Combination Chemotherapy in Treating Young Patients With Down Syndrome and Acute Myeloid Leukemia or Myelodysplastic Syndromes

Sponsor
Children's Oncology Group (Other)
Overall Status
Completed
CT.gov ID
NCT00369317
Collaborator
National Cancer Institute (NCI) (NIH)
205
97
1
178
2.1
0

Study Details

Study Description

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:
  1. 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.

  2. 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.

  3. Determine if the number of intrathecal chemotherapy treatments can be reduced in these patients.

  4. Determine if the total cumulative anthracycline dose can be reduced in these patients.

SECONDARY OBJECTIVES:
  1. Determine the type and degree of treatment-related toxicity in these patients.

  2. Determine the prevalence of leukemia phenotype and globin transcription factor 1 (GATA1) mutations of DS patients < 4 years of age at diagnosis.

  3. Determine the relationship of GATA1 mutations with leukemia phenotype and EFS rates of DS patients < 4 years of age at diagnosis.

  4. 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.

  5. Examine parameters of in vitro drug sensitivity and in vivo Ara-C pharmacokinetics.

  6. Examine gene expression profiles by microarrays and the relationship to leukemia phenotype and outcome.

  7. 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.

  8. 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.

Study Design

Study Type:
Interventional
Actual Enrollment :
205 participants
Allocation:
N/A
Intervention Model:
Single Group Assignment
Masking:
None (Open Label)
Primary Purpose:
Treatment
Official Title:
The Treatment of Down Syndrome Children With Acute Myeloid Leukemia (AML) and Myelodysplastic Syndromes (MDS) Under the Age of 4 Years
Study Start Date :
Mar 1, 2007
Actual Primary Completion Date :
Dec 1, 2013
Actual Study Completion Date :
Dec 31, 2021

Arms and Interventions

Arm Intervention/Treatment
Experimental: Treatment (combination chemotherapy)

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.

Drug: asparaginase
Given IM
Other Names:
  • ASNase
  • Colaspase
  • Crasnitin
  • Elspar
  • L-ASP
  • Drug: daunorubicin hydrochloride
    Given IV
    Other Names:
  • Cerubidin
  • Cerubidine
  • daunomycin hydrochloride
  • daunorubicin
  • RP-13057
  • Drug: cytarabine
    Given IV or IT
    Other Names:
  • ARA-C
  • arabinofuranosylcytosine
  • arabinosylcytosine
  • Cytosar-U
  • cytosine arabinoside
  • Drug: thioguanine
    Given orally
    Other Names:
  • 6-TG
  • Drug: etoposide
    Given IV
    Other Names:
  • EPEG
  • VP-16
  • VP-16-213
  • Other: laboratory biomarker analysis
    Correlative studies

    Outcome Measures

    Primary Outcome Measures

    1. Event-free Survival (EFS) at 3 Years [Time from study entry to induction failure, relapse, or death assessed at 3 years.]

    2. Overall Survival (OS) at 3 Years [Time from study entry to death, assessed at 3 years.]

    Secondary Outcome Measures

    1. Induction Remission Rate [End of induction therapy (day 112)]

      Proportion of participants with a remission after four courses of Induction therapy.

    2. 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.

    3. 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.

    4. 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.

    5. 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.

    6. Cytarabine Drug Sensitivity by R-Strip (MicroMath) Curve Fitting Program [Days 1, 2, 8, and 9 of induction II]

      Mean and standard deviation of peak plasma concentration. 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.

    7. Cytarabine Drug Sensitivity by R-Strip (MicroMath) Curve Fitting Program [Days 1, 2, 8, and 9 of induction II]

      Mean and standard deviation of area under the concentration time curve. 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.

    8. 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.

    9. 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.

