Trial Information

RANDOMIZED COMPARISONS OF ORAL MERCAPTOPURINE VS. ORAL THIOGUANINE AND INTRATHECAL METHOTREXATE VS. INTRATHECAL METHOTREXATE/CYTARABINE/HYDROCORTISONE FOR STANDARD ACUTE LYMPHOBLASTIC LEUKEMIA

OBJECTIVES: I. Identify response related factors predictive of relapse among children with
previously untreated standard risk acute lymphoblastic leukemia (ALL). II. Determine the
prognostic significance of residual leukemic blasts at specific times during induction
therapy: M3 marrow status (greater than 25% blasts) at day 7; M2 status (5%-25% blasts) at
day 14; and residual circulating leukemic blasts at days 7 and 14. III. Determine the
prognostic significance of residual leukemic burden, as measured by fluorescence activated
cell sorting/leukemic progenitor cell assay, on marrow aspirates acquired at the end of
induction therapy, at the beginning of maintenance therapy, and at the completion of all
therapy in patients with B precursor ALL. IV. Determine the prognostic significance of
residual t(1;19) detected in marrow aspirates by PCR-based analyses of the fusion transcript
E2A-PBX1 at the end of induction therapy, at the beginning of maintenance therapy, and at
the completion of all therapy. V. Examine the interrelationships among these
response-related prognostic factors and their correlation with ploidy, karyotype, and
immunophenotype. VI. Determine, in a randomized study, whether substitution of oral
thioguanine (TG) for oral mercaptopurine (MP) during consolidation, interim maintenance, and
maintenance therapy improves event-free survival for patients with standard-risk ALL. VII.
Study and compare the cellular pharmacokinetics of oral MP and oral TG during interim
maintenance and maintenance therapy in selected patients. VIII. Compare the concentrations
of MP and TG red blood cell metabolites (i.e., nucleotides, nucleosides, free bases, and
methylated metabolites) during interim maintenance and maintenance therapy, and determine
whether low levels of metabolites predict relapse in selected patients. IX. Determine the
activities of thiopurine methyltransferase and hypoxanthine guanine phosphoribosyl
transferase several times during interim maintenance and maintenance treatment, and compare
the activities between the two thiopurine treatment groups in selected patients. X. Compare
the incidence of central nervous system (CNS) relapse and event-free survival in patients
receiving intrathecal methotrexate (MTX) vs. triple intrathecal chemotherapy
(MTX/cytarabine/hydrocortisone) for presymptomatic CNS treatment. XI. Determine whether
cerebrospinal fluid (CSF) terminal deoxynucleotidyl transferase (TdT) positivity predicts
for CNS or marrow relapse by measuring TdT activity on CSF cytospins in cases with low white
blood cell count (less than 5 cells per cubic millimeter) and suspected or questionable
"blasts" during maintenance therapy. XII. Determine event-free survival in patients with
standard-risk ALL and M3 marrow at day 14 when treated with intensive therapy designed for
higher-risk ALL.

