Combination Chemotherapy in Treating Children With Newly Diagnosed Acute Lymphoblastic Leukemia
Information source: National Cancer Institute (NCI)
Information obtained from ClinicalTrials.gov on June 20, 2008
Link to the current ClinicalTrials.gov record.
Condition(s) targeted: Leukemia
Intervention: asparaginase (Drug); cyclophosphamide (Drug); cytarabine (Drug); daunorubicin hydrochloride (Drug); dexamethasone (Drug); doxorubicin hydrochloride (Drug); mercaptopurine (Drug); methotrexate (Drug); pegaspargase (Drug); prednisone (Drug); therapeutic hydrocortisone (Drug); thioguanine (Drug); vincristine (Drug); low-LET cobalt-60 gamma ray therapy (Procedure); low-LET photon therapy (Procedure)
Phase: Phase 3
Status: Completed
Sponsored by: Children's Cancer Group Official(s) and/or principal investigator(s):
Linda C. Stork, MD, Study Chair, Affiliation: Doernbecher Children's Hospital at Oregon Health & Science University
Summary
RATIONALE: Drugs used in chemotherapy use different ways to stop cancer cells from dividing
so they stop growing or die. Combining more than one drug and giving them in different ways
may kill more cancer cells. It is not yet known which regimen of combination chemotherapy is
more effective for acute lymphoblastic leukemia
PURPOSE: Randomized phase III trial to compare different regimens of combination chemotherapy
in treating children who have newly diagnosed acute lymphoblastic leukemia.
Clinical Details
Official title: RANDOMIZED COMPARISONS OF ORAL MERCAPTOPURINE VS. ORAL THIOGUANINE AND INTRATHECAL METHOTREXATE VS. INTRATHECAL METHOTREXATE/CYTARABINE/HYDROCORTISONE FOR STANDARD ACUTE LYMPHOBLASTIC LEUKEMIA
Study design: Treatment, Randomized
Detailed description:
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.
Eligibility
Minimum age: 1 Year.
Maximum age: 9 Years.
Gender(s): Both.
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)
PATIENT CHARACTERISTICS: Age: 1 through 9 Performance status: Not specified Hematopoietic:
See Disease Characteristics Hepatic: Not specified Renal: Not specified
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
Locations and Contacts
British Columbia Children's Hospital, Vancouver, British Columbia V6H 3V4, Canada
Children's Hospital Los Angeles, Los Angeles, California 90027-0700, United States
Children's Hospital of Orange County, Orange, California 92668, United States
Jonsson Comprehensive Cancer Center, UCLA, Los Angeles, California 90095-1781, United States
Long Beach Memorial Medical Center, Long Beach, California 90806, United States
UCSF Cancer Center and Cancer Research Institute, San Francisco, California 94115-0128, United States
Children's Hospital of Denver, Denver, Colorado 80218, United States
Children's National Medical Center, Washington, District of Columbia 20010-2970, United States
University of Chicago Cancer Research Center, Chicago, Illinois 60637, United States
Indiana University Cancer Center, Indianapolis, Indiana 46202-5265, United States
University of Iowa Hospitals and Clinics, Iowa City, Iowa 52242, United States
University of Michigan Comprehensive Cancer Center, Ann Arbor, Michigan 48109-0752, United States
Mayo Clinic Cancer Center, Rochester, Minnesota 55905, United States
University of Minnesota Cancer Center, Minneapolis, Minnesota 55455, United States
Children's Mercy Hospital - Kansas City, Kansas City, Missouri 64108, United States
University of Nebraska Medical Center, Omaha, Nebraska 68198-3330, United States
Herbert Irving Comprehensive Cancer Center, New York, New York 10032, United States
Kaplan Cancer Center, New York, New York 10016, United States
Memorial Sloan-Kettering Cancer Center, New York, New York 10021, United States
Lineberger Comprehensive Cancer Center, UNC, Chapel Hill, North Carolina 27599-7295, United States
IWK Grace Health Centre, Halifax, Nova Scotia B3J 3G9, Canada
Children's Hospital Medical Center - Cincinnati, Cincinnati, Ohio 45229-3039, United States
Children's Hospital of Columbus, Columbus, Ohio 43205-2696, United States
Ireland Cancer Center, Cleveland, Ohio 44106-5065, United States
Doernbecher Children's Hospital, Portland, Oregon 97201-3098, United States
Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104, United States
Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania 15213, United States
Vanderbilt Cancer Center, Nashville, Tennessee 37232-6838, United States
University of Texas - MD Anderson Cancer Center, Houston, Texas 77030, United States
Huntsman Cancer Institute, Salt Lake City, Utah 84132, United States
Children's Hospital and Medical Center - Seattle, Seattle, Washington 98105, United States
Fred Hutchinson Cancer Research Center, Seattle, Washington 98109, United States
Princess Margaret Hospital for Children, Perth, Western Australia 6001, Australia
University of Wisconsin Comprehensive Cancer Center, Madison, Wisconsin 53792, United States
Additional Information
Clinical trial summary from the National Cancer Institute's PDQ® database
Related publications: 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.
Starting date: May 1996
Last updated: May 23, 2008
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