Bortezomib and Combination Chemotherapy in Treating Younger Patients With Recurrent, Refractory, or Secondary Acute Myeloid Leukemia
Adult Acute Monoblastic Leukemia (M5a), Adult Acute Monocytic Leukemia (M5b), Adult Acute Myeloblastic Leukemia With Maturation (M2)
About this trial
This is an interventional treatment trial for Adult Acute Monoblastic Leukemia (M5a)
Eligibility Criteria
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/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
- 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
- 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 (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
- At least 1 day since prior green tea containing products, any products containing vitamin C, flavanoids or other antioxidants (e.g., vitamins, herbal supplements), and foods with high vitamin C content
- 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 enzyme-inducing anticonvulsant medications known to be potent inducers of the cytochrome P450 system, including phenytoin, carbamazepine, and phenobarbital
- Concurrent benzodiazepines and gabapentin allowed
- No concurrent grapefruit juice with bortezomib
- 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.
Sites / Locations
- University of Alabama at Birmingham
- Phoenix Childrens Hospital
- University of Arkansas for Medical Sciences
- Southern California Permanente Medical Group
- Miller Children's Hospital
- Children's Hospital and Research Center at Oakland
- Childrens Hospital of Orange County
- Packard Children's Hospital Stanford University
- University of California San Francisco Medical Center
- Connecticut Children's Medical Center
- Alfred I duPont Hospital for Children
- Children's National Medical Center
- Broward General Medical Center
- Lee Memorial Health System
- Nemours Children's Clinic - Jacksonville
- University of Miami Miller School of Medicine-Sylvester Cancer Center
- Nemours Childrens Clinic - Orlando
- Nemours Children's Clinic - Pensacola
- All Children's Hospital
- Saint Joseph Children's Hospital of Tampa
- Children's Healthcare of Atlanta - Egleston
- Memorial Health University Medical Center
- University of Hawaii
- Childrens Memorial Hospital
- Southern Illinois University
- Riley Hospital for Children
- University of Kentucky
- Tulane University Health Sciences Center
- Sinai Hospital of Baltimore
- Dana-Farber Cancer Institute
- C S Mott Children's Hospital
- Michigan State University - Breslin Cancer Center
- Helen DeVos Children's Hospital at Spectrum Health
- Children's Hospitals and Clinics of Minnesota - Minneapolis
- University of Minnesota Medical Center-Fairview
- Mayo Clinic
- University of Mississippi Medical Center
- The Childrens Mercy Hospital
- Washington University School of Medicine
- University of Nebraska Medical Center
- Nevada Cancer Research Foundation CCOP
- Hackensack University Medical Center
- UMDNJ - Robert Wood Johnson University Hospital
- Newark Beth Israel Medical Center
- Overlook Hospital
- University of New Mexico
- Columbia University Medical Center
- State University of New York Upstate Medical University
- University of North Carolina
- Carolinas Medical Center
- Wake Forest University Health Sciences
- Children's Hospital Medical Center of Akron
- Cincinnati Children's Hospital Medical Center
- Rainbow Babies and Childrens Hospital
- Cleveland Clinic Foundation
- Nationwide Children's Hospital
- The Children's Medical Center of Dayton
- University of Oklahoma Health Sciences Center
- Legacy Emanuel Hospital and Health Center
- Penn State Hershey Children's Hospital
- Children's Hospital of Philadelphia
- Childrens Hospital of Pittsburgh
- Rhode Island Hospital
- Palmetto Health Richland
- Sanford University of South Dakota Medical Center
- East Tennessee Childrens Hospital
- St. Jude Children's Research Hospital
- Driscoll Children's Hospital
- University of Texas Southwestern Medical Center
- Cook Children's Medical Center
- Baylor College of Medicine
- University of Texas Health Science Center
- Primary Children's Medical Center
- Seattle Children's Hospital
- Saint Vincent Hospital
- Marshfield Clinic
- Midwest Children's Cancer Center
- Princess Margaret Hospital for Children
- CancerCare Manitoba
- IWK Health Centre
- Hospital for Sick Children
- Hospital Sainte-Justine
Arms of the Study
Arm 1
Arm 2
Arm 3
Arm 4
Experimental
Experimental
Experimental
Experimental
Bortezomib 1.3mg/m2-assess efficacy-low anthracycline exposure
Bortezomib 1.0mg/m2-assess feasibility high anthracycline exp
Bortezomib 1.3 mg/m2-assess feasibility high anthracycline exp
Bortezomib 1.3 mg/m2-assess efficacy high anthracycline exp
Bortezomib 1.3mg/m2 to assess efficacy in low prior anthracycline exposure. Patients receive idarubicin IV (12 mg/m2/day) over 15 minutes on days 1-3, low-dose cytarabine IV (100 mg/m2/day) continuously over days 1-7, and bortezomib IV (1.3 mg/m2) on days 1, 4, and 8. All patients receive intrathecal cytarabine (30 mg - age 1-1.99 years, 50 mg - age 2-2.99 years, 70 mg - age ≥ 3 years) prior to courses 1 and 2. Treatment repeats every 28 days for up to 2 courses in the absence of disease progression or unacceptable toxicity (closed as of 08/01/10). Dosage modification based on age < 3 years old.
Bortezomib 1.0 mg/m2 to assess feasibility in high prior anthracycline exposure. Patients receive etoposide IV (150 mg/m2/dose) over 1 hour on days 1-5, high-dose cytarabine IV (1000 mg/m2/dose) over 1 hour twice daily on days 1-5, and bortezomib IV (1.0 mg/m2) on days 1, 4, and 8. All patients receive intrathecal cytarabine (30 mg - age 1-1.99 years, 50 mg - age 2-2.99 years, 70 mg - age ≥ 3 years) prior to courses 1 and 2. Treatment repeats every 28 days for up to 2 courses in the absence of disease progression or unacceptable toxicity.
Bortezomib 1.3 mg/m2 to assess feasibility in high prior anthracycline exposure. Patients receive etoposide IV (150 mg/m2/dose) over 1 hour on days 1-5, high-dose cytarabine IV (1000 mg/m2/dose) over 1 hour twice daily on days 1-5, and bortezomib IV (1.3 mg/m2) on days 1, 4, and 8. All patients receive intrathecal cytarabine (30 mg - age 1-1.99 years, 50 mg - age 2-2.99 years, 70 mg - age ≥ 3 years) prior to courses 1 and 2. Treatment repeats every 28 days for up to 2 courses in the absence of disease progression or unacceptable toxicity (dose-finding phase closed as of 10/10).
Bortezomib 1.3 mg/m2 to assess efficacy in high prior anthracycline exposure. Patients receive etoposide IV (150 mg/m2/dose) over 1 hour on days 1-5, high-dose cytarabine IV (1000 mg/m2/dose) over 1 hour twice daily on days 1-5, and bortezomib IV (1.3 mg/m2) on days 1, 4, and 8. All patients receive intrathecal cytarabine (30 mg - age 1-1.99 years, 50 mg - age 2-2.99 years, 70 mg - age ≥ 3 years) prior to courses 1 and 2. Treatment repeats every 28 days for up to 2 courses in the absence of disease progression or unacceptable toxicity