Alternate Title
Basic Trial Information
Objectives
Entry Criteria
Expected Enrollment
Outline
Published Results
Related Publications
Trial Contact Information
Registry Information

Alternate Title

Combination Chemotherapy in Treating Children With Newly Diagnosed Acute Lymphoblastic Leukemia

Basic Trial Information

Phase	Type	Status	Age	Sponsor	Protocol IDs
Phase III	Treatment	Completed	1 to 9	NCI	CCG-1952 NCT00002744

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.

Entry Criteria

Disease Characteristics:

Newly diagnosed acute lymphoblastic leukemia (ALL) obtained by bone marrow
aspirate or bone marrow biopsy 

No greater than 25% L3 blasts

Initial white blood cell count less than 50,000/mm3 (performed at CCG
institution)

Massive lymphadenopathy, massive splenomegaly, and/or large mediastinal mass
allowed

CNS or testicular leukemia allowed

Allogeneic bone marrow transplant should be considered (if donor available)
for patients with Philadelphia chromosome (t[9;22][q34;q11]) or translocation
(4;11)(q21;q23)

Prior/Concurrent Therapy:

No prior treatment for ALL

Biologic therapy:
  Not specified

Chemotherapy:
  Intrathecal cytarabine (IT ARA-C) may begin prior to registration provided
  systemic chemotherapy initiated within 72 hours after IT ARA-C

Endocrine therapy:
  See Radiotherapy
  At least 1 month since prior systemic steroids
     Steroids given for less than 48 hours allowed
  Inhaled corticosteroids allowed at any time

Radiotherapy:
  Radiotherapy or dexamethasone for mediastinal mass causing superior
  mediastinal syndrome allowed prior to registration, if indicated

Surgery:
  Not specified

Patient Characteristics:

Age:
  1 through 9

Performance status:
  Not specified

Hematopoietic:
  See Disease Characteristics

Hepatic:
  Not specified


Renal:
  Not specified

Expected Enrollment

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

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.

Malempati S, Gaynon PS, Sather H, et al.: Outcome after relapse among children with standard-risk acute lymphoblastic leukemia: Children's Oncology Group study CCG-1952. J Clin Oncol 25 (36): 5800-7, 2007.[PUBMED Abstract]

Matloub Y, Lindemulder S, Gaynon PS, et al.: Intrathecal triple therapy decreases central nervous system relapse but fails to improve event-free survival when compared with intrathecal methotrexate: results of the Children's Cancer Group (CCG) 1952 study for standard-risk acute lymphoblastic leukemia, reported by the Children's Oncology Group. Blood 108 (4): 1165-73, 2006.[PUBMED Abstract]

Bassal M, La MK, Whitlock JA, et al.: Lymphoblast biology and outcome among children with Down syndrome and ALL treated on CCG-1952. Pediatr Blood Cancer 44 (1): 21-8, 2005.[PUBMED Abstract]

Malempati S, Gaynon PS, Sather H, et al.: Outcome after relapse among children with standard risk (SR) ALL treated on CCG-1952. [Abstract] Blood 104 (11): A-520, 2004.

Stork LC, Sather H, Hutchinson RJ, et al.: Comparison of mercaptopurine (MP) with thioguanine (TG) and IT methotrexate (ITM) with IT "triples" (ITT) in children with SR-ALL: results of CCG-1952. [Abstract] Blood 100 (11 Pt 1): A-585, 156a, 2002.

Stork LC, Sather H, Yanofsky R, et al.: Hyperdiploidy with trisomy 10 and TEL-AML1 expression among children with standard risk acute lymphoblastic leukemia (SR-ALL): a CCG-1952 report. [Abstract] Proceedings of the American Society of Clinical Oncology 20: A-1476, 2001.

Gaynon PS, Stork L, Sather H, et al.: Leukemic progenitor cell content of pre- and post-induction chemotherapy bone marrow specimens from children with newly diagnosed or relapsed acute lymphoblastic leukemia (ALL). [Abstract] Proceedings of the American Society of Clinical Oncology 18: A-2187, 567a, 1999.

Stork LC, Erdmann G, Adamson P, et al.: Oral 6-thioguanine causes relatively mild and reversible hepatic veno-occlusive disease(VOD). J Pediatr Hematol Oncol 20: 400a, 1998.

Matloub Y, Asselin BL, Stork LC, et al.: Outcome of children with T-Cell acute lymphoblastic leukemia (T-ALL) and standard risk (SR) features: results of CCG-1952, CCG-1991 and POG 9404. [Abstract] Blood 104 (11): A-680, 195a, 2004.

Trial Contact Information

Trial Lead Organizations

Children's Cancer Group

Linda Stork, MD, Protocol chair		Ph: 503-494-1543

Registry Information
Official Title		RANDOMIZED COMPARISONS OF ORAL MERCAPTOPURINE VS. ORAL THIOGUANINE AND INTRATHECAL METHOTREXATE VS. INTRATHECAL METHOTREXATE/CYTARABINE/HYDROCORTISONE FOR STANDARD ACUTE LYMPHOBLASTIC LEUKEMIA
Trial Start Date		1996-05-01
Registered in ClinicalTrials.gov		NCT00002744
Date Submitted to PDQ		1996-05-01
Information Last Verified		2007-12-20
NCI Grant/Contract Number		CA13539