Combination Chemotherapy in Treating Young Patients With Newly Diagnosed Acute Promyelocytic Leukemia
- Conditions
- Myeloid NeoplasmChildhood Acute Promyelocytic Leukemia With PML-RARA
- Interventions
- Other: Diagnostic Laboratory Biomarker Analysis
- Registration Number
- NCT00866918
- Lead Sponsor
- Children's Oncology Group
- Brief Summary
This phase III trial is studying combination chemotherapy to see how well it works in treating young patients with newly diagnosed acute promyelocytic leukemia. Drugs used in chemotherapy 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) may kill more cancer cells.
- Detailed Description
PRIMARY OBJECTIVES:
I. To decrease the total anthracycline dose from the best current published results in standard risk childhood acute promyelocytic leukemia (APL) while still maintaining a comparable event-free survival (EFS).
SECONDARY OBJECTIVES:
I. To assign treatment based on risk stratification by white blood cell count (WBC) at diagnosis.
II. To estimate the induction failure rate, toxic death rate, disease-free survival rate and overall survival rate in both standard and high risk APL patients.
III. To monitor for cardiotoxicity in an idarubicin/mitoxantrone based regimen. IV. To document the toxicity of a traditional chemotherapy/all-trans retinoic acid (ATRA) (tretinoin) based regimen combined with arsenic trioxide therapy.
V. To study the relationship of Fms-like tyrosine kinase 3 (FLT3) mutations to clinical features and outcome in APL.
VI. To study risk factors for pseudotumor cerebri in APL. VII. To study the relationship of early progenitor cell involvement to treatment failure in FLT3 positive APL.
VIII. To compare the EFS of children enrolled on AAML0631 with the EFS of children enrolled on C9710 who were between the ages of 2 and 21 and did not receive arsenic trioxide.
IX. To estimate the proportion of patients who carry a cryptic t(15;17), i.e., those who are positive for a promyelocytes.(PML)-retinoic acid receptor alpha (RARA) fusion transcript by polymerase chain reaction (PCR) analysis but have normal chromosomes.
X. To estimate the proportion of patients with variant RARA partners. XI. To compare the outcome of patients with only a t(15;17) with that of patients who carry a t(15;17) and other chromosomal abnormalities.
OUTLINE: This is a multicenter study. Patients are assigned to 1 of 2 arms based on risk factor (standard-risk \[WBC less than 10,000/mm\^3\] or high-risk \[WBC 10,000/mm\^3 or higher\]).
ARM I (STANDARD-RISK):
INDUCTION THERAPY: Patients receive tretinoin orally (PO) twice daily (BID) on days 1-30 and idarubicin intravenously (IV) over 15 minutes once on days 3, 5, and 7.
CONSOLIDATION THERAPY:
CONSOLIDATION 1: Patients receive arsenic trioxide IV over 2 hours on days 1-5, 8-12, 15-19, 22-26, and 29-33 and tretinoin PO BID on days 1-14. Treatment repeats every 5 weeks for 2 courses, followed by a 2-week break, and then treatment repeats for 2 more courses. Beginning 1 week later or when blood counts recover, patients proceed to consolidation 2.
CONSOLIDATION 2: Patients receive cytarabine intrathecally (IT) on day 1, tretinoin PO BID on days 1-14, high-dose cytarabine IV over 3 hours every 12 hours on days 1-3, and mitoxantrone hydrochloride IV over 15-30 minutes once on days 3 and 4. Patients proceed to consolidation 3 1 week later or when blood counts recover.
CONSOLIDATION 3: Patients receive cytarabine IT on day 1, tretinoin PO BID on days 1-14, and idarubicin IV over 15 minutes once daily on days 1, 3, and 5. High-risk patients and those standard-risk patients who are positive for minimal residual disease by real-time quantitative (RQ)-PCR receive consolidation 4 one week later or when blood counts recover. All other standard-risk patients proceed to maintenance therapy.
MAINTENANCE THERAPY: Patients receive cytarabine IT on day 1 (course 1 only), tretinoin PO BID on days 1-14, mercaptopurine PO once daily (QD) on days 1-84, methotrexate PO once on days 1, 8, 15, 22, 29, 36, 43, 50, 57, 64, 71, and 78. Treatment repeats every 12 weeks for 9 courses.
