• 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/µL WBCs in CSF and cytospin positive for blasts, or > 5/uL WBCs but negative by Steinherz/Bleyer algorithm:
• CNS 2a: < 10/µL RBCs; < 5/µL WBCs and cytospin positive for blasts
• CNS 2b: ≥ 10/µL RBCs; < 5/µL WBCs and cytospin positive for blasts
• CNS 2c: ≥ 10/µL RBCs; ≥ 5/µL WBCs and cytospin positive for blasts but negative by Steinherz/Bleyer algorithm
• Patients with CNS3 disease (presence of ≥ 5/µL WBCs in CSF and cytospin positive for blasts [in the absence of a traumatic lumbar puncture] and/or clinical signs of CNS leukemia) are not eligible
CNS toxicity ≤ grade 2

PATIENT CHARACTERISTICS:

Lansky (patients ≤ 16 years of age) or Karnofsky (patients > 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 < 6 months of age
  • 0.5 mg/dL for patients 6 months to < 1 year of age
  • 0.6 mg/dL for patients 1 to < 2 years of age
  • 0.8 mg/dL for patients 2 to < 6 years of age
  • 1 mg/dL for patients 6 to < 10 years of age
  • 1.2 mg/dL for patients 10 to < 13 years of age
  • 1.5 mg/dL (male) or 1.4 mg/dL (female) for patients 13 to < 16 years of age
  • 1.7 mg/dL (male) or 1.4 mg/dL (female) for patients ≥ 16 years of age
  • Total bilirubin ≤ 1.5 times upper limit of normal (ULN) for age
  • ALT < 3.0 times ULN for age (unless elevation due to leukemia involvement)
  • Shortening fraction ≥ 27% by ECHO OR LVEF ≥ 50% by gated radionuclide
  • Normal respiratory rate and pulse oximetry > 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

PRIOR CONCURRENT THERAPY:

• See Disease Characteristics
• 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 (small port)
• At least 8 weeks since prior craniospinal radiotherapy or = 50% radiation of pelvis
• At least 6 weeks since prior other bone marrow radiation
• No prior radiotherapy to > 25% of lung volume
• No prior total-body irradiation as part of a hematopoietic stem cell conditioning regimen
• At least 2 months since prior stem cell transplantation
• No concurrent graft-vs-host disease prophylactic medication
• No prior bortezomib or other proteasome inhibitors
• No other concurrent investigational drugs
• More than 4 days since prior growth factors that support platelet or white cell number or function
• No concurrent anticonvulsant medications known to be potent inducers of the cytochrome P450 system, including phenytoin, carbamazepine, and phenobarbital
• Concurrent benzodiazepines and gabapentin allowed
• No other concurrent cancer chemotherapy or immunomodulating agents
• No concurrent corticosteroids as anti-emetic therapy
• Concurrent corticosteroids therapy allowed as treatment or prophylaxis for anaphylactic reactions, symptoms of cytarabine syndrome, and as treatment for presumptive bortezomib-induced pulmonary toxicity
• Concurrent radiotherapy allowed for patients who present with a chloroma that is producing or threatens to produce an irreversible neurologic deficit

Patricia Green Sharpe MSN MHSA RN, Director, Department of Clinical Trials/Oncology Data Services
Memorial Health University Medical Center
William & Iffath Hoskins Center for Biomedical Research & Education at Memorial Health University Medical Center
4700 Waters Avenue
Savannah, GA 31404
Phone: 912 350-7887
Fax: 912 350-8183
EMail: sharppa1@memorialhealth.com

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