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    N/A to 4 Years
    Sexes Eligible for Study:
    All
    Accepts Healthy Volunteers:
    No
    Inclusion Criteria:
    • 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

    Contacts and Locations

    Locations

    Site City State Country Postal Code
    1 Phoenix Childrens Hospital Phoenix Arizona United States 85016
    2 Southern California Permanente Medical Group Downey California United States 90242
    3 Miller Children's Hospital Long Beach California United States 90806
    4 Children's Hospital Los Angeles Los Angeles California United States 90027
    5 Children's Hospital Central California Madera California United States 93636-8762
    6 Children's Hospital and Research Center at Oakland Oakland California United States 94609-1809
    7 Kaiser Permanente-Oakland Oakland California United States 94611
    8 Childrens Hospital of Orange County Orange California United States 92868-3874
    9 Lucile Packard Children's Hospital Stanford University Palo Alto California United States 94304
    10 Rady Children's Hospital - San Diego San Diego California United States 92123
    11 University of California San Francisco Medical Center-Parnassus San Francisco California United States 94143
    12 Children's Hospital Colorado Aurora Colorado United States 80045
    13 Alfred I duPont Hospital for Children Wilmington Delaware United States 19803
    14 Children's National Medical Center Washington District of Columbia United States 20010
    15 Lombardi Comprehensive Cancer Center at Georgetown University Washington District of Columbia United States 20057
    16 Broward Health Medical Center Fort Lauderdale Florida United States 33316
    17 Memorial Healthcare System - Joe DiMaggio Children's Hospital Hollywood Florida United States 33021
    18 Nemours Children's Clinic - Jacksonville Jacksonville Florida United States 32207-8426
    19 Florida Hospital Orlando Florida United States 32803
    20 All Children's Hospital Saint Petersburg Florida United States 33701
    21 Children's Healthcare of Atlanta - Egleston Atlanta Georgia United States 30322
    22 University of Hawaii Honolulu Hawaii United States 96813
    23 Saint Luke's Mountain States Tumor Institute Boise Idaho United States 83712
    24 Lurie Children's Hospital-Chicago Chicago Illinois United States 60614
    25 Loyola University Medical Center Maywood Illinois United States 60153
    26 Advocate Lutheran General Hospital. Park Ridge Illinois United States 60068
    27 Saint Jude Midwest Affiliate Peoria Illinois United States 61602
    28 Southern Illinois University Springfield Illinois United States 62702
    29 Indiana University Medical Center Indianapolis Indiana United States 46202
    30 Riley Hospital for Children Indianapolis Indiana United States 46202
    31 Saint Vincent Hospital and Health Services Indianapolis Indiana United States 46260
    32 Kosair Children's Hospital Louisville Kentucky United States 40202
    33 Tulane University Health Sciences Center New Orleans Louisiana United States 70112
    34 Eastern Maine Medical Center Bangor Maine United States 04401
    35 Sinai Hospital of Baltimore Baltimore Maryland United States 21215
    36 Johns Hopkins University-Sidney Kimmel Cancer Center Baltimore Maryland United States 21287
    37 Walter Reed National Military Medical Center Bethesda Maryland United States 20889-5600
    38 C S Mott Children's Hospital Ann Arbor Michigan United States 48109
    39 Wayne State University-Karmanos Cancer Institute Detroit Michigan United States 48201
    40 Saint John Hospital and Medical Center Detroit Michigan United States 48236
    41 Hurley Medical Center Flint Michigan United States 48502
    42 Helen DeVos Children's Hospital at Spectrum Health Grand Rapids Michigan United States 49503
    43 Children's Hospitals and Clinics of Minnesota - Minneapolis Minneapolis Minnesota United States 55404
    44 University of Minnesota Medical Center-Fairview Minneapolis Minnesota United States 55455
    45 University of Mississippi Medical Center Jackson Mississippi United States 39216
    46 The Childrens Mercy Hospital Kansas City Missouri United States 64108
    47 Children's Hospital and Medical Center of Omaha Omaha Nebraska United States 68114
    48 University of Nebraska Medical Center Omaha Nebraska United States 68198
    49 Nevada Cancer Research Foundation CCOP Las Vegas Nevada United States 89106