ARM II (HIGH-RISK):
INDUCTION THERAPY: Patients receive tretinoin PO BID on days 1-30 and idarubicin IV over 15 minutes once on days 1, 3, and 5. Patients proceed to consolidation therapy one week later or when blood counts recover.
CONSOLIDATION THERAPY: Patients receive consolidation 1, 2, and 3 as in Arm I.
CONSOLIDATION 4: Patients receive cytarabine IT on day 1, tretinoin PO BID on days 1-14, high-dose cytarabine IV over 3 hours every 12 hours on days 1-3, and idarubicin IV over 15 minutes once on day 4. Patients who demonstrate molecular complete remission (CR) and remain in hematological CR proceed to maintenance therapy 1 week later or when blood counts recover.
MAINTENANCE THERAPY: Patients receive maintenance therapy as in Arm I.
After completion of study treatment, patients are followed every month for 1 year, every 3 months for 2 years, every 6 months for 2 years, and then annually for 5 years.
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 106
- Patients must be newly diagnosed with a clinical diagnosis of acute promyelocytic leukemia initially by morphology (bone marrow or peripheral blood); bone marrow is highly preferred but in cases where marrow cannot be obtained at diagnosis, peripheral blood will be accepted; APL is considered a hematological emergency and treatment should be initiated as quickly as possible without waiting for molecular or cytogenetic/fluorescence in situ hybridization (FISH) confirmation; for patients who are unable to begin receiving ATRA in a timely manner following a presumed diagnosis of APL, consideration should be given to initiating ATRA and proceeding with treatment outside of the AAML0631 protocol; if the RQ-PCR results are known at the time of study enrollment, the patient must demonstrate PML-RARA and/or RARA-PML transcripts by RQ-PCR to be eligible; patients without evidence of APL by bone marrow or peripheral blood morphology but with isolated myeloid sarcoma (myeloblastoma; chloroma, including leukemia cutis) are eligible provided that the t(15;17) translocation is documented on either marrow or tumor tissue by cytogenetics, FISH, or PCR prior to study enrollment; in this situation, touch preps from the tumor site can be evaluated by FISH with PML-RARA probes; NOTE: A lumbar puncture is not required to be enrolled on study; if the diagnosis of APL is known or suspected, extreme caution must be exercised in performing a lumbar puncture during active coagulopathy; in addition a computed tomography (CT) or magnetic resonance imaging (MRI) should be considered to rule out the possibility of an associated chloroma if central nervous system (CNS) disease is suspected or proven; if CNS disease is documented, patients are still eligible
- No minimal performance status criteria
- The patient must not have received systemic definitive treatment for APL or other suspected leukemia, including cytotoxic chemotherapy, retinoids, or arsenic; prior therapy with corticosteroids, hydroxyurea, or leukopheresis will not exclude the patient; if a patient received intrathecal cytarabine prior to the diagnosis of APL being known, the patient will still be eligible as long as they meet all other eligibility requirements
- Pregnant women or nursing mothers are excluded; treatment under this protocol would expose an unborn child to significant risks; patients should not be pregnant or plan to become pregnant while on treatment; women and men of reproductive potential should agree to use an effective means of birth control; there is an extremely high risk of fetal malformation if pregnancy occurs while on ATRA in any amount even for short periods
- Patients with a pre-existing prolonged QT Syndrome will not be eligible for this protocol due to the use of arsenic trioxide which can prolong the QT interval
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Arm I (standard risk, combination chemotherapy) Idarubicin See Detailed Description Arm II (high risk, combination chemotherapy) Mitoxantrone Hydrochloride See Detailed Description. Arm I (standard risk, combination chemotherapy) Diagnostic Laboratory Biomarker Analysis See Detailed Description Arm I (standard risk, combination chemotherapy) Mitoxantrone Hydrochloride See Detailed Description Arm II (high risk, combination chemotherapy) Diagnostic Laboratory Biomarker Analysis See Detailed Description. Arm I (standard risk, combination chemotherapy) Arsenic Trioxide See Detailed Description Arm I (standard risk, combination chemotherapy) Cytarabine See Detailed Description Arm I (standard risk, combination chemotherapy) Methotrexate See Detailed Description Arm I (standard risk, combination chemotherapy) Mercaptopurine See Detailed Description Arm I (standard risk, combination chemotherapy) Tretinoin See Detailed Description Arm II (high risk, combination chemotherapy) Arsenic Trioxide See Detailed Description. Arm II (high risk, combination chemotherapy) Cytarabine See Detailed Description. Arm II (high risk, combination chemotherapy) Methotrexate See Detailed Description. Arm II (high risk, combination chemotherapy) Tretinoin See Detailed Description. Arm II (high risk, combination chemotherapy) Idarubicin See Detailed Description. Arm II (high risk, combination chemotherapy) Mercaptopurine See Detailed Description.
