Bortezomib and Combination Chemotherapy in Treating Younger Patients With Recurrent, Refractory, or Secondary Acute Myeloid Leukemia

Inclusion Criteria

• Diagnosis of acute myeloid leukemia (AML) according to WHO classification
• At least 5% blasts in the bone marrow
• With or without extramedullary disease
• To be eligible for the dose-finding phase (closed as of 10/10) :
• Relapsed patients must meet the following criteria:
• Must have had a prior diagnosis of AML, but may NOT have inv(16) or t(8;21) cytogenetics
• May be in first or any subsequent relapse
• If in first relapse, remission duration must be less than one year
• Refractory patients must meet the following criteria:
• Must have had a prior diagnosis of AML
• May have received one or more attempt at remission induction
• Patients with treatment-related AML may be previously treated or untreated for secondary AML
• To be eligible for the efficacy phase:
• Relapsed patients must meet the following criteria:
• Must have had a prior diagnosis of AML, with no restriction on prior cytogenetics
• Must be in first relapse
• Must not have received prior reinduction therapy
• Refractory patients must meet the following criteria:
• Must have had a prior diagnosis of AML
• Must not have received more than one attempt at remission induction (which may consist of up to two therapy courses)
• Patients with treatment-related AML must be previously untreated for secondary AML
• No juvenile myelomonocytic leukemia or acute promyelocytic leukemia (APL; FAB M3)
• Patients with the following CNS status are eligible only in the absence of neurologic symptoms suggestive of CNS leukemia, such as cranial nerve palsy:
• CNS 1, defined as absence of blasts in cerebral spinal fluid (CSF) on cytospin preparation, regardless of the number of WBCs
• CNS 2, defined as presence of 5/uL WBCs but negative by Steinherz/Bleyer algorithm:
• CNS 2a: 16 years of age) performance status (PS) 50-100%
• ECOG PS 0-2
• No Down syndrome
• No Fanconi anemia, Kostmann syndrome, Shwachman syndrome, or any other known bone marrow failure syndrome
• No evidence of active graft-vs-host disease
• Creatinine clearance or radioisotope glomerular filtration rate ≥ 70 mL/min OR serum creatinine based on age/gender as follows:
• 0.4 mg/dL for patients 1 month to 94% on room air
• FEV\_1 ≥ 80% of predicted
• FVC and DLCO > 50% (corrected for hemoglobin)
• Patients who are unable to perform pulmonary function tests (PFTs) (e.g., because of young age) will be excluded provided they have a medical history of significant prior pulmonary events or chronic pulmonary disease (e.g., pneumonia requiring mechanical ventilation support, pulmonary GVHD, pneumonectomy, or pulmonary toxin exposure)
• Children with histories of resolved bronchiolitis, resolved viral pneumonias and well-controlled asthma are eligible, even if they are unable to perform PFTs
• Patients with seizure disorder may be enrolled if on a non-enzyme-inducing anticonvulsant and if seizures are well-controlled
• No uncontrolled infection
• No known allergy to idarubicin, cytarabine, etoposide, boron, mannitol or bortezomib
• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception
• Concurrent radiotherapy allowed for patients who present with a chloroma that is producing or threatens to produce an irreversible neurologic deficit
• Recovered from all prior chemotherapy, immunotherapy, or radiotherapy
• More than 2 weeks since prior cytotoxic chemotherapy (4 weeks for nitrosoureas), except for hydroxyurea, which is allowed up to 24 hours prior to first dose of study drug, and intrathecal chemotherapy, which is allowed immediately up to administration of study drug
• Prior steroid allowed as clinically indicated for patients with asthma
• Hydrocortisone and methylprednisolone allowed as premedication in patients with a history of severe allergic reactions
• At least 7 days since prior biologic agents, such as steroids, retinoids, or donor lymphocyte infusion without conditioning
• At least 2 weeks since prior local palliative radiotherapy