Combination Chemotherapy in Treating Young Patients With Down Syndrome and Acute Myeloid Leukemia or Myelodysplastic Syndromes
- Conditions
- Childhood Acute Erythroleukemia (M6)Childhood Acute Megakaryocytic Leukemia (M7)Childhood Acute Minimally Differentiated Myeloid Leukemia (M0)Childhood Acute Basophilic LeukemiaChildhood Acute Myeloblastic Leukemia With Maturation (M2)Childhood Acute Eosinophilic LeukemiaChildhood Acute Monocytic Leukemia (M5b)Childhood Acute Myelomonocytic Leukemia (M4)Childhood Myelodysplastic Syndromesde Novo Myelodysplastic Syndromes
- Interventions
- Other: laboratory biomarker analysis
- Registration Number
- NCT00369317
- Lead Sponsor
- Children's Oncology Group
- Brief Summary
This phase III trial is studying how well combination chemotherapy works in treating young patients with Down syndrome and acute myeloid leukemia or myelodysplastic syndromes. 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. Determine the event-free survival (EFS) and overall survival rates in pediatric patients with Down syndrome (DS) and acute myeloid leukemia AML or myelodysplastic syndromes MDS treated with induction therapy comprising cytarabine, daunorubicin hydrochloride, thioguanine, and asparaginase followed by intensification therapy comprising cytarabine and etoposide.
II. Determine if the EFS rate in these patients can be increased with an intensified course of cytarabine therapy during induction therapy, compared to the EFS rate of patients in protocol COG-A2971.
III. Determine if the number of intrathecal chemotherapy treatments can be reduced in these patients.
IV. Determine if the total cumulative anthracycline dose can be reduced in these patients.
SECONDARY OBJECTIVES:
I. Determine the type and degree of treatment-related toxicity in these patients.
II. Determine the prevalence of leukemia phenotype and globin transcription factor 1 (GATA1) mutations of DS patients \< 4 years of age at diagnosis.
III. Determine the relationship of GATA1 mutations with leukemia phenotype and EFS rates of DS patients \< 4 years of age at diagnosis.
IV. Determine the relationship of minimal residual disease monitored by flow cytometry and remission status during and after completion of therapy based on bone marrow morphology.
V. Examine parameters of in vitro drug sensitivity and in vivo Ara-C pharmacokinetics.
VI. Examine gene expression profiles by microarrays and the relationship to leukemia phenotype and outcome.
VII. Examine the relationship of functional polymorphisms in phase I and phase II detoxification genes and DNA repair pathways that may modify susceptibility to leukemia and outcome of therapy in DS children.
VIII. Assess the effect of karyotypic abnormalities on survival. IX. Establish a DS leukemia cell bank for future biological studies.
OUTLINE: This is a nonrandomized, multicenter study.
INDUCTION THERAPY: Patients undergo 4 courses of induction therapy. Each course is 28 days.
COURSE I: Patients receive intrathecal (IT) cytarabine on day 1\* and cytarabine IV continuously over 96 hours, daunorubicin hydrochloride IV continuously over 96 hours, and oral thioguanine twice daily on days 1-4.
NOTE: \*Patients with Central Nervous System (CNS) disease receive cytarabine IT twice weekly for up to 6 doses; patients with persistent CNS leukemia after 6 doses of IT cytarabine are removed from the study.
COURSE II: Patients receive high-dose cytarabine IV over 3 hours twice daily on days 1, 2, 8, and 9 and asparaginase intramuscularly (IM) on days 2 and 9.
COURSE III: Patients receive treatment as in course 1.
COURSE IV: Patients receive cytarabine IV, daunorubicin hydrochloride IV, and oral thioguanine as in course 1.
Induction therapy continues in the absence of disease progression or unacceptable toxicity. Patients with partial response, relapsed, or refractory disease after completion of course 4 are taken off study. Patients achieving complete response proceed to intensification therapy.
INTENSIFICATION THERAPY: Patients receive cytarabine IV continuously over 168 hours on days 1-7 and etoposide IV over 1 hour on days 1-3. Treatment repeats every 28 days for 2 courses in the absence of disease progression or unacceptable toxicity.
After completion of study treatment, patients are followed up periodically for 5 years and then annually thereafter.
