Combination Chemotherapy in Treating Children With Newly Diagnosed Acute Lymphoblastic Leukemia

Sponsor

Children's Oncology Group (Other)

Overall Status

Completed

CT.gov ID

NCT00002744

Collaborator

National Cancer Institute (NCI) (NIH)

1,970

Enrollment

Locations

Arms

130

Duration (Months)

57.9

Patients Per Site

0.4

Patients Per Site Per Month

Study Details

Study Description

Brief 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.

Condition or Disease	Intervention/Treatment	Phase
Leukemia	Drug: 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 sulfate Radiation: low-LET cobalt-60 gamma ray therapy Radiation: low-LET photon therapy	Phase 3

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

Arm II: Patients receive 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.

Study Design

Study Type:

Interventional

Actual Enrollment :

1970 participants

Allocation:

Randomized

Intervention Model:

Single Group Assignment

Masking:

Single

Primary Purpose:

Treatment

Official Title:

Randomized Comparisons of Oral Mercaptopurine vs Oral Thioguanine and IT Methotrexate vs ITT for Standard Risk Acute Lymphoblastic Leukemia

Study Start Date :

May 1, 1996

Actual Primary Completion Date :

Mar 1, 2007

Actual Study Completion Date :

Mar 1, 2007

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Arm I Therapy defined in description.	Drug: asparaginase Other Names: L-Asparaginase - Erwinia NSC-106977 Drug: cyclophosphamide Other Names: Cytoxan NSC-26271. Drug: cytarabine Other Names: Cytosine Arabinoside Ara-C Cytosar-U Drug: daunorubicin hydrochloride Other Names: NSC-82151 Drug: dexamethasone Other Names: Decadron NSC-34521 Drug: doxorubicin hydrochloride Other Names: Adriamycin NSC-123127 Drug: mercaptopurine Other Names: 6-MP Purinethol Drug: methotrexate Other Names: NSC-740 Drug: pegaspargase Other Names: PEG Asparaginase Oncaspar® Drug: prednisone Other Names: NSC-10023 Drug: therapeutic hydrocortisone Drug: thioguanine Other Names: 6-TG NSC-752 Drug: vincristine sulfate Other Names: Oncovin NSC-67574 Radiation: low-LET cobalt-60 gamma ray therapy Radiation: low-LET photon therapy
Experimental: Arm 2 Therapy defined in description.	Drug: asparaginase Other Names: L-Asparaginase - Erwinia NSC-106977 Drug: cyclophosphamide Other Names: Cytoxan NSC-26271. Drug: cytarabine Other Names: Cytosine Arabinoside Ara-C Cytosar-U Drug: daunorubicin hydrochloride Other Names: NSC-82151 Drug: dexamethasone Other Names: Decadron NSC-34521 Drug: doxorubicin hydrochloride Other Names: Adriamycin NSC-123127 Drug: mercaptopurine Other Names: 6-MP Purinethol Drug: methotrexate Other Names: NSC-740 Drug: pegaspargase Other Names: PEG Asparaginase Oncaspar® Drug: prednisone Other Names: NSC-10023 Drug: therapeutic hydrocortisone Drug: thioguanine Other Names: 6-TG NSC-752 Drug: vincristine sulfate Other Names: Oncovin NSC-67574 Radiation: low-LET cobalt-60 gamma ray therapy Radiation: low-LET photon therapy
Experimental: Arm 3 Therapy defined in description.	Drug: asparaginase Other Names: L-Asparaginase - Erwinia NSC-106977 Drug: cyclophosphamide Other Names: Cytoxan NSC-26271. Drug: cytarabine Other Names: Cytosine Arabinoside Ara-C Cytosar-U Drug: daunorubicin hydrochloride Other Names: NSC-82151 Drug: dexamethasone Other Names: Decadron NSC-34521 Drug: doxorubicin hydrochloride Other Names: Adriamycin NSC-123127 Drug: mercaptopurine Other Names: 6-MP Purinethol Drug: methotrexate Other Names: NSC-740 Drug: pegaspargase Other Names: PEG Asparaginase Oncaspar® Drug: prednisone Other Names: NSC-10023 Drug: therapeutic hydrocortisone Drug: thioguanine Other Names: 6-TG NSC-752 Drug: vincristine sulfate Other Names: Oncovin NSC-67574 Radiation: low-LET cobalt-60 gamma ray therapy Radiation: low-LET photon therapy
Experimental: Arm 4 Therapy defined in description.	Drug: asparaginase Other Names: L-Asparaginase - Erwinia NSC-106977 Drug: cyclophosphamide Other Names: Cytoxan NSC-26271. Drug: cytarabine Other Names: Cytosine Arabinoside Ara-C Cytosar-U Drug: daunorubicin hydrochloride Other Names: NSC-82151 Drug: dexamethasone Other Names: Decadron NSC-34521 Drug: doxorubicin hydrochloride Other Names: Adriamycin NSC-123127 Drug: mercaptopurine Other Names: 6-MP Purinethol Drug: methotrexate Other Names: NSC-740 Drug: pegaspargase Other Names: PEG Asparaginase Oncaspar® Drug: prednisone Other Names: NSC-10023 Drug: therapeutic hydrocortisone Drug: thioguanine Other Names: 6-TG NSC-752 Drug: vincristine sulfate Other Names: Oncovin NSC-67574 Radiation: low-LET cobalt-60 gamma ray therapy Radiation: low-LET photon therapy

