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

Phase 2

Completed

Conditions: Adult Acute Monoblastic Leukemia (M5a)
Adult Acute Monocytic Leukemia (M5b)
Childhood Acute Megakaryocytic Leukemia (M7)
Childhood Acute Minimally Differentiated Myeloid Leukemia (M0)
Childhood Acute Myeloblastic Leukemia Without Maturation (M1)
Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities
Adult Acute Myeloid Leukemia With Del(5q)
Adult Acute Myelomonocytic Leukemia (M4)
Childhood Acute Eosinophilic Leukemia
Childhood Acute Erythroleukemia (M6)

Interventions: Drug: idarubicin
Drug: cytarabine
Drug: bortezomib
Drug: etoposide
Other: laboratory biomarker analysis

Registration Number: NCT00666588

Lead Sponsor: National Cancer Institute (NCI)

Brief Summary: This phase II trial is studying the side effects and best dose of bortezomib and to see how well it works when given together with combination chemotherapy in treating younger patients with recurrent, refractory, or secondary acute myeloid leukemia (AML). Bortezomib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as idarubicin, cytarabine, and etoposide, work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. Giving more than one drug (combination chemotherapy) together with bortezomib may kill more cancer cells

Detailed Description: PRIMARY OBJECTIVES:

I. To determine the toxicities and tolerability of bortezomib in combination with standard-relapse AML therapy (idarubicin/cytarabine or etoposide/high-dose cytarabine) in pediatric and young adult patients with relapsed or primary-refractory or secondary AML.

II. To estimate the complete response rate to the Arm A and Arm B regimens.

SECONDARY OBJECTIVES:

I. To determine whether bortezomib inhibits proteasome activity, NF-kB activity and induces apoptosis pathway proteins in leukemia myeloblasts. II. To determine the feasibility of measuring AML stem cells in relapsed and recovering bone marrow.

OUTLINE: This is a multicenter, dose-escalation study of bortezomib. Patients are stratified according to anthracycline\*-equivalent cumulative exposure (≤ 400 mg/m² vs \> 400 mg/m²). Patients are assigned to 1 of 2 groups.

GROUP I (efficacy phase, patients with ≤ 400 mg/m² anthracycline-equivalent cumulative exposure - Closed as of 08/01/10): Patients receive idarubicin IV over 15 minutes on days 1-3, low-dose cytarabine IV continuously over days 1-7, and bortezomib IV on days 1, 4, and 8.

GROUP II (dose-finding phase (closed as of 10/10) and efficacy phase, patients with \> 400 mg/m² anthracycline\*-equivalent cumulative exposure): Patients receive etoposide IV over 1 hour on days 1-5, high-dose cytarabine IV over 1 hour twice daily on days 1-5, and bortezomib IV on days 1, 4, and 8.

NOTE: \* Anthracycline restriction no longer required for group 2 as of 10/02/10.

All patients receive intrathecal cytarabine prior to courses 1 and 2. In both arms, treatment repeats every 28 days for up to 2 courses in the absence of disease progression or unacceptable toxicity.

After completion of study therapy, patients are followed periodically for at least 5 years.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 52

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.

Exclusion Criteria

Not provided

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Bortezomib 1.3mg/m2-assess efficacy-low anthracycline exposure	laboratory biomarker analysis	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 1.0mg/m2-assess feasibility high anthracycline exp	laboratory biomarker analysis	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-assess feasibility high anthracycline exp	laboratory biomarker analysis	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-assess efficacy high anthracycline exp	laboratory biomarker analysis	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
Bortezomib 1.3mg/m2-assess efficacy-low anthracycline exposure	bortezomib	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 1.3mg/m2-assess efficacy-low anthracycline exposure	cytarabine	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 1.3mg/m2-assess efficacy-low anthracycline exposure	idarubicin	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 1.0mg/m2-assess feasibility high anthracycline exp	cytarabine	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 1.0mg/m2-assess feasibility high anthracycline exp	bortezomib	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 1.0mg/m2-assess feasibility high anthracycline exp	etoposide	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-assess feasibility high anthracycline exp	cytarabine	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-assess feasibility high anthracycline exp	etoposide	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-assess feasibility high anthracycline exp	bortezomib	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-assess efficacy high anthracycline exp	cytarabine	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
Bortezomib 1.3 mg/m2-assess efficacy high anthracycline exp	bortezomib	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
Bortezomib 1.3 mg/m2-assess efficacy high anthracycline exp	etoposide	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

Primary Outcome Measures

Name	Time	Method
Dose Limiting Toxicity	During Course 1	Number of participants with dose limiting toxicity.
Overall Response (Complete Remission [CR] and CR With Partial Recovery [CRp]) During Course 1	After course 1	Overall response (complete remission \[CR\] and CR with partial recovery \[CRp\]) during course 1.

