Nilotinib and Combination Chemotherapy in Treating Patients With Newly Diagnosed Acute Lymphoblastic Leukemia

OBJECTIVES:

Primary

• To determine the clinical efficacy of nilotinib and combination chemotherapy, in terms of hematologic and molecular complete remission (CR) rates, in patients with newly diagnosed Philadelphia chromosome-positive acute lymphoblastic leukemia or acute mixed lineage leukemia.

Secondary

• To establish the prognostic factors for patients treated with this regimen.
• To determine the duration of CR in patients treated with this regimen.
• To determine the duration of progression-free and overall survival of these patients.
• To determine the toxicity of this regimen in these patients.

OUTLINE: This is a multicenter study. Patients are stratified according to age (15 to 64 years vs ≥ 65 years).

• Induction therapy: Patients receive daunorubicin hydrochloride IV continuously over 24 hours on days 1-3, vincristine sulfate IV on days 1 and 8, and oral prednisolone on days 1-14. Patients undergo bone marrow examination on day 14. Patients in hematologic remission proceed to consolidation therapy. Patients with residual leukemic cells > 5% receive an additional dose of daunorubicin hydrochloride IV continuously over 24 hours on day 15 before proceeding to consolidation therapy.
• Consolidation therapy: For course 1, patients receive daunorubicin hydrochloride IV continuously over 24 hours on days 1 and 2, vincristine sulfate IV on days 1 and 8, and oral prednisolone on days 1-14. For courses 2 and 4, patients receive cytarabine IV over 2 hours and etoposide IV over 3 hours on days 1-4. For courses 3 and 5, patients receive methotrexate IV continuously over 36 hours on days 1, 2, 15, and 16 and leucovorin calcium IV every 6 hours for 3 doses and then orally until blood methotrexate levels are in a safe range.

Patients also receive oral nilotinib twice daily beginning on day 8 of induction therapy and continuing until the completion of consolidation therapy.

After completion of consolidation therapy, patients with a hematopoietic stem cell donor proceed to allogeneic hematopoietic stem cell transplantation (HSCT). Patients who do not undergo HSCT continue to receive oral nilotinib twice daily for up to 2 years after completion of consolidation therapy.

After completion of study therapy, patients are followed periodically for up to 1 year.

DISEASE CHARACTERISTICS:

• Newly diagnosed acute lymphoblastic leukemia or acute mixed lineage leukemia

• Positive for Bcr-Abl fusion transcript (Philadelphia chromosome-positive disease) by RT-PCR

PATIENT CHARACTERISTICS:

• ECOG performance status 0-2
• Total bilirubin < 2 mg/dL
• SGOT < 3 times upper limit of normal (ULN)
• Alkaline phosphatase ≤ 2.5 times ULN (unless considered tumor-related)
• Creatinine < 2.0 mg/dL ULN
• Serum amylase and lipase ≤ 1.5 times ULN
• Potassium, magnesium, and phosphorus normal (supplementation allowed)
• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception
• No rare hereditary problems with galactose intolerance, severe lactase deficiency, or glucose-galactose malabsorption
• No known sensitivity to any of the study drugs
• No severe medical condition that, in the opinion of the investigator, would preclude study participation
• No impaired cardiac function, including any of the following:

• LVEF < 45% or below the lower limit of normal by ECHO
• Long QT syndrome or known family history of long QT syndrome
• Clinically significant resting bradycardia (< 50 beats per minute)
• QTc > 450 msec on baseline ECG (using the QTcF formula)
• Myocardial infarction within the past 12 months
• Other clinically significant heart disease, including any of the following:

• Unstable angina
• Congestive heart failure
• Uncontrolled hypertension
• Uncontrolled arrhythmias
• No other primary malignant disease requiring systemic treatment
• No acute or chronic liver, pancreatic, or severe renal disease
• No other severe and/or life-threatening medical disease
• No history of significant congenital or acquired bleeding disorder unrelated to cancer
• No impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of study drug
• No history of non-compliance

PRIOR CONCURRENT THERAPY:

• More than 30 days since prior investigational agents
• No concurrent medications that have the potential to prolong the QTc interval
• No concurrent strong CYP3A4 inhibitors
• No concurrent therapeutic coumarin derivatives