Outcome Measures

Primary Outcome Measures

Event Free Survival []
Primary outcome index used in examining the randomized treatment groups will be event-free survival (EFS) from the time of randomization (i.e., end of Induction), where the life table events will consist of the first occurrence of leukemic relapse at any site, death, or occurrence of a second malignancy.

Secondary Outcome Measures

Comparisons of CNS relapse incidence rates []
Comparisons of CNS relapse incidence rates for the IT MTX versus ITT groups is also planned as an important endpoint.

Eligibility Criteria

Criteria

Ages Eligible for Study:

1 Year to 9 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Long Beach Memorial Medical Center	Long Beach	California	United States	90806
2	Children's Hospital Los Angeles	Los Angeles	California	United States	90027-0700
3	Jonsson Comprehensive Cancer Center, UCLA	Los Angeles	California	United States	90095-1781
4	Children's Hospital of Orange County	Orange	California	United States	92668
5	UCSF Cancer Center and Cancer Research Institute	San Francisco	California	United States	94115-0128
6	Children's Hospital of Denver	Denver	Colorado	United States	80218
7	Children's National Medical Center	Washington	District of Columbia	United States	20010-2970
8	University of Chicago Cancer Research Center	Chicago	Illinois	United States	60637
9	Indiana University Cancer Center	Indianapolis	Indiana	United States	46202-5265
10	University of Iowa Hospitals and Clinics	Iowa City	Iowa	United States	52242
11	University of Michigan Comprehensive Cancer Center	Ann Arbor	Michigan	United States	48109-0752
12	University of Minnesota Cancer Center	Minneapolis	Minnesota	United States	55455
13	Mayo Clinic Cancer Center	Rochester	Minnesota	United States	55905
14	Children's Mercy Hospital - Kansas City	Kansas City	Missouri	United States	64108
15	University of Nebraska Medical Center	Omaha	Nebraska	United States	68198-3330
16	Kaplan Cancer Center	New York	New York	United States	10016
17	Memorial Sloan-Kettering Cancer Center	New York	New York	United States	10021
18	Herbert Irving Comprehensive Cancer Center	New York	New York	United States	10032
19	Lineberger Comprehensive Cancer Center, UNC	Chapel Hill	North Carolina	United States	27599-7295
20	Children's Hospital Medical Center - Cincinnati	Cincinnati	Ohio	United States	45229-3039
21	Ireland Cancer Center	Cleveland	Ohio	United States	44106-5065
22	Children's Hospital of Columbus	Columbus	Ohio	United States	43205-2696
23	Doernbecher Children's Hospital	Portland	Oregon	United States	97201-3098
24	Children's Hospital of Philadelphia	Philadelphia	Pennsylvania	United States	19104
25	Children's Hospital of Pittsburgh	Pittsburgh	Pennsylvania	United States	15213
26	Vanderbilt Cancer Center	Nashville	Tennessee	United States	37232-6838
27	University of Texas - MD Anderson Cancer Center	Houston	Texas	United States	77030
28	Huntsman Cancer Institute	Salt Lake City	Utah	United States	84132
29	Children's Hospital and Medical Center - Seattle	Seattle	Washington	United States	98105
30	Fred Hutchinson Cancer Research Center	Seattle	Washington	United States	98109
31	University of Wisconsin Comprehensive Cancer Center	Madison	Wisconsin	United States	53792
32	Princess Margaret Hospital for Children	Perth	Western Australia	Australia	6001
33	British Columbia Children's Hospital	Vancouver	British Columbia	Canada	V6H 3V4
34	IWK Grace Health Centre	Halifax	Nova Scotia	Canada	B3J 3G9