Combination Chemotherapy in Treating Adults With Acute Lymphocytic Leukemia
NCT ID: NCT00002531
Last Updated: 2013-09-17
Study Results
Results pending
The study team has not published outcome measurements, participant flow, or safety data for this trial yet. Check back later for updates.
Basic Information
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Recruitment Status
UNKNOWN
Clinical Phase
PHASE2
Study Classification
INTERVENTIONAL
Study Start Date
1993-01-31
Brief Summary
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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 may kill more cancer cells.
PURPOSE: Randomized phase II trial to study the effectiveness of various combination chemotherapy regimens in treating patients with acute lymphocytic leukemia.
PURPOSE: Randomized phase II trial to study the effectiveness of various combination chemotherapy regimens in treating patients with acute lymphocytic leukemia.
Detailed Description
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OBJECTIVES: I. Develop risk-adapted therapy for patients with low-risk, high-risk, T-cell, or B-cell acute lymphocytic leukemia (ALL). II. Determine the complete remission rate in these patients treated with the following strategies: increased doses of cyclophosphamide during induction and reinduction, early use of high-dose cytarabine plus mitoxantrone (for high-risk patients), and increased doses of methotrexate (for B-cell ALL patients). III. Determine the duration of remission and survival of patients in all risk groups treated with intensified consolidation and subtype-specific chemotherapy. IV. Compare the effects of intensified vs conventional maintenance therapy in patients of all risk groups.
OUTLINE: This is a randomized, multicenter study. Patients are assigned to 1 of 4 treatment groups based on disease status. Patients in groups 1-3 with a large leukemic cell mass, in particular those with a WBC greater than 25,000/mm3 and/or marked organomegaly, receive preinduction therapy comprising oral prednisolone (PRDL) 3 times a day on days 1-7 and vincristine (VCR) IV on day 1. Group 1 (low-risk acute lymphocytic leukemia (ALL)): First induction therapy: Patients receive oral PRDL 3 times a day on days 1-7 of weeks 1-4, asparaginase (ASP) IV over 30 minutes on days 1-7 of weeks 3 and 4, VCR IV and daunorubicin IV over 30 minutes on day 1 of weeks 1-4, and methotrexate (MTX) IT on day 1 of week 1. Patients who achieve complete remission (CR) after first induction therapy proceed to first consolidation therapy on group 1. Second induction therapy: Patients receive oral cyclophosphamide (CTX) IV on day 1 of weeks 5, 7, and 9; cytarabine (ARA-C) IV over 1 hour or subcutaneously on days 3-6 and MTX IT on day 3 of weeks 5-8; and oral mercaptopurine (MP) on days 1-7 of weeks 5-8 and day 1 of week 9. Patients who achieve CR during second induction therapy undergo prophylactic cranial irradiation 5 days a week for 2.4 weeks. Patients who achieve CR after second induction therapy proceed to group 3. First consolidation therapy: Patients receive high-dose MTX IV continuously with leucovorin calcium (CF) rescue on day 1, ASP IV over 1 hour on day 2, and oral MP on days 1-5 of weeks 13 and 15; and teniposide (VM-26) IV over 1 hour and ARA-C IV over 1 hour on days 1-5 of week 17. Triple intrathecal therapy (TIT) comprising MTX, ARA-C, and dexamethasone (DM) is also administered on day 1 of week 17. First reinduction therapy: Patients receive oral PRDL three times a day on days 1-7 and VCR IV and doxorubicin (DOX) IV over 30 minutes on day 1 of weeks 21-24, and TIT on day 1 of week 21. Second reinduction therapy: Patients receive CTX IV and TIT on day 1 of week 25, and ARA-C IV over 1 hour on days 3-6 and oral thioguanine (TG) on days 1-7 of weeks 25 and 26. Second consolidation therapy: Patients receive oral MP daily and oral MTX weekly during weeks 29-32, 34-38, 40-44, 46-50, and 52; high-dose MTX, CF rescue, and ASP as in first consolidation therapy during weeks 33 and 45; and VM-26, ARA-C, and TIT as in first consolidation therapy during weeks 39 and 51. Group 2 (T-cell ALL with or without mediastinal involvement): First induction therapy: Patients receive treatment as in first induction therapy on group 1. Patients with residual tumor greater than 2 cm after first induction therapy also undergo mediastinal radiotherapy 5 days a weeks for 2.4-2.7 weeks concurrently with prophylactic cranial irradiation. Second induction therapy: Patients receive treatment as