none of the following features:
Newborn Down syndrome patients with VHR features are assigned to AR1 group NOTE: A new classification scheme for adult non-Hodgkin's lymphoma has been adopted by PDQ. The terminology of "indolent" or "aggressive" lymphoma will replace the former terminology of "low", "intermediate", or "high" grade lymphoma. However, this protocol uses the former terminology.
PATIENT CHARACTERISTICS:
Age:
Performance status:
Life expectancy:
Hematopoietic:
Hepatic:
Renal:
PRIOR CONCURRENT THERAPY:
Biologic therapy:
Chemotherapy:
Endocrine therapy:
Radiotherapy:
Surgery:
Other:
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Data sourced from clinicaltrials.gov
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