OUTLINE: This is a randomized study. Patients are stratified according to participating
institution. The following acronyms are used: ARA-C Cytarabine, NSC-63878 ASP Asparaginase
(E. coli), NSC-109229 CTX Cyclophosphamide, NSC-26271 DM Dexamethasone, NSC-34521 DNR
Daunorubicin, NSC-82151 DOX Doxorubicin, NSC-123127 HC Hydrocortisone, NSC-10483 MP
Mercaptopurine, NSC-755 MTX Methotrexate, NSC-740 PEG-ASP Pegaspargase, NSC-624239 PRED
Prednisone, NSC-10023 TG Thioguanine, NSC-752 TIT Triple Intrathecal Therapy (IT MTX/IT
ARA-C/IT HC) VCR Vincristine, NSC-67574 Induction: All patients receive oral PRED on days
0-27, VCR IV on days 0, 7, 14, and 21, and ASP IM 3 times a week for 3 weeks beginning on
day 2-4. ARA-C IT is administered on day 0, and MTX IT is administered on days 7 and 28
(days 7, 14, 21, and 28 if CNS disease at diagnosis). Following Induction, patients who
achieve remission are randomly assigned to 1 of 4 treatment arms. Arm I: Consolidation
(begins day 28 of Induction): PRED is tapered from Induction over 10 days. Patients receive
VCR IV on day 0, oral MP on days 1-27, and MTX IT on days 7, 14, and 21 (only day 7 if CNS
disease at diagnosis). Interim Maintenance 1 (begins day 28 of Consolidation): Patients
receive oral PRED on days 0-4 and 28-32, VCR IV days 0 and 28, oral MTX on days 0, 7, 14,
21, 28, 35, 42, and 49, and oral MP on days 0-49. Delayed Intensification 1 (begins day 56
of Interim Maintenance 1): Patients receive oral DM on days 0-6 and 14-20, VCR IV on days 0,
7, and 14, DOX IV over 15-120 min on days 0, 7, and 14, ASP IM twice a week for 2 weeks
beginning day 2-4, CTX IV over 20-30 min on day 28, oral TG on days 28-41, ARA-C IV or SC on
days 29-32 and 36-39, and MTX IT on days 0, 28, and 35. Interim Maintenance 2 (begins day 56
of Delayed Intensification 1): Patients receive PRED/VCR/MTX/MP as in Interim Maintenance 1.
Delayed Intensification 2 (begins day 56 of Interim Maintenance 2): Patients receive
DM/VCR/DOX/ASP, CTX/TG/ARA-C, and MTX IT as in Delayed Intensification 1. Maintenance
(begins day 56 of Delayed Intensification 2): Patients receive oral PRED on days 0-4, 28-32,
and 56-60, VCR IV on days 0, 28, and 56, oral MP on days 0-83, oral MTX on days 7, 14, 21,
28, 35, 42, 49, 56, 63, 70, and 77 (omitted during wk of IT therapy), and MTX IT on day 0.
Treatment continues every 84 days for 2 years (girls) or 3 years (boys) from the beginning
of Interim Maintenance 1. Arm II: Patients recevie treatment as in arm I, except TIT is TIT
substituted for MTX IT. Arm III: Patients receive treatment as in arm I with oral TG
substituted for oral MTX in Consolidation, Interim Maintenance 1 and 2, and Maintenance. If
secondary veno-occlusive disease occurs, MP is substituted for TG during Maintenance. Arm
IV: Patients receive treatment as in arm III with TIT substituted for MTX IT. If secondary
veno-occlusive disease occurs, MP is substituted for TG during Maintenance. Patients with M3
marrow after 2 weeks or M2 marrow after 4 weeks of Induction, or with Philadelphia
chromosome (t[9;22][q34;q11]), t(4;11)(q21;q23), or hypodiploidy, proceed to the following
more intensive treatment regimen for further therapy: Induction (begins day 14 to day 19 of
initial Induction): Patients receive oral PRED on days 14-27, VCR IV on days 14 and 21 (day
14 dose omitted if day 14 dose from original Induction already given), DNR IV continuously
on days 14-16 (48 hours total), ASP IM three times a week for 9 total doses (including those
received on original Induction), MTX IT on days 28 and 35 (days 21, 28, and 35 if CNS
disease at diagnosis). Patients with M1/M2 bone marrow after day 35 proceed to
Consolidation. Consolidation (begins day 28 or 35 of Induction in this regimen, depending on
timing of entry on this regimen): PRED is tapered from Induction over 10 days. Patients
receive CTX IV 20-30 minutes on days 0 and 28, oral MP on days 0-13 and 28-41, ARA-C IV or
SC on days 1-4, 8-11, 29-32, and 36-39, VCR IV on days 14, 21, 42, and 49, PEG-ASP IM on
days 14 and 42, and MTX IT on days 7, 14, and 21 (only day 7 if CNS disease at diagnosis).
Patients with M1 or M2 marrow and no extramedullary leukemia after day 63 proceed to Interim
Maintenance 1. Interim Maintenance 1 (begins day 63 of Consolidation): Patients receive VCR
IV on days 0, 10, 20, 30, and 40, MTX IV on days 0, 10, 20, 30, and 40, and PEG-ASP IM on
days 1 and 21. Patients with M1 bone marrow after day 56 proceed to Delayed Intensification
I. Delayed Intensification 1 (begins day 56 of Interim Maintenance 1): Patients receive oral
DM on days 0-6 and 14-20, VCR IV on days 0, 7, 14, 42, and 49, DOX IV over 15-120 minutes on
days 0, 7, and 14, PEG-ASP IM on days 3 and 42, CTX IV over 20-30 minutes on day 28, oral TG
on days 28-41, ARA-C IV or SC on days 29-32 and 36-39, and MTX IT on days 28 and 35. Interim
Maintenance 2 (begins day 56 of Delayed Intensification 1): Patients receive VCR/MTX/PEG-ASP
as in Interim Maintenance 1, and MTX IT on days 0, 20, and 40. Delayed Intensification 2
(begins day 56 of Interim Maintenance 2): Patients receive DM/VCR/DOX/PEG-ASP, CTX/TG/ARA-C,
and MTX IT as in Delayed Intensification 1. Maintenance (begins day 56 of Delayed
Intensification 2): Patients receive PRED/VCR/MP/MTX, and MTX IT as in arm I Maintenance.
Patients with CNS or testicular involvement at diagnosis receive appropriate radiotherapy
concurrent with Consolidation. Radiotherapy begins within 4 days of initiation of
Consolidation. Craniospinal irradiation is given 5 days a week. Testicular irradiation is
given to both testes 5 days a week over 2-3 weeks. Patients are followed every 6-8 weeks
during year 1, every 3 months during year 2, every 6 months during year 3, and then annually
thereafter.

PROJECTED ACCRUAL: A total of 1970 patients will be accrued for this study within 3.5 years.