Combination Chemotherapy in Treating Children With Acute Lymphocytic Leukemia
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 the drugs in different combinations may kill more cancer cells.
PURPOSE: Randomized phase III trial to compare the effectiveness of standard combination chemotherapy treatment with more intensive combination chemotherapy in treating children with acute lymphocytic leukemia.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
Phase 3 |
Detailed Description
OBJECTIVES: I. Compare the outcomes in children with higher risk acute lymphocytic leukemia (ALL) treated with postinduction chemotherapy based on marrow response on day 7 of induction therapy: for patients with rapid early response (M1/M2), standard vs intensified consolidation chemotherapy and standard vs prolonged duration of intensification chemotherapy; for patients with slow early response, addition of doxorubicin vs idarubicin and cyclophosphamide to intensification chemotherapy. II. Decrease the incidence of avascular necrosis by alternating dexamethasone dosing in patients undergoing 2 courses of delayed intensification. III. Assess the impact of day 7 marrow status on outcome in these patients.
- Determine prognosis more precisely by supplementing presenting clinical features, immunophenotype, ploidy, cytogenetics, and early marrow response with BAX/BCL-2 ratios, pattern of tyrosine kinase activation, leukemic burden following induction and intensification therapy, and development of high antibody titer to E. coli asparaginase. V. Correlate the traditional prognostic factors of day 7 marrow response, immunophenotype, ploidy, cytogenetics, and early marrow response with BAX/BCL-2 ratios.
OUTLINE: This is a partially randomized, multicenter study. Patients are stratified by center. Patients receive one course of the VPLD regimen comprised of vincristine IV and daunorubicin IV over 15 minutes to 2 hours on days 0 and 7, oral prednisone daily on days 0-7, intrathecal cytarabine on day 0, and asparaginase or pegaspargase intramuscularly on days 3, 5, and 7. Patients are assigned to 1 of 2 two postinduction chemotherapy groups based on bone marrow response on day 7 of induction. Patients with M1/M2 marrow on day 7 are considered rapid early responders. Patients with M3 marrow on day 7 are considered slow early responders. Group 1: Rapid early responders Patients receive 2 additional courses of VPLD induction chemotherapy. Patients are then randomized to 1 of 4 treatment arms: Arm I: Beginning on day 35 of induction therapy, patients receive standard Berlin-Frankfurt-Munster (BFM) regimen with standard delayed intensification. Standard BFM for patients in arm I consists of the following: consolidation over 5 weeks with cyclophosphamide, cytarabine, and mercaptopurine; interim maintenance over 8 weeks with oral methotrexate and mercaptopurine (MTX/MP); and delayed intensification over 7 weeks consisting of reinduction with vincristine, doxorubicin, oral dexamethasone, and asparaginase or pegaspargase followed by reconsolidation with cyclophosphamide, thioguanine, and cytarabine. Arm II: Patients receive standard BFM regimen with double delayed intensification. Patients receive therapy similar to those in arm I, but dexamethasone is interrupted for 1 week during delayed intensification and the intensification regimen is repeated, separated by an 8 week interim maintenance course of oral MTX/MP. Arm III: Patients receive augmented BFM regimen with standard delayed intensification. Patients receive 9 weeks of consolidation therapy with 2 courses of vincristine and pegaspargase alternating with the arm I consolidation therapy. Vincristine, intravenous methotrexate, and pegaspargase (the Capizzi I regimen) are substituted for oral MTX/MP in the interim maintenance regimen. Pegaspargase is substituted for asparaginase and two additional doses of vincristine are administered during delayed intensification. Arm IV: Patients receive augmented BFM regimen with double delayed intensification. Patients receive intensified chemotherapy throughout, combining the additional therapy given to patients in arms II and III. Patients receiving augmented BFM regimen receive pegaspargase instead of asparaginase. Patients with CNS disease at diagnosis are treated only on arm IV. Patients who are Philadelphia chromosome positive and do not have a bone marrow donor are nonrandomly assigned to the treatment group for slow early responders. All RER patients receive the same maintenance therapy with vincristine/prednisone and oral MTX/MP. Intrathecal methotrexate is administered periodically throughout protocol treatment. Group 2: Slow early responders Patients receive augmented BFM consolidation therapy and Capizzi I interim maintenance identical to that received by rapid early responders in arm IV. Patients are then randomized to receive double delayed intensification with either idarubicin or doxorubicin and concurrent cyclophosphamide. All patients receive the same maintenance therapy with vincristine/prednisone and oral MTX/MP. Intrathecal MTX is administered periodically throughout protocol treatment. Patients with CNS disease at entry receive craniospinal irradiation daily for 5 consecutive days beginning on day 0 of consolidation therapy. All slow early responders at diagnosis receive cranial irradiation daily for 5 consecutive days during consolidation therapy. Patients with testicular leukemia at diagnosis receive bilateral testicular irradiation daily for 5 consecutive days during consolidation chemotherapy. Groups 1 and 2: Maintenance therapy continues for 2 years for girls or 3 years for boys beyond completion of consolidation therapy. Patients are followed every 4-6 weeks for 1 year, every 3 months for 1 year, every 6 months for 2 years, and then annually thereafter.