Secondary Outcome Measures

Name	Time	Method
NF-kB Activity by Enzyme-linked Immunosorbent Assay (ELISA)	At baseline, prior to and up to 24 hours after bortezomib treatment	NF-kB activity will be measured as a continuous variable (ng NF-kB/Mg protein). Differences in NF-κB activity between time points will be assessed using summary statistics such as mean, standard deviation, and range. We may perform exploratory analyses to determine if single time point measurements, or the difference between time points, correlate with treatment response.
Feasibility of Stem Cell Quantitation: Percentage of Leukemia Initiation Cells (LIC) Depletion	At baseline and after completion of course 1	Descriptive statistics to assess mean +/- standard deviation for the percentage leukemia initiation cells (LIC) depletion.
Proteasome Inhibition Activity	At baseline	Mean and standard deviation of β1 and β5- Results are ratios (proteasome subunit/β-actin based on loading of 15 µg total protein, normalized to CEM).
Protein Expression Assessed by Western Blot	At baseline, prior to and up to 24 hours after bortezomib treatment	Relative expression of apoptotic and cell cycle proteins will be characterized using descriptive statistics. If differences are noted between pre and post-treatment protein expression, pairwise comparisons will be made using paired t-test or an equivalent nonparametric test if the data are non-normally distributed. The normality assumption will be assessed on the log-transformed data prior to paired t-test evaluation.