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 205
-
Diagnosis DS or DS mosaicism by karyotype or chromosomal analysis
-
Diagnosis of myelodysplastic syndromes (MDS) with < 30% blasts or acute myeloid leukemia (AML)
- Newly diagnosed disease
-
Patients with a history of transient myeloproliferative disorder (TMD) are eligible provided the patient is diagnosed with AML or MDS at > 90 days of age AND meets either of the following criteria:
- At least 30% blasts in the bone marrow regardless of time since resolution of TMD
- More than 8 weeks since resolution of TMD with ≥ 5% blasts in the bone marrow
-
Immunophenotype required for study entry
-
No promyelocytic leukemia
-
Shortening fraction ≥ 27% by echocardiogram OR ejection fraction ≥ 50% by radionuclide angiogram
-
Bilirubin ≤ 1.5 times upper limit of normal (ULN)
-
AST or ALT < 2.5 times ULN
-
Creatinine adjusted according to age as follows:
- No greater than 0.4 mg/dL (≤ 5 months)
- No greater than 0.5 mg/dL (6 months -11 months)
- No greater than 0.6 mg/dL (1 year-23 months)
- No greater than 0.8 mg/dL (2 years-5 years)
- No greater than 1.0 mg/dL (6 years-9 years)
- No greater than 1.2 mg/dL (10 years-12 years)
- No greater than 1.4 mg/dL (13 years and over [female])
- No greater than 1.5 mg/dL (13 years to 15 years [male])
- No greater than 1.7 mg/dL (16 years and over [male])
-
Creatinine clearance or radioisotope glomerular filtration rate at least 70 mL/min
-
No evidence of dyspnea at rest
-
No exercise intolerance
-
Pulse oximetry > 94%
-
No prior chemotherapy, radiotherapy, or any antileukemic therapy
- Intrathecal cytarabine therapy given at diagnosis allowed
-
Prior therapy for TMD allowed
Not provided
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- SINGLE_GROUP
- Arm && Interventions
Group Intervention Description Treatment (combination chemotherapy) daunorubicin hydrochloride INDUCTION THERAPY COURSE I: Patients receive cytarabine IT on day 1 and cytarabine IV continuously over 96 hours, daunorubicin hydrochloride IV continuously, and oral thioguanine BID on days 1-4. COURSE II: Patients receive high-dose cytarabine IV over 3 hours BID on days 1, 2, 8, and 9 and asparaginase (IM) on days 2 and 9. COURSE III: Patients receive treatment as in course I. COURSE IV: Patients receive cytarabine IV, daunorubicin hydrochloride IV, and oral thioguanine as in course I INTENSIFICATION THERAPY: Patients receive cytarabine IV continuously over 168 hours on days 1-7 and etoposide IV over 1 hour on days 1-3. Treatment repeats every 28 days for 2 courses in the absence of disease progression or unacceptable toxicity. Treatment (combination chemotherapy) laboratory biomarker analysis INDUCTION THERAPY COURSE I: Patients receive cytarabine IT on day 1 and cytarabine IV continuously over 96 hours, daunorubicin hydrochloride IV continuously, and oral thioguanine BID on days 1-4. COURSE II: Patients receive high-dose cytarabine IV over 3 hours BID on days 1, 2, 8, and 9 and asparaginase (IM) on days 2 and 9. COURSE III: Patients receive treatment as in course I. COURSE IV: Patients receive cytarabine IV, daunorubicin hydrochloride IV, and oral thioguanine as in course I INTENSIFICATION THERAPY: Patients receive cytarabine IV continuously over 168 hours on days 1-7 and etoposide IV over 1 hour on days 1-3. Treatment repeats every 28 days for 2 courses in the absence of disease progression or unacceptable toxicity. Treatment (combination chemotherapy) cytarabine INDUCTION THERAPY COURSE I: Patients receive cytarabine IT on day 1 and cytarabine IV continuously over 96 hours, daunorubicin hydrochloride IV continuously, and oral thioguanine BID on days 1-4. COURSE II: Patients receive high-dose cytarabine IV over 3 hours BID on days 1, 2, 8, and 9 and asparaginase (IM) on days 2 and 9. COURSE III: Patients receive treatment as in course I. COURSE IV: Patients receive cytarabine IV, daunorubicin hydrochloride IV, and oral thioguanine as in course I INTENSIFICATION THERAPY: Patients receive cytarabine IV continuously over 168 hours on days 1-7 and etoposide IV over 1 hour on days 1-3. Treatment repeats every 28 days for 2 courses in the absence of disease progression or unacceptable toxicity. Treatment (combination chemotherapy) thioguanine INDUCTION THERAPY COURSE I: Patients receive cytarabine