PROJECTED ACCRUAL: Approximately 1,520 patients will be accrued for this study over 4 years.
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: Arm A - Standard BFM of Standard Duration (RER) Induction chemotherapy Days 0 - 7. Prednisone 60 mg/m² PO 4 x day. Vincristine sulfate 1.5 mg/m² IV push weekly x 2 Days 0 and 7. Daunomycin (daunorubicin hydrochloride) 25 mg/m² IV push (over 15 min.) weekly x 2 Days 0 and 7. IT Cytosine Arabinoside (cytarabine, Ara-C) Day 0. Asparaginase 6000 IU/m² IM x 3 Days 3, 5, and 7. Day 7 Bone Marrow. Consolidation (Phase II) (5 weeks) Prednisone Taper, cyclophosphamide, cytosine arabinoside (Ara-C), mercaptopurine, vincristine sulfate, pegaspargase, IT Methotrexate and radiation therapy. |
Drug: asparaginase
Given IV
Other Names:
Drug: cyclophosphamide
Given IV
Other Names:
Drug: cytarabine
Given IV
Other Names:
Drug: daunorubicin hydrochloride
Given IV
Other Names:
Drug: dexamethasone
Given IV
Other Names:
Drug: doxorubicin hydrochloride
Given IV
Other Names:
Drug: idarubicin
Given IV
Other Names:
Drug: mercaptopurine
Given IV
Other Names:
Drug: methotrexate
Given PO
Other Names:
Drug: pegaspargase
Given IV
Other Names:
Drug: prednisone
Given PO
Other Names:
Drug: thioguanine
Given IV
Other Names:
Drug: vincristine sulfate
Given IV
Other Names:
Radiation: radiation therapy
|
| Experimental: Arm B - Standard BFM with Double Delayed Intensification (RER) Induction chemotherapy Days 0 - 7. Prednisone 60 mg/m² PO 4 x day. Vincristine sulfate 1.5 mg/m² IV push weekly x 2 Days 0 and 7. Daunomycin (daunorubicin hydrochloride) 25 mg/m² IV push (over 15 min.) weekly x 2 Days 0 and 7. IT Cytosine Arabinoside (cytarabine, Ara-C) Day 0. Asparaginase 6000 IU/m² IM x 3 Days 3, 5, and 7. Day 7 Bone Marrow Consolidation (5 weeks) (Phase II) Prednisone Taper, cyclophosphamide, cytosine arabinoside (Ara-C), mercaptopurine, vincristine sulfate, pegaspargase, IT Methotrexate and radiation therapy. |
Drug: asparaginase
Given IV
Other Names:
Drug: cyclophosphamide
Given IV
Other Names:
Drug: cytarabine
Given IV
Other Names:
Drug: daunorubicin hydrochloride
Given IV
Other Names:
Drug: dexamethasone
Given IV
Other Names:
Drug: doxorubicin hydrochloride
Given IV
Other Names:
Drug: idarubicin
Given IV
Other Names:
Drug: mercaptopurine
Given IV
Other Names:
Drug: methotrexate
Given PO
Other Names:
Drug: pegaspargase
Given IV
Other Names:
Drug: prednisone
Given PO
Other Names:
Drug: thioguanine
Given IV
Other Names:
Drug: vincristine sulfate
Given IV
Other Names:
Radiation: radiation therapy
|
