combination chemotherapy in treating adults with acute lymphocytic leukemia

Conditions: Leukemia

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 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.

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.

Eligibility 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

Keywords: 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