in second induction therapy on group 1. First consolidation therapy: Patients receive high-dose ARA-C IV over 3 hours every 12 hours on days 1-4 and mitoxantrone (DHAD) IV over 30 minutes on days 3-5 during week 13; and high-dose MTX, CF rescue, ASP, and MP as in first consolidation therapy on group 1 during week 17. First reinduction therapy: Patients receive treatment as in first reinduction therapy on group 1. Second reinduction therapy: Patients receive treatment as in second reinduction therapy on group 1. Second consolidation therapy: Patients receive MP and MTX as in second consolidation therapy on group 1; CTX IV, ARA-C IV continuously, and TIT on day 1 during weeks 33 and 45; and VM-26, ARA-C, and TIT as in first consolidation therapy on group 1 during weeks 39 and 51. Group 3 (high-risk ALL): First induction therapy: Patients receive treatment as in first induction therapy on group 1. Second induction therapy: Patients receive CNS-effective chemotherapy comprising high-dose ARA-C every 12 hours on days 1-4 and DHAD IV over 30 minutes on days 3-5 during week 6. First consolidation therapy: Patients receive high-dose MTX, CF rescue, and ASP as in first consolidation therapy on group 1; and CTX, ARA-C, and TIT as in second consolidation therapy on group 2 during week 17. First reinduction therapy: Patients receive treatment as in first reinduction therapy on group 1. Second reinduction therapy: Patients receive treatment as in second reinduction therapy on group 1. Second consolidation therapy: Patients receive MP and MTX as in second consolidation therapy on group 1; treatment as in second induction therapy on group 3 during week 33; high-dose MTX, CF rescue, ASP, and MP as in first consolidation therapy on group 1 during week 39; CTX, ARA-C, and TIT as in second consolidation therapy on group 2 during week 45; and VM-26, ARA-C, and TIT as in first consolidation therapy on group 1 during week 51. Groups 1-3: Patients who are age 15 to 50, achieve first CR, and have a suitable donor undergo allogeneic bone marrow transplantation. Patients who are under age 40 undergo bone marrow transplantation from a matched unrelated donor. Patients who have Philadelphia chromosome/bcr-abl positive disease and no suitable donor undergo purged autologous peripheral blood stem cell transplantation instead of reinduction therapy during first CR. CNS therapy: Patients with CNS disease at entry receive TIT 2 or 3 times weekly beginning immediately upon diagnosis and continuing until 5 doses after blasts are cleared from the CSF. Patients on group 1 and 2 undergo irradiation of the entire neuraxis 5 days a week for 2.7-3.2 weeks during second induction therapy. Maintenance therapy: After completion of 1 year of treatment on group 1, 2, or 3, patients are randomized to 1 of 2 treatment arms. Arm I: Patients receive MP daily and MTX weekly on odd-numbered months between months 13-30; CTX, ARA-C, and TIT as in second consolidation therapy on group 2 during months 14, 20, and 26; VM-26, ARA-C, and TIT as in first consolidation therapy on group 1 during months 16, 22, and 28; and high-dose MTX, CF rescue, and ASP as in first consolidation therapy on group 1 during months 18, 24, and 30. Arm II: Patients receive MP plus MTX as in second consolidation therapy on group 1 continuously and TIT every 2 months during months 13-30. Group 4 (B-cell ALL): Pretreatment: Patients who are age 50 and under receive CTX IV over 1 hour and oral PRDL 3 times a day on days 1-5. Patients who are over age 50 receive CTX IV and oral DM on days 1, 3, and 5. Treatment: Patients receive alternating therapy on blocks A and B. Block A therapy consists of VCR IV, MTX IV continuously, and CF rescue on day 1; ifosfamide IV over 1 hour and oral DM on days 1-5; VM-26 IV over 1 hour and ARA-C IV over 1 hour every 12 hours on days 4 and 5; and TIT on days 1 and 5. Block B therapy consists of VCR IV, MTX IV continuously, and CF rescue on day 1; CTX IV over 1 hour and oral DM on days 1-5; DOX IV over 15 minutes on days 4 and 5; and TIT on days 1 and 5. Blocks A and B continue every 3 weeks for a total of 6 courses. Patients who have not achieved CR after 3 courses or who develop disease progression at any time may optionally receive vindesine, ARA-C, etoposide, and DM. Patients with CNS disease undergo craniospinal irradiation after 2 courses of systemic chemotherapy (block A and B therapy). Patients receive TIT 2-3 times weekly until CSF is clear after block A therapy only if response is unsatisfactory.