Trial Locations

Locations (82): Children's Healthcare of Atlanta - Egleston
🇺🇸
Atlanta, Georgia, United States
Nationwide Children's Hospital
🇺🇸
Columbus, Ohio, United States
University of Arkansas for Medical Sciences
🇺🇸
Little Rock, Arkansas, United States
University of Kentucky
🇺🇸
Lexington, Kentucky, United States
St. Jude Children's Research Hospital
🇺🇸
Memphis, Tennessee, United States
Hackensack University Medical Center
🇺🇸
Hackensack, New Jersey, United States
Overlook Hospital
🇺🇸
Summit, New Jersey, United States
Newark Beth Israel Medical Center
🇺🇸
Newark, New Jersey, United States
University of North Carolina
🇺🇸
Chapel Hill, North Carolina, United States
Palmetto Health Richland
🇺🇸
Columbia, South Carolina, United States
East Tennessee Childrens Hospital
🇺🇸
Knoxville, Tennessee, United States
Sanford University of South Dakota Medical Center
🇺🇸
Sioux Falls, South Dakota, United States
IWK Health Centre
🇨🇦
Halifax, Nova Scotia, Canada
Baylor College of Medicine
🇺🇸
Houston, Texas, United States
Southern California Permanente Medical Group
🇺🇸
Downey, California, United States
Children's Hospital and Research Center at Oakland
🇺🇸
Oakland, California, United States
Childrens Hospital of Orange County
🇺🇸
Orange, California, United States
Helen DeVos Children's Hospital at Spectrum Health
🇺🇸
Grand Rapids, Michigan, United States
University of New Mexico
🇺🇸
Albuquerque, New Mexico, United States
Carolinas Medical Center
🇺🇸
Charlotte, North Carolina, United States
Michigan State University - Breslin Cancer Center
🇺🇸
East Lansing, Michigan, United States
Childrens Hospital of Pittsburgh
🇺🇸
Pittsburgh, Pennsylvania, United States
Children's Hospital Medical Center of Akron
🇺🇸
Akron, Ohio, United States
The Children's Medical Center of Dayton
🇺🇸
Dayton, Ohio, United States
Cleveland Clinic Foundation
🇺🇸
Cleveland, Ohio, United States
The Childrens Mercy Hospital
🇺🇸
Kansas City, Missouri, United States
Children's Hospital of Philadelphia
🇺🇸
Philadelphia, Pennsylvania, United States
Dana-Farber Cancer Institute
🇺🇸
Boston, Massachusetts, United States
Penn State Hershey Children's Hospital
🇺🇸
Hershey, Pennsylvania, United States
C S Mott Children's Hospital
🇺🇸
Ann Arbor, Michigan, United States
Columbia University Medical Center
🇺🇸
New York, New York, United States
Rainbow Babies and Childrens Hospital
🇺🇸
Cleveland, Ohio, United States
CancerCare Manitoba
🇨🇦
Winnipeg, Manitoba, Canada
State University of New York Upstate Medical University
🇺🇸
Syracuse, New York, United States
Hospital Sainte-Justine
🇨🇦
Montreal, Quebec, Canada
Saint Vincent Hospital
🇺🇸
Green Bay, Wisconsin, United States
Hospital for Sick Children
🇨🇦
Toronto, Ontario, Canada
Seattle Children's Hospital
🇺🇸
Seattle, Washington, United States
University of Miami Miller School of Medicine-Sylvester Cancer Center
🇺🇸
Miami, Florida, United States
Nevada Cancer Research Foundation CCOP
🇺🇸
Las Vegas, Nevada, United States
Children's Hospitals and Clinics of Minnesota - Minneapolis
🇺🇸
Minneapolis, Minnesota, United States
University of Minnesota Medical Center-Fairview
🇺🇸
Minneapolis, Minnesota, United States
Cincinnati Children's Hospital Medical Center
🇺🇸
Cincinnati, Ohio, United States
University of Texas Health Science Center
🇺🇸
San Antonio, Texas, United States
University of California San Francisco Medical Center
🇺🇸
San Francisco, California, United States
Primary Children's Medical Center
🇺🇸
Salt Lake City, Utah, United States
Princess Margaret Hospital for Children
🇦🇺
Perth, Western Australia, Australia
Washington University School of Medicine
🇺🇸
Saint Louis, Missouri, United States
University of Mississippi Medical Center
🇺🇸
Jackson, Mississippi, United States
Phoenix Childrens Hospital
🇺🇸
Phoenix, Arizona, United States
University of Oklahoma Health Sciences Center
🇺🇸
Oklahoma City, Oklahoma, United States
University of Alabama at Birmingham
🇺🇸
Birmingham, Alabama, United States
Saint Joseph Children's Hospital of Tampa
🇺🇸
Tampa, Florida, United States
Mayo Clinic
🇺🇸
Rochester, Minnesota, United States
University of Nebraska Medical Center
🇺🇸
Omaha, Nebraska, United States
Legacy Emanuel Hospital and Health Center
🇺🇸
Portland, Oregon, United States
Midwest Children's Cancer Center
🇺🇸
Milwaukee, Wisconsin, United States
Miller Children's Hospital
🇺🇸
Long Beach, California, United States
Alfred I duPont Hospital for Children
🇺🇸
Wilmington, Delaware, United States
Packard Children's Hospital Stanford University
🇺🇸
Palo Alto, California, United States
Connecticut Children's Medical Center
🇺🇸
Hartford, Connecticut, United States
Lee Memorial Health System
🇺🇸
Fort Myers, Florida, United States
Broward General Medical Center
🇺🇸
Fort Lauderdale, Florida, United States
Children's National Medical Center
🇺🇸
Washington, District of Columbia, United States
Nemours Children's Clinic - Jacksonville
🇺🇸
Jacksonville, Florida, United States
Memorial Health University Medical Center
🇺🇸
Savannah, Georgia, United States
University of Hawaii
🇺🇸
Honolulu, Hawaii, United States
Southern Illinois University
🇺🇸
Springfield, Illinois, United States
Childrens Memorial Hospital
🇺🇸
Chicago, Illinois, United States
Tulane University Health Sciences Center
🇺🇸
New Orleans, Louisiana, United States
Sinai Hospital of Baltimore
🇺🇸
Baltimore, Maryland, United States
UMDNJ - Robert Wood Johnson University Hospital
🇺🇸
New Brunswick, New Jersey, United States
Nemours Childrens Clinic - Orlando
🇺🇸
Orlando, Florida, United States
Nemours Children's Clinic - Pensacola
🇺🇸
Pensacola, Florida, United States
All Children's Hospital
🇺🇸
Saint Petersburg, Florida, United States
Riley Hospital for Children
🇺🇸
Indianapolis, Indiana, United States
University of Texas Southwestern Medical Center
🇺🇸
Dallas, Texas, United States
Cook Children's Medical Center
🇺🇸
Fort Worth, Texas, United States
Driscoll Children's Hospital
🇺🇸
Corpus Christi, Texas, United States
Marshfield Clinic
🇺🇸
Marshfield, Wisconsin, United States
Wake Forest University Health Sciences
🇺🇸
Winston-Salem, North Carolina, United States
Rhode Island Hospital
🇺🇸
Providence, Rhode Island, United States