• Maximum tolerated dose of alemtuzumab as measured by CTC version 3.0 (Phase I) [ Designated as safety issue: Yes ]
  
• Feasibility and toxicity profile (including dose-limiting toxicity) (Phase II) [ Designated as safety issue: Yes ]
  

• Pharmacokinetics [ Designated as safety issue: No ]
  
• Toxicity profile as measured by CTC version 3.0 (Phase II) [ Designated as safety issue: Yes ]
  
• Correlation of antibody treatment with alemtuzumab and modulation of minimal residual disease (Phase II) [ Designated as safety issue: No ]
  
• Disease-free survival (DFS) (Phase II) [ Designated as safety issue: No ]
  
• Overall survival (OS) (Phase II) [ Designated as safety issue: No ]
  

OBJECTIVES:

• Determine the feasibility and toxicity profiles of escalating doses of alemtuzumab during post-remission intensification therapy in patients with untreated acute lymphoblastic leukemia.
• Determine the maximum tolerated dose of this drug in these patients. (Phase I portion closed to accrual as of 7/5/2005)
• Determine the disease-free and overall survival of patients treated with this regimen.
• Determine whether this drug can further reduce minimal residual disease states in these patients.
• Correlate pretreatment characteristics (e.g., cytogenetics and molecular changes) with disease-free and overall survival in patients treated with this regimen.
• Determine the feasibility of combining this regimen with imatinib mesylate in patients with Philadelphia chromosome-positive disease.

OUTLINE: This is a multicenter, dose-escalation study of alemtuzumab. All courses are 28 days in length except courses 3 and 7 which are 42 days.

Treatment continues in the absence of disease progression or unacceptable toxicity.

• Course 1 (induction): Patients receive daunorubicin IV over 5-60 minutes on days 1-3; cyclophosphamide IV over 15-30 minutes on day 1; vincristine IV over 1-2 minutes on days 1, 8, 15, and 22; oral dexamethasone on days 1-7 and 15-21; asparaginase subcutaneously (SC) on days 5, 8, 11, 15, 18, and 22; and filgrastim (G-CSF) SC once daily beginning on day 4 and continuing until blood counts recover.* Beginning no earlier than day 15, patients with Philadelphia chromosome (Ph)-positive disease also receive oral imatinib mesylate once daily until day 28. Patients > 60 years of age with Ph-positive disease achieving a complete remission are removed from study. NOTE: *Patients 60 years of age and over do not receive cyclophosphamide and receive dexamethasone on days 1-7 only.
• Course 2 (early intensification): After sufficient recovery from course 1, patients receive cyclophosphamide IV over 15-30 minutes on day 1; cytarabine IV over 3 hours on days 1-3; methotrexate intrathecally (IT) on day 1; asparaginase SC on days 15, 18, and 22; and G-CSF once daily beginning on day 4 and continuing until blood counts recover. Patients with Ph-positive disease also receive oral imatinib mesylate once daily on days 1-28.

• Course 3 (CNS prophylaxis): After sufficient recovery from course 2, patients receive vincristine IV over 1-2 minutes, methotrexate IV over 3 hours, and methotrexate IT on days 1, 15, and 29; oral methotrexate every 6 hours for 4 doses beginning 6 hours after the start of methotrexate IV infusion on days 1, 15, and 29; oral mercaptopurine on days 1-35; leucovorin calcium IV over 5-10 minutes on days 2, 16, and 30; and oral leucovorin calcium every 6 hours for 8 doses beginning 12 hours after IV leucovorin calcium on days 3 and 4, 17 and 18, and 31 and 32. Patients with Ph-positive disease also receive oral imatinib mesylate once daily on days 1-42. Patients who have CD52^+ disease as determined by pretreatment immunohistochemistry, and meet all of the following criteria proceed to course 4.

  • M_0 or M_1 marrow with absolute neutrophil count at least 1,500/mm^3 and platelet count at least 100,000/mm^3
  • AST less than 3 times upper limit of normal
  • Cytomegalovirus polymerase chain reaction negative
  • No serious infection All other patients proceed to course 5.

• Course 4 (immunotherapy):

  • Phase I: Patients receive alemtuzumab SC 3 times per week for 4 weeks. Cohorts of at least 6 patients receive escalating doses of alemtuzumab until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 4 of 6 or 5 of 12 patients experience dose-limiting toxicity.
  • Phase II: Patients receive treatment as in phase I at the MTD of alemtuzumab.
• Course 5 (late intensification): Beginning 2-6 weeks after the completion of course 4, patients receive treatment as in course 1 except with dexamethasone on days 1-7 only.
• Course 6 (late intensification): After sufficient recovery from course 5, patients receive treatment as in course 2.
• Course 7 (CNS intensification): After sufficient recovery from course 6, patients receive treatment as in course 3.
• Course 8 (maintenance therapy): After completion of courses 1-7 and in the absence of disease progression, patients receive maintenance therapy.

Patients receive oral mercaptopurine daily; vincristine IV over 1-2 minutes on day 1; oral methotrexate once weekly on days 1, 8, 15, and 22; and oral dexamethasone on days 1-5. Courses repeat every 28 days for up to 24 months from study entry. Patients with Ph-positive disease also receive oral imatinib mesylate once daily beginning on day 1 and continuing until completion of study therapy.

For testicular disease at study entry that persists or worsens after 4 weeks of therapy or testicular disease that develops after study therapy has begun, patients undergo testicular radiotherapy once daily 5 days a week for 13 treatments.

Patients with CNS leukemia receive methotrexate IT 1-2 times weekly for 5 weeks and leucovorin calcium IV 24 hours after each methotrexate dose.

Patients also undergo cranial radiotherapy once daily 5 days a week for 12 treatments. Radiotherapy begins on day 5 of course 1 for patients with CNS leukemia at study entry or the day after diagnosis of CNS leukemia for patients who develop disease after study therapy has begun. If remission is achieved, patients continue study therapy and receive methotrexate once monthly for 12 months.

Patients are followed every 3 months for 1 year, every 6 months for 2 years, and then annually for up to 10 years from study entry.

PROJECTED ACCRUAL: A total of 18-36 patients will be accrued for the phase I portion of the study within 5-12 months (closed to accrual as of 7/5/2005).

A total of 236-282 patients will be accrued for the phase II portion of the study within 33-42 months.