PROJECTED ACCRUAL: Approximately 700 patients will be accrued for this study within 4 years.
OUTLINE: This is a randomized, multicenter study. Patients are assigned to 1 of 4 treatment groups based on disease status. Patients in groups 1-3 with a large leukemic cell mass, in particular those with a WBC greater than 25,000/mm3 and/or marked organomegaly, receive preinduction therapy comprising oral prednisolone (PRDL) 3 times a day on days 1-7 and vincristine (VCR) IV on day 1. Group 1 (low-risk acute lymphocytic leukemia (ALL)): First induction therapy: Patients receive oral PRDL 3 times a day on days 1-7 of weeks 1-4, asparaginase (ASP) IV over 30 minutes on days 1-7 of weeks 3 and 4, VCR IV and daunorubicin IV over 30 minutes on day 1 of weeks 1-4, and methotrexate (MTX) IT on day 1 of week 1. Patients who achieve complete remission (CR) after first induction therapy proceed to first consolidation therapy on group 1. Second induction therapy: Patients receive oral cyclophosphamide (CTX) IV on day 1 of weeks 5, 7, and 9; cytarabine (ARA-C) IV over 1 hour or subcutaneously on days 3-6 and MTX IT on day 3 of weeks 5-8; and oral mercaptopurine (MP) on days 1-7 of weeks 5-8 and day 1 of week 9. Patients who achieve CR during second induction therapy undergo prophylactic cranial irradiation 5 days a week for 2.4 weeks. Patients who achieve CR after second induction therapy proceed to group 3. First consolidation therapy: Patients receive high-dose MTX IV continuously with leucovorin calcium (CF) rescue on day 1, ASP IV over 1 hour on day 2, and oral MP on days 1-5 of weeks 13 and 15; and teniposide (VM-26) IV over 1 hour and ARA-C IV over 1 hour on days 1-5 of week 17. Triple intrathecal therapy (TIT) comprising MTX, ARA-C, and dexamethasone (DM) is also administered on day 1 of week 17. First reinduction therapy: Patients receive oral PRDL three times a day on days 1-7 and VCR IV and doxorubicin (DOX) IV over 30 minutes on day 1 of weeks 21-24, and TIT on day 1 of week 21. Second reinduction therapy: Patients receive CTX IV and TIT on day 1 of week 25, and ARA-C IV over 1 hour on days 3-6 and oral thioguanine (TG) on days 1-7 of weeks 25 and 26. Second consolidation therapy: Patients receive oral MP daily and oral MTX weekly during weeks 29-32, 34-38, 40-44, 46-50, and 52; high-dose MTX, CF rescue, and ASP as in first consolidation therapy during weeks 33 and 45; and VM-26, ARA-C, and TIT as in first consolidation therapy during weeks 39 and 51. Group 2 (T-cell ALL with or without mediastinal involvement): First induction therapy: Patients receive treatment as in first induction therapy on group 1. Patients with residual tumor greater than 2 cm after first induction therapy also undergo mediastinal radiotherapy 5 days a weeks for 2.4-2.7 weeks concurrently with prophylactic cranial irradiation. Second induction therapy: Patients receive treatment as in second induction therapy on group 1. First consolidation therapy: Patients receive high-dose ARA-C IV over 3 hours every 12 hours on days 1-4 and mitoxantrone (DHAD) IV over 30 minutes on days 3-5 during week 13; and high-dose MTX, CF rescue, ASP, and MP as in first consolidation therapy on group 1 during week 17. First reinduction therapy: Patients receive treatment as in first reinduction therapy on group 1. Second reinduction therapy: Patients receive treatment as in second reinduction therapy on group 1. Second consolidation therapy: Patients receive MP and MTX as in second consolidation therapy on group 1; CTX IV, ARA-C IV continuously, and TIT on day 1 during weeks 33 and 45; and VM-26, ARA-C, and TIT as in first consolidation therapy on group 1 during weeks 39 and 51. Group 3 (high-risk ALL): First induction therapy: Patients receive treatment