| Experimental: Arm C - Augumented BFM of Standard Duration (RER) Induction chemotherapy Days 0 - 7. Prednisone 60 mg/m² PO 4 x day. Vincristine sulfate 1.5 mg/m² IV push weekly x 2 Days 0 and 7. Daunomycin (daunorubicin hydrochloride) 25 mg/m² IV push (over 15 min.) weekly x 2 Days 0 and 7. IT Cytosine Arabinoside (cytarabine, Ara-C) Day 0. Asparaginase 6000 IU/m² IM x 3 Days 3, 5, and 7. Day 7 Bone Marrow Consolidation (9 weeks) (Phase II) Prednisone Taper, cyclophosphamide, cytosine arabinoside (Ara-C), mercaptopurine, vincristine sulfate, pegaspargase, IT Methotrexate and radiation therapy. |
Drug: asparaginase
Given IV
Other Names:
Drug: cyclophosphamide
Given IV
Other Names:
Drug: cytarabine
Given IV
Other Names:
Drug: daunorubicin hydrochloride
Given IV
Other Names:
Drug: dexamethasone
Given IV
Other Names:
Drug: doxorubicin hydrochloride
Given IV
Other Names:
Drug: idarubicin
Given IV
Other Names:
Drug: mercaptopurine
Given IV
Other Names:
Drug: methotrexate
Given PO
Other Names:
Drug: pegaspargase
Given IV
Other Names:
Drug: prednisone
Given PO
Other Names:
Drug: thioguanine
Given IV
Other Names:
Drug: vincristine sulfate
Given IV
Other Names:
Radiation: radiation therapy
|
| Experimental: Arm D - Augmented BFM with Dbl Delayed Intensification (RER) Induction chemotherapy Days 0 - 7. Prednisone 60 mg/m² PO 4 x day. Vincristine sulfate 1.5 mg/m² IV push weekly x 2 Days 0 and 7. Daunomycin (daunorubicin hydrochloride) 25 mg/m² IV push (over 15 min.) weekly x 2 Days 0 and 7. IT Cytosine Arabinoside (cytarabine, Ara-C) Day 0. Asparaginase 6000 IU/m² IM x 3 Days 3, 5, and 7. Day 7 Bone Marrow Consolidation (9 weeks) (Phase II) Prednisone Taper, cyclophosphamide, cytosine arabinoside (Ara-C), mercaptopurine, vincristine sulfate, pegaspargase, IT Methotrexate and radiation therapy. |
Drug: asparaginase
Given IV
Other Names:
Drug: cyclophosphamide
Given IV
Other Names:
Drug: cytarabine
Given IV
Other Names:
Drug: daunorubicin hydrochloride
Given IV
Other Names:
Drug: dexamethasone
Given IV
Other Names:
Drug: doxorubicin hydrochloride
Given IV
Other Names:
Drug: idarubicin
Given IV
Other Names:
Drug: mercaptopurine
Given IV
Other Names:
Drug: methotrexate
Given PO
Other Names:
Drug: pegaspargase
Given IV
Other Names:
Drug: prednisone
Given PO
Other Names:
Drug: thioguanine
Given IV
Other Names:
Drug: vincristine sulfate
Given IV
Other Names:
Radiation: radiation therapy
|
Outcome Measures
Primary Outcome Measures
- Event Free Survival [from the time of randomization where the life table events will consist of the first occurrence of the following events: failure to achieve remission, leukemic relapse at any site, death, or occurrence of a second malignancy.]
The primary outcome index used in examining most of the randomized treatment groups will be event-free survival (EFS).