IT on day 1 and cytarabine IV continuously over 96 hours, daunorubicin hydrochloride IV continuously, and oral thioguanine BID on days 1-4. COURSE II: Patients receive high-dose cytarabine IV over 3 hours BID on days 1, 2, 8, and 9 and asparaginase (IM) on days 2 and 9. COURSE III: Patients receive treatment as in course I. COURSE IV: Patients receive cytarabine IV, daunorubicin hydrochloride IV, and oral thioguanine as in course I INTENSIFICATION THERAPY: Patients receive cytarabine IV continuously over 168 hours on days 1-7 and etoposide IV over 1 hour on days 1-3. Treatment repeats every 28 days for 2 courses in the absence of disease progression or unacceptable toxicity. Treatment (combination chemotherapy) asparaginase INDUCTION THERAPY COURSE I: Patients receive cytarabine IT on day 1 and cytarabine IV continuously over 96 hours, daunorubicin hydrochloride IV continuously, and oral thioguanine BID on days 1-4. COURSE II: Patients receive high-dose cytarabine IV over 3 hours BID on days 1, 2, 8, and 9 and asparaginase (IM) on days 2 and 9. COURSE III: Patients receive treatment as in course I. COURSE IV: Patients receive cytarabine IV, daunorubicin hydrochloride IV, and oral thioguanine as in course I INTENSIFICATION THERAPY: Patients receive cytarabine IV continuously over 168 hours on days 1-7 and etoposide IV over 1 hour on days 1-3. Treatment repeats every 28 days for 2 courses in the absence of disease progression or unacceptable toxicity. Treatment (combination chemotherapy) etoposide INDUCTION THERAPY COURSE I: Patients receive cytarabine IT on day 1 and cytarabine IV continuously over 96 hours, daunorubicin hydrochloride IV continuously, and oral thioguanine BID on days 1-4. COURSE II: Patients receive high-dose cytarabine IV over 3 hours BID on days 1, 2, 8, and 9 and asparaginase (IM) on days 2 and 9. COURSE III: Patients receive treatment as in course I. COURSE IV: Patients receive cytarabine IV, daunorubicin hydrochloride IV, and oral thioguanine as in course I INTENSIFICATION THERAPY: Patients receive cytarabine IV continuously over 168 hours on days 1-7 and etoposide IV over 1 hour on days 1-3. Treatment repeats every 28 days for 2 courses in the absence of disease progression or unacceptable toxicity.
- Primary Outcome Measures
Name Time Method Event-free Survival (EFS) at 3 Years Time from study entry to induction failure, relapse, or death assessed at 3 years. Overall Survival (OS) at 3 Years Time from study entry to death, assessed at 3 years.
- Secondary Outcome Measures
Name Time Method Induction Remission Rate End of induction therapy (day 112) Proportion of participants with a remission after four courses of Induction therapy.
Percentage of Patients Experiencing Grade 3 or 4 Toxicity Assessed by the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 From the beginning of induction therapy to the end of intensification therapy Proportion of participants with at least one grade 3 or higher adverse event during therapy.
Prevalence of Leukemia Phenotype of DS Patients < 4 Years of Age at Diagnosis by Flow Cytometry At the start of therapy Proportion of participants having megakaryoblastic subtype (AMkL) phenotype among patients with phenotype data available.
Prevalence of of GATA1 Mutations of DS Patients < 4 Years of Age at Diagnosis At baseline and at the end of therapy (intensification) or disease relapse Proportion of participants having GATA1 mutation among patients with phenotype data available.
Proportions of Patients in Morphologic Remission With Positive MRD by Flow Cytometry After Induction I therapy (day 28 from start of therapy) Proportion of participants in complete remission by morphology and with positive MRD by flow cytometry among patients having evaluable remission and MRD assessment.
Cytarabine Drug Sensitivity by R-Strip (MicroMath) Curve Fitting Program Days 1, 2, 8, and 9 of induction II Mean and standard deviation of half-life of elimination. Specimen draws were performed only with dose 1, day 1 of induction II of AraC. First sample drawn pre-infusion, then drawn 30 mins prior to the end of the infusion, and then drawn for 6 time periods post infusion up to 8 hours post infusion (and before the 2nd dose of AraC). Results are based from these multiple time points on Day 1 of Induction II only.