- Primary Outcome Measures
Name Time Method Event-free Survival (EFS) At 3 years from study entry EFS - time from study entry until failure to achieve complete remission during consolidation, relapse, or death. For further clarification see definitions provided in the protocol.
- Secondary Outcome Measures
Name Time Method Hematologic Remission Rate End of consolidation, course 1: up to 5 months Proportion of patients in hematologic remission at end of consolidation, course 1 are reported.
Hematologic, Molecular, and Cytogenetic Remission Rate End of consolidation, course 3; up to 7 months (for Standard Risk) or end of consolidation, course 4; up to 9 months (for High Risk) Proportion of patients in hematologic, molecular, and cytogenetic remission at end of consolidation, course 3 and 4 are reported. Patients were determined to be in remission by all three criteria.
Overall Survival (OS) At 3 years from study entry OS - time from study entry to death.
Trial Locations
- Locations (121)
Overlook Hospital
🇺🇸Summit, New Jersey, United States
Rutgers Cancer Institute of New Jersey-Robert Wood Johnson University Hospital
🇺🇸New Brunswick, New Jersey, United States
Valley Children's Hospital
🇺🇸Madera, California, United States
Children's Hospital of Philadelphia
🇺🇸Philadelphia, Pennsylvania, United States
Johns Hopkins University/Sidney Kimmel Cancer Center
🇺🇸Baltimore, Maryland, United States
Children's Oncology Group
🇺🇸Philadelphia, Pennsylvania, United States
Children's Healthcare of Atlanta - Egleston
🇺🇸Atlanta, Georgia, United States
Emory University Hospital/Winship Cancer Institute
🇺🇸Atlanta, Georgia, United States
Alfred I duPont Hospital for Children
🇺🇸Wilmington, Delaware, United States
Johns Hopkins All Children's Hospital
🇺🇸Saint Petersburg, Florida, United States
Southern Illinois University School of Medicine
🇺🇸Springfield, Illinois, United States
Lurie Children's Hospital-Chicago
🇺🇸Chicago, Illinois, United States
Nemours Children's Clinic-Jacksonville
🇺🇸Jacksonville, Florida, United States
Lucile Packard Children's Hospital Stanford University
🇺🇸Palo Alto, California, United States
Harbor-University of California at Los Angeles Medical Center
🇺🇸Torrance, California, United States
Nemours Children's Clinic - Pensacola
🇺🇸Pensacola, Florida, United States
Sacred Heart Hospital
🇺🇸Pensacola, Florida, United States
Saint Mary's Hospital
🇺🇸West Palm Beach, Florida, United States
Lee Memorial Health System
🇺🇸Fort Myers, Florida, United States
Saint Jude Midwest Affiliate
🇺🇸Peoria, Illinois, United States
Golisano Children's Hospital of Southwest Florida
🇺🇸Fort Myers, Florida, United States
Children's National Medical Center
🇺🇸Washington, District of Columbia, United States
Advocate Children's Hospital-Oak Lawn
🇺🇸Oak Lawn, Illinois, United States
Saint Joseph's Regional Medical Center
🇺🇸Paterson, New Jersey, United States
Hackensack University Medical Center
🇺🇸Hackensack, New Jersey, United States
Penn State Children's Hospital
🇺🇸Hershey, Pennsylvania, United States
Driscoll Children's Hospital
🇺🇸Corpus Christi, Texas, United States
Loyola University Medical Center
🇺🇸Maywood, Illinois, United States
Carolinas Medical Center/Levine Cancer Institute
🇺🇸Charlotte, North Carolina, United States
Cardinal Glennon Children's Medical Center
🇺🇸Saint Louis, Missouri, United States
Dayton Children's Hospital
🇺🇸Dayton, Ohio, United States