as in first induction therapy on group 1. Second induction therapy: Patients receive CNS-effective chemotherapy comprising high-dose ARA-C every 12 hours on days 1-4 and DHAD IV over 30 minutes on days 3-5 during week 6. First consolidation therapy: Patients receive high-dose MTX, CF rescue, and ASP as in first consolidation therapy on group 1; and CTX, ARA-C, and TIT as in second consolidation therapy on group 2 during week 17. First reinduction therapy: Patients receive treatment as in first reinduction therapy on group 1. Second reinduction therapy: Patients receive treatment as in second reinduction therapy on group 1. Second consolidation therapy: Patients receive MP and MTX as in second consolidation therapy on group 1; treatment as in second induction therapy on group 3 during week 33; high-dose MTX, CF rescue, ASP, and MP as in first consolidation therapy on group 1 during week 39; CTX, ARA-C, and TIT as in second consolidation therapy on group 2 during week 45; and VM-26, ARA-C, and TIT as in first consolidation therapy on group 1 during week 51. Groups 1-3: Patients who are age 15 to 50, achieve first CR, and have a suitable donor undergo allogeneic bone marrow transplantation. Patients who are under age 40 undergo bone marrow transplantation from a matched unrelated donor. Patients who have Philadelphia chromosome/bcr-abl positive disease and no suitable donor undergo purged autologous peripheral blood stem cell transplantation instead of reinduction therapy during first CR. CNS therapy: Patients with CNS disease at entry receive TIT 2 or 3 times weekly beginning immediately upon diagnosis and continuing until 5 doses after blasts are cleared from the CSF. Patients on group 1 and 2 undergo irradiation of the entire neuraxis 5 days a week for 2.7-3.2 weeks during second induction therapy. Maintenance therapy: After completion of 1 year of treatment on group 1, 2, or 3, patients are randomized to 1 of 2 treatment arms. Arm I: Patients receive MP daily and MTX weekly on odd-numbered months between months 13-30; CTX, ARA-C, and TIT as in second consolidation therapy on group 2 during months 14, 20, and 26; VM-26, ARA-C, and TIT as in first consolidation therapy on group 1 during months 16, 22, and 28; and high-dose MTX, CF rescue, and ASP as in first consolidation therapy on group 1 during months 18, 24, and 30. Arm II: Patients receive MP plus MTX as in second consolidation therapy on group 1 continuously and TIT every 2 months during months 13-30. Group 4 (B-cell ALL): Pretreatment: Patients who are age 50 and under receive CTX IV over 1 hour and oral PRDL 3 times a day on days 1-5. Patients who are over age 50 receive CTX IV and oral DM on days 1, 3, and 5. Treatment: Patients receive alternating therapy on blocks A and B. Block A therapy consists of VCR IV, MTX IV continuously, and CF rescue on day 1; ifosfamide IV over 1 hour and oral DM on days 1-5; VM-26 IV over 1 hour and ARA-C IV over 1 hour every 12 hours on days 4 and 5; and TIT on days 1 and 5. Block B therapy consists of VCR IV, MTX IV continuously, and CF rescue on day 1; CTX IV over 1 hour and oral DM on days 1-5; DOX IV over 15 minutes on days 4 and 5; and TIT on days 1 and 5. Blocks A and B continue every 3 weeks for a total of 6 courses. Patients who have not achieved CR after 3 courses or who develop disease progression at any time may optionally receive vindesine, ARA-C, etoposide, and DM. Patients with CNS disease undergo craniospinal irradiation after 2 courses of systemic chemotherapy (block A and B therapy). Patients receive TIT 2-3 times weekly until CSF is clear after block A therapy only if response is unsatisfactory.
PROJECTED ACCRUAL: Approximately 700 patients will be accrued for this study within 4 years.
