Clinical trial NCT00002744: Combination Chemotherapy in Treating Children With Newly Diagnosed Acute Lymphoblastic Leukemia
Official title: Randomized Comparisons of Oral Mercaptopurine vs Oral Thioguanine and IT Methotrexate vs ITT for Standard Risk Acute Lymphoblastic Leukemia
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Leukemia
Keywords: untreated childhood acute lymphoblastic leukemia
L1 childhood acute lymphoblastic leukemia
L2 childhood acute lymphoblastic leukemia
Lead sponsor: Children's Oncology Group
Sponsor class: NETWORK
Collaborators: name: National Cancer Institute (NCI)
First posted: 2004-09-01
Enrollment: 1970
Sex: ALL
Minimum age (years): 1
Maximum age (years): 9
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.

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 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.

Eligibility 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

Primary outcomes:
measure: Event Free Survival
Secondary outcomes:
measure: Comparisons of CNS relapse incidence rates
Other outcomes:
Locations:
city: Long Beach
country: United States
facility: Long Beach Memorial Medical Center
state: California
city: Los Angeles
country: United States
facility: Children's Hospital Los Angeles
state: California
city: Los Angeles
country: United States
facility: Jonsson Comprehensive Cancer Center, UCLA
state: California
city: Orange
country: United States
facility: Children's Hospital of Orange County
state: California
city: San Francisco
country: United States
facility: UCSF Cancer Center and Cancer Research Institute
state: California
city: Denver
country: United States
facility: Children's Hospital of Denver
state: Colorado
city: Washington
country: United States
facility: Children's National Medical Center
state: District of Columbia
city: Chicago
country: United States
facility: University of Chicago Cancer Research Center
state: Illinois
city: Indianapolis
country: United States
facility: Indiana University Cancer Center
state: Indiana
city: Iowa City
country: United States
facility: University of Iowa Hospitals and Clinics
state: Iowa
city: Ann Arbor
country: United States
facility: University of Michigan Comprehensive Cancer Center
state: Michigan
city: Minneapolis
country: United States
facility: University of Minnesota Cancer Center
state: Minnesota
city: Rochester
country: United States
facility: Mayo Clinic Cancer Center
state: Minnesota
city: Kansas City
country: United States
facility: Children's Mercy Hospital - Kansas City
state: Missouri
city: Omaha
country: United States
facility: University of Nebraska Medical Center
state: Nebraska
city: New York
country: United States
facility: Kaplan Cancer Center
state: New York
city: New York
country: United States
facility: Memorial Sloan-Kettering Cancer Center
state: New York
city: New York
country: United States
facility: Herbert Irving Comprehensive Cancer Center
state: New York
city: Chapel Hill
country: United States
facility: Lineberger Comprehensive Cancer Center, UNC
state: North Carolina
city: Cincinnati
country: United States
facility: Children's Hospital Medical Center - Cincinnati
state: Ohio
city: Cleveland
country: United States
facility: Ireland Cancer Center
state: Ohio
city: Columbus
country: United States
facility: Children's Hospital of Columbus
state: Ohio
city: Portland
country: United States
facility: Doernbecher Children's Hospital
state: Oregon
city: Philadelphia
country: United States
facility: Children's Hospital of Philadelphia
state: Pennsylvania
city: Pittsburgh
country: United States
facility: Children's Hospital of Pittsburgh
state: Pennsylvania
city: Nashville
country: United States
facility: Vanderbilt Cancer Center
state: Tennessee
city: Houston
country: United States
facility: University of Texas - MD Anderson Cancer Center
state: Texas
city: Salt Lake City
country: United States
facility: Huntsman Cancer Institute
state: Utah
city: Seattle
country: United States
facility: Children's Hospital and Medical Center - Seattle
state: Washington
city: Seattle
country: United States
facility: Fred Hutchinson Cancer Research Center
state: Washington
city: Madison
country: United States
facility: University of Wisconsin Comprehensive Cancer Center
state: Wisconsin
city: Perth
country: Australia
facility: Princess Margaret Hospital for Children
state: Western Australia
city: Vancouver
country: Canada
facility: British Columbia Children's Hospital
state: British Columbia
city: Halifax
country: Canada
facility: IWK Grace Health Centre
state: Nova Scotia
Study officials:
affiliation: Doernbecher Children's Hospital at Oregon Health and Science University
name: Linda C. Stork, MD
role: STUDY_CHAIR
References:
citation: Nguyen K, Devidas M, Cheng SC, La M, Raetz EA, Carroll WL, Winick NJ, Hunger SP, Gaynon PS, Loh ML; Children's Oncology Group. Factors influencing survival after relapse from acute lymphoblastic leukemia: a Children's Oncology Group study. Leukemia. 2008 Dec;22(12):2142-50. doi: 10.1038/leu.2008.251. Epub 2008 Sep 25.
citation: 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.
citation: Stork LC, Matloub Y, Broxson E, La M, Yanofsky R, Sather H, Hutchinson R, Heerema NA, Sorrell AD, Masterson M, Bleyer A, Gaynon PS. Oral 6-mercaptopurine versus oral 6-thioguanine and veno-occlusive disease in children with standard-risk acute lymphoblastic leukemia: report of the Children's Oncology Group CCG-1952 clinical trial. Blood. 2010 Apr 8;115(14):2740-8. doi: 10.1182/blood-2009-07-230656. Epub 2010 Feb 1.
citation: Kadan-Lottick NS, Brouwers P, Breiger D, Kaleita T, Dziura J, Northrup V, Chen L, Nicoletti M, Bostrom B, Stork L, Neglia JP. Comparison of neurocognitive functioning in children previously randomly assigned to intrathecal methotrexate compared with triple intrathecal therapy for the treatment of childhood acute lymphoblastic leukemia. J Clin Oncol. 2009 Dec 10;27(35):5986-92. doi: 10.1200/JCO.2009.23.5408. Epub 2009 Nov 2.
citation: Malempati S, Gaynon PS, Sather H, La MK, Stork LC; Children's Oncology Group. Outcome after relapse among children with standard-risk acute lymphoblastic leukemia: Children's Oncology Group study CCG-1952. J Clin Oncol. 2007 Dec 20;25(36):5800-7. doi: 10.1200/JCO.2007.10.7508.
citation: Matloub Y, Lindemulder S, Gaynon PS, Sather H, La M, Broxson E, Yanofsky R, Hutchinson R, Heerema NA, Nachman J, Blake M, Wells LM, Sorrell AD, Masterson M, Kelleher JF, Stork LC; Children's Oncology Group. 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. 2006 Aug 15;108(4):1165-73. doi: 10.1182/blood-2005-12-011809. Epub 2006 Apr 11.
citation: Bassal M, La MK, Whitlock JA, Sather HN, Heerema NA, Gaynon PS, Stork LC. Lymphoblast biology and outcome among children with Down syndrome and ALL treated on CCG-1952. Pediatr Blood Cancer. 2005 Jan;44(1):21-8. doi: 10.1002/pbc.20193.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.