NYP/Columbia University Medical Center/Herbert Irving Comprehensive Cancer Center
🇺🇸New York, New York, United States
Roswell Park Cancer Institute
🇺🇸Buffalo, New York, United States
Spectrum Health at Butterworth Campus
🇺🇸Grand Rapids, Michigan, United States
Michigan State University Clinical Center
🇺🇸East Lansing, Michigan, United States
Morristown Medical Center
🇺🇸Morristown, New Jersey, United States
Sanford Broadway Medical Center
🇺🇸Fargo, North Dakota, United States
Eastern Maine Medical Center
🇺🇸Bangor, Maine, United States
State University of New York Upstate Medical University
🇺🇸Syracuse, New York, United States
Novant Health Presbyterian Medical Center
🇺🇸Charlotte, North Carolina, United States
Helen DeVos Children's Hospital at Spectrum Health
🇺🇸Grand Rapids, Michigan, United States
Penn State Milton S Hershey Medical Center
🇺🇸Hershey, Pennsylvania, United States
UMass Memorial Medical Center - University Campus
🇺🇸Worcester, Massachusetts, United States
T C Thompson Children's Hospital
🇺🇸Chattanooga, Tennessee, United States
Children's Hospital of Pittsburgh of UPMC
🇺🇸Pittsburgh, Pennsylvania, United States
University of New Mexico Cancer Center
🇺🇸Albuquerque, New Mexico, United States
San Jorge Children's Hospital
🇵🇷San Juan, Puerto Rico
BI-LO Charities Children's Cancer Center
🇺🇸Greenville, South Carolina, United States
Cook Children's Medical Center
🇺🇸Fort Worth, Texas, United States
Marshfield Medical Center-Marshfield
🇺🇸Marshfield, Wisconsin, United States
McMaster Children's Hospital at Hamilton Health Sciences
🇨🇦Hamilton, Ontario, Canada
Children's Hospital of Eastern Ontario
🇨🇦Ottawa, Ontario, Canada
IWK Health Centre
🇨🇦Halifax, Nova Scotia, Canada
British Columbia Children's Hospital
🇨🇦Vancouver, British Columbia, Canada
Centre Hospitalier Universitaire de Quebec
🇨🇦Quebec, Canada
Saint Vincent Hospital Cancer Center Green Bay
🇺🇸Green Bay, Wisconsin, United States
Hospital for Sick Children
🇨🇦Toronto, Ontario, Canada
Dana-Farber Cancer Institute
🇺🇸Boston, Massachusetts, United States
Seattle Children's Hospital
🇺🇸Seattle, Washington, United States
Indiana University/Melvin and Bren Simon Cancer Center
🇺🇸Indianapolis, Indiana, United States
Riley Hospital for Children
🇺🇸Indianapolis, Indiana, United States
Ascension Saint Vincent Indianapolis Hospital
🇺🇸Indianapolis, Indiana, United States
Nevada Cancer Research Foundation NCORP
🇺🇸Las Vegas, Nevada, United States
Rady Children's Hospital - San Diego
🇺🇸San Diego, California, United States
Cincinnati Children's Hospital Medical Center
🇺🇸Cincinnati, Ohio, United States
Duke University Medical Center
🇺🇸Durham, North Carolina, United States
Methodist Children's Hospital of South Texas
🇺🇸San Antonio, Texas, United States
University of Texas Health Science Center at San Antonio
🇺🇸San Antonio, Texas, United States
CancerCare Manitoba
🇨🇦Winnipeg, Manitoba, Canada
Children's Hospital of Orange County
🇺🇸Orange, California, United States
Baystate Medical Center
🇺🇸Springfield, Massachusetts, United States
Washington University School of Medicine
🇺🇸Saint Louis, Missouri, United States
University of Mississippi Medical Center
🇺🇸Jackson, Mississippi, United States
UCSF Medical Center-Mount Zion
🇺🇸San Francisco, California, United States
UCSF Medical Center-Parnassus
🇺🇸San Francisco, California, United States
Wayne State University/Karmanos Cancer Institute