Conditions
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Leukemia
Keywords
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untreated adult acute lymphoblastic leukemia
T-cell adult acute lymphoblastic leukemia
B-cell adult acute lymphoblastic leukemia
non-T, non-B adult acute lymphoblastic leukemia
Study Design
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Primary Study Purpose
TREATMENT
Interventions
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asparaginase
Intervention Type
DRUG
cyclophosphamide
Intervention Type
DRUG
cytarabine
Intervention Type
DRUG
daunorubicin hydrochloride
Intervention Type
DRUG
dexamethasone
Intervention Type
DRUG
doxorubicin hydrochloride
Intervention Type
DRUG
etoposide
Intervention Type
DRUG
ifosfamide
Intervention Type
DRUG
leucovorin calcium
Intervention Type
DRUG
mercaptopurine
Intervention Type
DRUG
methotrexate
Intervention Type
DRUG
mitoxantrone hydrochloride
Intervention Type
DRUG
prednisolone
Intervention Type
DRUG
teniposide
Intervention Type
DRUG
thioguanine
Intervention Type
DRUG
vincristine sulfate
Intervention Type
DRUG
vindesine
Intervention Type
DRUG
allogeneic bone marrow transplantation
Intervention Type
PROCEDURE
peripheral blood stem cell transplantation
Intervention Type
PROCEDURE
radiation therapy
Intervention Type
RADIATION
Eligibility Criteria
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Inclusion Criteria
DISEASE CHARACTERISTICS: Diagnosis of low-risk acute lymphocytic leukemia (ALL) (common ALL or pre-B-cell) Must meet 1 of the following 2 conditions: Age 51 to 65 and meets the following criteria: No mediastinal mass No T-cell or B-cell disease Age 15 to 50 and meets the following criteria: Philadelphia chromosome (Ph) negative bcr-abl negative Initial WBC less than 30,000/mm3 OR Diagnosis of T-cell ALL with or without mediastinal involvement Age 15 to 50 OR Diagnosis of high-risk ALL (common ALL or pre-B-cell) Age 15 to 50 and meets 1 of the following criteria: Ph positive bcr-abl positive Pre-pre-B-cell disease, i.e., t(4;11) Initial WBC greater than 30,000/mm3 OR Diagnosis of B-cell ALL
PATIENT CHARACTERISTICS: Age: See Disease Characteristics 15 to 65 Performance status: Not specified Life expectancy: Not specified Hematopoietic: See Disease Characteristics Hepatic: Not specified Renal: No renal failure Cardiovascular: No cardiomyopathy Other: HIV-1 and HIV-2 negative No severe psychiatric disease
PRIOR CONCURRENT THERAPY: Biologic therapy: Not specified Chemotherapy: No prior cytostatic drugs except vincristine Endocrine therapy: Prior corticosteroids allowed Radiotherapy: Not specified Surgery: Not specified Other: No more than 2 weeks of prior therapy No other prior cytostatic drugs
PATIENT CHARACTERISTICS: Age: See Disease Characteristics 15 to 65 Performance status: Not specified Life expectancy: Not specified Hematopoietic: See Disease Characteristics Hepatic: Not specified Renal: No renal failure Cardiovascular: No cardiomyopathy Other: HIV-1 and HIV-2 negative No severe psychiatric disease
PRIOR CONCURRENT THERAPY: Biologic therapy: Not specified Chemotherapy: No prior cytostatic drugs except vincristine Endocrine therapy: Prior corticosteroids allowed Radiotherapy: Not specified Surgery: Not specified Other: No more than 2 weeks of prior therapy No other prior cytostatic drugs
Minimum Eligible Age
15 Years
Maximum Eligible Age
65 Years
Eligible Sex
ALL
Accepts Healthy Volunteers
No
Sponsors
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Johann Wolfgang Goethe University Hospital
OTHER
Sponsor Role
lead
Principal Investigators
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Dieter Hoelzer, MD, PhD
Role: STUDY_CHAIR
Johann Wolfgang Goethe University Hospital
Locations
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Klinikum der J.W. Goethe Universitaet
Frankfurt, , Germany
Site Status
Countries
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Germany
References
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Bruggemann M, Raff T, Flohr T, Gokbuget N, Nakao M, Droese J, Luschen S, Pott C, Ritgen M, Scheuring U, Horst HA, Thiel E, Hoelzer D, Bartram CR, Kneba M; German Multicenter Study Group for Adult Acute Lymphoblastic Leukemia. Clinical significance of minimal residual disease quantification in adult patients with standard-risk acute lymphoblastic leukemia. Blood. 2006 Feb 1;107(3):1116-23. doi: 10.1182/blood-2005-07-2708. Epub 2005 Sep 29.
Reference Type
BACKGROUND
Burmeister T, Goekbuget N, Schwartz S, et al.: Outcome of adult ALL patients with fusion transcript E2A-PBX1: results from the GMALL therapy trials 5/93 and 6/99. [Abstract] Blood 108 (11): A-1888, 2006.
Reference Type
BACKGROUND
Other Identifiers
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GER-GMALL-ALL-05/93
Identifier Type: -
Identifier Source: secondary_id
EU-93002
Identifier Type: -
Identifier Source: secondary_id
CDR0000078421
Identifier Type: -
Identifier Source: org_study_id