Gene Expression Profiles by Microarrays At baseline and at the time of relapse (if available) A hierarchical clustering algorithm is used to assemble the genes into a dendrogram or tree structure with branches containing genes with similar patterns of expression. This ordered representation can be graphically displayed with colors that reflect the qualitative and quantitative relationships of the expressed genes.
Trial Locations
- Locations (97)
Nationwide Children's Hospital
🇺🇸Columbus, Ohio, United States
Johns Hopkins University-Sidney Kimmel Cancer Center
🇺🇸Baltimore, Maryland, United States
Hospital for Sick Children
🇨🇦Toronto, Ontario, Canada
Ny Cancer%
🇺🇸Valhalla, New York, United States
Children's Healthcare of Atlanta - Egleston
🇺🇸Atlanta, Georgia, United States
Children's Hospital Los Angeles
🇺🇸Los Angeles, California, United States
Children's Hospital of Pittsburgh of UPMC
🇺🇸Pittsburgh, Pennsylvania, United States
Cleveland Clinic Foundation
🇺🇸Cleveland, Ohio, United States
Indiana University Medical Center
🇺🇸Indianapolis, Indiana, United States
Riley Hospital for Children
🇺🇸Indianapolis, Indiana, United States
Baylor College of Medicine
🇺🇸Houston, Texas, United States
Nevada Cancer Research Foundation CCOP
🇺🇸Las Vegas, Nevada, United States
Rady Children's Hospital - San Diego
🇺🇸San Diego, California, United States
Children's Hospitals and Clinics of Minnesota - Minneapolis
🇺🇸Minneapolis, Minnesota, United States
University of Minnesota Medical Center-Fairview
🇺🇸Minneapolis, Minnesota, United States
Duke University Medical Center
🇺🇸Durham, North Carolina, United States
Miller Children's Hospital
🇺🇸Long Beach, California, United States
Children's Hospital Central California
🇺🇸Madera, California, United States
Children's Hospital and Research Center at Oakland
🇺🇸Oakland, California, United States
University of Vermont
🇺🇸Burlington, Vermont, United States
Cook Children's Medical Center
🇺🇸Fort Worth, Texas, United States
Children's Hospital
🇨🇦London, Ontario, Canada
Saint Christopher's Hospital for Children
🇺🇸Philadelphia, Pennsylvania, United States
University of Texas Health Science Center at San Antonio
🇺🇸San Antonio, Texas, United States
Children's Hospital Medical Center of Akron
🇺🇸Akron, Ohio, United States
All Children's Hospital
🇺🇸Saint Petersburg, Florida, United States
Princess Margaret Hospital for Children
🇦🇺Perth, Western Australia, Australia
Children's Hospital of Philadelphia
🇺🇸Philadelphia, Pennsylvania, United States
Palmetto Health Richland
🇺🇸Columbia, South Carolina, United States
Cancer Centre of Southeastern Ontario at Kingston General Hospital
🇨🇦Kingston, Ontario, Canada
Saint Jude Midwest Affiliate
🇺🇸Peoria, Illinois, United States
Mary Bridge Children's Hospital and Health Center
🇺🇸Tacoma, Washington, United States
Penn State Hershey Children's Hospital
🇺🇸Hershey, Pennsylvania, United States
San Jorge Children's Hospital
🇵🇷Santurce, Puerto Rico
Childrens Hospital-King's Daughters
🇺🇸Norfolk, Virginia, United States
University of California San Francisco Medical Center-Parnassus
🇺🇸San Francisco, California, United States
Vanderbilt-Ingram Cancer Center
🇺🇸Nashville, Tennessee, United States
Memorial Sloan-Kettering Cancer Center
🇺🇸New York, New York, United States
British Columbia Children's Hospital
🇨🇦Vancouver, British Columbia, Canada
Sinai Hospital of Baltimore
🇺🇸Baltimore, Maryland, United States
Janeway Child Health Centre
🇨🇦Saint John's, Newfoundland and Labrador, Canada
Children's Hospital Colorado
🇺🇸Aurora, Colorado, United States
Primary Children's Hospital
🇺🇸Salt Lake City, Utah, United States
Walter Reed National Military Medical Center
🇺🇸Bethesda, Maryland, United States
Saint John Hospital and Medical Center
🇺🇸Detroit, Michigan, United States
Wayne State University-Karmanos Cancer Institute