Eligibility Criteria
Criteria
DISEASE CHARACTERISTICS: Acute lymphocytic leukemia (ALL) with M3 bone marrow No FAB L3 morphology CNS or overt testicular leukemia at diagnosis allowed High risk status 10-21 years old with any white blood count (WBC) 1-9 years old with WBC of 50,000/mm3 or greater
PATIENT CHARACTERISTICS: Age: 1 to 21 Performance status: Not specified Life expectancy:
Not specified Hematopoietic: See Disease Characteristics Hepatic: Not specified Renal: Not specified
PRIOR CONCURRENT THERAPY: No prior therapy for ALL except: Emergency therapy for blast crisis, superior vena cava syndrome, or renal failure due to leukemic infiltration Biologic therapy: Not specified Chemotherapy: Intrathecal cytarabine or methotrexate allowed at diagnostic lumbar puncture Induction therapy must begin within 72 hours after intrathecal injection Endocrine therapy: At least 1-2 months since prior prednisone, for less than 48 hours, for reactive airway disease Inhalational steroids allowed Radiotherapy: Not specified 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 | 92868 |
| 5 | UCSF Cancer Center and Cancer Research Institute | San Francisco | California | United States | 94143-0128 |
| 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 | 60637-1470 |
| 9 | Indiana University Cancer Center | Indianapolis | Indiana | United States | 46202-5289 |
| 10 | Holden Comprehensive Cancer Center at The University of Iowa | Iowa City | Iowa | United States | 52242-1009 |
| 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 | Missouri | United States | 64108 |
| 15 | University of Nebraska Medical Center | Omaha | Nebraska | United States | 68198-3330 |
| 16 | Saint Peter's University Hospital | New Brunswick | New Jersey | United States | 08901-1780 |
| 17 | NYU School of Medicine's Kaplan Comprehensive Cancer Center | New York | New York | United States | 10016 |
| 18 | Memorial Sloan-Kettering Cancer Center | New York | New York | United States | 10021 |
| 19 | Mount Sinai School of Medicine | New York | New York | United States | 10029 |
| 20 | Herbert Irving Comprehensive Cancer Center | New York | New York | United States | 10032 |
| 21 | Lineberger Comprehensive Cancer Center, UNC | Chapel Hill | North Carolina | United States | 27599-7295 |
| 22 | Children's Hospital Medical Center - Cincinnati | Cincinnati | Ohio | United States | 45229-3039 |
| 23 | Ireland Cancer Center | Cleveland | Ohio | United States | 44106-5065 |
| 24 | Children's Hospital of Columbus | Columbus | Ohio | United States | 43205-2696 |
| 25 | Doernbecher Children's Hospital | Portland | Oregon | United States | 97201-3098 |
| 26 | Children's Hospital of Philadelphia | Philadelphia | Pennsylvania | United States | 19104 |
| 27 | Children's Hospital of Pittsburgh | Pittsburgh | Pennsylvania | United States | 15213 |
| 28 | Vanderbilt-Ingram Cancer Center | Nashville | Tennessee | United States | 37232-6838 |
| 29 | University of Texas - MD Anderson Cancer Center | Houston | Texas | United States | 77030-4009 |
| 30 | Children's Hospital and Regional Medical Center - Seattle | Seattle | Washington | United States | 98105 |
| 31 | Fred Hutchinson Cancer Research Center | Seattle | Washington | United States | 98109-1024 |
| 32 | University of Wisconsin Comprehensive Cancer Center | Madison | Wisconsin | United States | 53792-6164 |
| 33 | Princess Margaret Hospital for Children | Perth | Western Australia | Australia | 6001 |
| 34 | British Columbia Children's Hospital | Vancouver | British Columbia | Canada | V6H 3V4 |
| 35 | IWK Health Centre | Halifax | Nova Scotia | Canada | B3J 3G9 |
Sponsors and Collaborators
- Children's Oncology Group
- National Cancer Institute (NCI)
Investigators
- Study Chair: Nita L. Seibel, MD, Children's National Research Institute
Study Documents (Full-Text)
None provided.More Information
Publications
- Avramis VI, Panosyan EH. Pharmacokinetic/pharmacodynamic relationships of asparaginase formulations: the past, the present and recommendations for the future. Clin Pharmacokinet. 2005;44(4):367-93. Review.
- Butturini AM, Dorey FJ, Lange BJ, Henry DW, Gaynon PS, Fu C, Franklin J, Siegel SE, Seibel NL, Rogers PC, Sather H, Trigg M, Bleyer WA, Carroll WL. Obesity and outcome in pediatric acute lymphoblastic leukemia. J Clin Oncol. 2007 May 20;25(15):2063-9.
- 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.
- Seibel NL, Asselin BL, Nachman JB, et al.: Treatment of high risk T-cell acute lymphoblastic leukemia (T-ALL): comparison of recent experience of the Children's Cancer Group (CCG) and Pediatric Oncology Group (POG). [Abstract] Blood 104 (11): A-681, 2004.
- 1961
- CCG-1961
- CDR0000064953