🇺🇸Detroit, Michigan, United States
Ascension Saint John Hospital
🇺🇸Detroit, Michigan, United States
University of Oklahoma Health Sciences Center
🇺🇸Oklahoma City, Oklahoma, United States
Primary Children's Hospital
🇺🇸Salt Lake City, Utah, United States
Arkansas Children's Hospital
🇺🇸Little Rock, Arkansas, United States
Kaiser Permanente Downey Medical Center
🇺🇸Downey, California, United States
Loma Linda University Medical Center
🇺🇸Loma Linda, California, United States
Miller Children's and Women's Hospital Long Beach
🇺🇸Long Beach, California, United States
UCLA / Jonsson Comprehensive Cancer Center
🇺🇸Los Angeles, California, United States
UCSF Benioff Children's Hospital Oakland
🇺🇸Oakland, California, United States
University of Connecticut
🇺🇸Farmington, Connecticut, United States
Sinai Hospital of Baltimore
🇺🇸Baltimore, Maryland, United States
Children's Hospitals and Clinics of Minnesota - Minneapolis
🇺🇸Minneapolis, Minnesota, United States
Rainbow Babies and Childrens Hospital
🇺🇸Cleveland, Ohio, United States
Cleveland Clinic Foundation
🇺🇸Cleveland, Ohio, United States
Nationwide Children's Hospital
🇺🇸Columbus, Ohio, United States
ProMedica Toledo Hospital/Russell J Ebeid Children's Hospital
🇺🇸Toledo, Ohio, United States
Greenville Cancer Treatment Center
🇺🇸Greenville, South Carolina, United States
Saint Jude Children's Research Hospital
🇺🇸Memphis, Tennessee, United States
Children's Hospital of Alabama
🇺🇸Birmingham, Alabama, United States
Oregon Health and Science University
🇺🇸Portland, Oregon, United States
University of Alabama at Birmingham Cancer Center
🇺🇸Birmingham, Alabama, United States
Children's Hospital Colorado
🇺🇸Aurora, Colorado, United States
Saint Joseph's Hospital/Children's Hospital-Tampa
🇺🇸Tampa, Florida, United States
Mayo Clinic in Rochester
🇺🇸Rochester, Minnesota, United States
Children's Hospital of Wisconsin
🇺🇸Milwaukee, Wisconsin, United States
Children's Hospital Los Angeles
🇺🇸Los Angeles, California, United States
Memorial Health University Medical Center
🇺🇸Savannah, Georgia, United States
C S Mott Children's Hospital
🇺🇸Ann Arbor, Michigan, United States
Wake Forest University Health Sciences
🇺🇸Winston-Salem, North Carolina, United States
Prisma Health Richland Hospital
🇺🇸Columbia, South Carolina, United States
Phoenix Childrens Hospital
🇺🇸Phoenix, Arizona, United States
Connecticut Children's Medical Center
🇺🇸Hartford, Connecticut, United States
University of Arkansas for Medical Sciences
🇺🇸Little Rock, Arkansas, United States
MedStar Georgetown University Hospital
🇺🇸Washington, District of Columbia, United States
Centre Hospitalier Universitaire Sainte-Justine
🇨🇦Montreal, Quebec, Canada
AdventHealth Orlando
🇺🇸Orlando, Florida, United States
Nemours Children's Clinic - Orlando
🇺🇸Orlando, Florida, United States
Orlando Health Cancer Institute
🇺🇸Orlando, Florida, United States
University of Hawaii Cancer Center
🇺🇸Honolulu, Hawaii, United States
University of Kentucky/Markey Cancer Center
🇺🇸Lexington, Kentucky, United States
Norton Children's Hospital
🇺🇸Louisville, Kentucky, United States
Tulane University Health Sciences Center
🇺🇸New Orleans, Louisiana, United States
Children's Mercy Hospitals and Clinics
🇺🇸Kansas City, Missouri, United States
Montefiore Medical Center - Moses Campus
🇺🇸Bronx, New York, United States
UNC Lineberger Comprehensive Cancer Center
🇺🇸Chapel Hill, North Carolina, United States