🇺🇸Detroit, Michigan, United States
Children's Hospital and Medical Center of Omaha
🇺🇸Omaha, Nebraska, United States
University of Nebraska Medical Center
🇺🇸Omaha, Nebraska, United States
Legacy Emanuel Hospital and Health Center
🇺🇸Portland, Oregon, United States
University of Rochester
🇺🇸Rochester, New York, United States
University of Oklahoma Health Sciences Center
🇺🇸Oklahoma City, Oklahoma, United States
Oregon Health and Science University
🇺🇸Portland, Oregon, United States
Midwest Children's Cancer Center
🇺🇸Milwaukee, Wisconsin, United States
Phoenix Childrens Hospital
🇺🇸Phoenix, Arizona, United States
Lucile Packard Children's Hospital Stanford University
🇺🇸Palo Alto, California, United States
Covenant Children's Hospital
🇺🇸Lubbock, Texas, United States
C S Mott Children's Hospital
🇺🇸Ann Arbor, Michigan, United States
University of Texas Southwestern Medical Center
🇺🇸Dallas, Texas, United States
Southern California Permanente Medical Group
🇺🇸Downey, California, United States
Kaiser Permanente-Oakland
🇺🇸Oakland, California, United States
Childrens Hospital of Orange County
🇺🇸Orange, California, United States
Alfred I duPont Hospital for Children
🇺🇸Wilmington, Delaware, United States
Lombardi Comprehensive Cancer Center at Georgetown University
🇺🇸Washington, District of Columbia, United States
Broward Health Medical Center
🇺🇸Fort Lauderdale, Florida, United States
Children's National Medical Center
🇺🇸Washington, District of Columbia, United States
Memorial Healthcare System - Joe DiMaggio Children's Hospital
🇺🇸Hollywood, Florida, United States
Nemours Children's Clinic - Jacksonville
🇺🇸Jacksonville, Florida, United States
University of Hawaii
🇺🇸Honolulu, Hawaii, United States
Lurie Children's Hospital-Chicago
🇺🇸Chicago, Illinois, United States
Saint Luke's Mountain States Tumor Institute
🇺🇸Boise, Idaho, United States
Advocate Lutheran General Hospital.
🇺🇸Park Ridge, Illinois, United States
Saint Vincent Hospital and Health Services
🇺🇸Indianapolis, Indiana, United States
Loyola University Medical Center
🇺🇸Maywood, Illinois, United States
Southern Illinois University
🇺🇸Springfield, Illinois, United States
Eastern Maine Medical Center
🇺🇸Bangor, Maine, United States
Tulane University Health Sciences Center
🇺🇸New Orleans, Louisiana, United States
University of Mississippi Medical Center
🇺🇸Jackson, Mississippi, United States
Helen DeVos Children's Hospital at Spectrum Health
🇺🇸Grand Rapids, Michigan, United States
Hurley Medical Center
🇺🇸Flint, Michigan, United States
Hackensack University Medical Center
🇺🇸Hackensack, New Jersey, United States
UMDNJ - Robert Wood Johnson University Hospital
🇺🇸New Brunswick, New Jersey, United States
Roswell Park Cancer Institute
🇺🇸Buffalo, New York, United States
Saint Peter's University Hospital
🇺🇸New Brunswick, New Jersey, United States
Columbia University Medical Center
🇺🇸New York, New York, United States
Newark Beth Israel Medical Center
🇺🇸Newark, New Jersey, United States
State University of New York Upstate Medical University
🇺🇸Syracuse, New York, United States
Carolinas Medical Center
🇺🇸Charlotte, North Carolina, United States
Sanford Medical Center-Fargo
🇺🇸Fargo, North Dakota, United States
St. Jude Children's Research Hospital
🇺🇸Memphis, Tennessee, United States
Seattle Children's Hospital
🇺🇸Seattle, Washington, United States
CancerCare Manitoba
🇨🇦Winnipeg, Manitoba, Canada
Children's Hospital of Eastern Ontario
🇨🇦Ottawa, Ontario, Canada
Florida Hospital
🇺🇸Orlando, Florida, United States
Kosair Children's Hospital
🇺🇸Louisville, Kentucky, United States
University of North Carolina
🇺🇸Chapel Hill, North Carolina, United States
The Childrens Mercy Hospital
🇺🇸Kansas City, Missouri, United States
Rhode Island Hospital
🇺🇸Providence, Rhode Island, United States