PRIMARY OBJECTIVES: I. To determine the clinical efficacy (2-year disease-free survival rate) of nilotinib and combination chemotherapy in adult patients newly diagnosed with Philadelphia chromosome positive B-cell acute lymphoblastic leukemia or blast crisis of chronic myeloid leukemia. SECONDARY OBJECTIVES: I. Determine the 2-year overall survival rate. II. Determine the complete response (CR) rates (hematological, cytogenetic, and molecular) in patients treated with this regimen. III. Determine the CR duration in patients treated with this regimen. IV. Assess the safety and toxicity of this regimen by National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. TERTIARY OBJECTIVES: I. Assess the prognostic and predictive factors for patients treated with this regimen. II. Assess the cerebrospinal fluid (CSF) penetration for Nilotinib (CSF Nilotinib levels) in humans. III. Assess the Abelson (ABL) kinase domain mutations frequency at diagnosis, during therapy, and at relapse. OUTLINE: INDUCTION AND CONSOLIDATION SCHEDULE A (COURSES 1, 3, 5, 7): Patients receive cyclophosphamide intravenously (IV) twice daily (BID) over 2 hours on days 1-3, mesna IV continuously on days 1-3, doxorubicin hydrochloride IV push on day 4, vincristine sulfate IV on days 4 and 11, dexamethasone IV or orally (PO) on days 1-4 and 11-14, methotrexate intrathecally (IT) on day 2, cytarabine IT on day 8, and nilotinib PO BID on days 1-14. Patients with CD20-positive disease also receive rituximab IV on days 1 and 11. INDUCTION AND CONSOLIDATION SCHEDULE B (COURSES 2, 4, 6, 8): Patients receive methotrexate IV continuously over 24 hours on day 1, cytarabine IV over 2 hours on days 2-3, leucovorin calcium IV every 6 hours on days 2-3, methotrexate IT on day 2, cytarabine IT on day 8, and nilotinib PO BID on days 1-14. Patients with CD20-positive disease also receive rituximab IV on days 1 and 11. MAINTENANCE (COURSES 9-32): Patients receive nilotinib PO BID on days 1-28 (days 1-14 for minimal residual disease [MRD]-positive patients), vincristine sulfate IV on day 1, and prednisone PO on days 1 to 5. Patients also receive rituximab IV on day 1 of each course if CD20-positive, every sixth course if MRD-negative, or every third course if MRD-positive. INTENSIFICATION: Patients receive treatment as in Schedule A in courses 14 and 21 of maintenance therapy and treatment as in Schedule B in courses 15 and 22 of maintenance therapy. DELAYED MAINTENANCE (COURSES 33-36): Patients receive nilotinib PO BID on days 1 to 84. Treatment repeats every 84 days for up to 4 courses. Treatment continues in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up every 6-12 months for 4 years.
Last updated: 03/05/2013