    50 Hackensack University Medical Center Hackensack New Jersey United States 07601
    51 Saint Peter's University Hospital New Brunswick New Jersey United States 08901
    52 UMDNJ - Robert Wood Johnson University Hospital New Brunswick New Jersey United States 08903
    53 Newark Beth Israel Medical Center Newark New Jersey United States 07112
    54 Roswell Park Cancer Institute Buffalo New York United States 14263
    55 Columbia University Medical Center New York New York United States 10032
    56 Memorial Sloan-Kettering Cancer Center New York New York United States 10065
    57 University of Rochester Rochester New York United States 14642
    58 State University of New York Upstate Medical University Syracuse New York United States 13210
    59 Ny Cancer% Valhalla New York United States 10595
    60 University of North Carolina Chapel Hill North Carolina United States 27599
    61 Carolinas Medical Center Charlotte North Carolina United States 28203
    62 Duke University Medical Center Durham North Carolina United States 27710
    63 Sanford Medical Center-Fargo Fargo North Dakota United States 58122
    64 Children's Hospital Medical Center of Akron Akron Ohio United States 44308
    65 Cleveland Clinic Foundation Cleveland Ohio United States 44195
    66 Nationwide Children's Hospital Columbus Ohio United States 43205
    67 University of Oklahoma Health Sciences Center Oklahoma City Oklahoma United States 73104
    68 Legacy Emanuel Hospital and Health Center Portland Oregon United States 97227
    69 Oregon Health and Science University Portland Oregon United States 97239
    70 Penn State Hershey Children's Hospital Hershey Pennsylvania United States 17033
    71 Children's Hospital of Philadelphia Philadelphia Pennsylvania United States 19104
    72 Saint Christopher's Hospital for Children Philadelphia Pennsylvania United States 19134
    73 Children's Hospital of Pittsburgh of UPMC Pittsburgh Pennsylvania United States 15224
    74 Rhode Island Hospital Providence Rhode Island United States 02903
    75 Palmetto Health Richland Columbia South Carolina United States 29203
    76 St. Jude Children's Research Hospital Memphis Tennessee United States 38105
    77 Vanderbilt-Ingram Cancer Center Nashville Tennessee United States 37232
    78 University of Texas Southwestern Medical Center Dallas Texas United States 75390
    79 Cook Children's Medical Center Fort Worth Texas United States 76104
    80 Baylor College of Medicine Houston Texas United States 77030
    81 Covenant Children's Hospital Lubbock Texas United States 79410
    82 University of Texas Health Science Center at San Antonio San Antonio Texas United States 78229-3900
    83 Primary Children's Hospital Salt Lake City Utah United States 84113
    84 University of Vermont Burlington Vermont United States 05401
    85 Childrens Hospital-King's Daughters Norfolk Virginia United States 23507
    86 Seattle Children's Hospital Seattle Washington United States 98105
    87 Mary Bridge Children's Hospital and Health Center Tacoma Washington United States 98405
    88 Midwest Children's Cancer Center Milwaukee Wisconsin United States 53226
    89 Princess Margaret Hospital for Children Perth Western Australia Australia 6008
    90 British Columbia Children's Hospital Vancouver British Columbia Canada V6H 3V4
    91 CancerCare Manitoba Winnipeg Manitoba Canada R3E 0V9
    92 Janeway Child Health Centre Saint John's Newfoundland and Labrador Canada A1B 3V6
    93 Cancer Centre of Southeastern Ontario at Kingston General Hospital Kingston Ontario Canada K7L 5P9
    94 Children's Hospital London Ontario Canada N6A 5W9
    95 Children's Hospital of Eastern Ontario Ottawa Ontario Canada K1H 8L1
    96 Hospital for Sick Children Toronto Ontario Canada M5G 1X8
    97 San Jorge Children's Hospital Santurce Puerto Rico 00912

    Sponsors and Collaborators

    • Children's Oncology Group
    • National Cancer Institute (NCI)

    Investigators

    • Principal Investigator: Jeffrey Taub, MD, Children's Oncology Group

    Study Documents (Full-Text)

    None provided.

    More Information

    Additional Information:

    Publications

    None provided.
    Responsible Party:
    Children's Oncology Group
    ClinicalTrials.gov Identifier:
    NCT00369317
    Other Study ID Numbers:
    • AAML0431
    • NCI-2009-00318
    • CDR0000492776
    • COG-AAML0431
    • AAML0431
    • U10CA098543
    First Posted:
    Aug 29, 2006
    Last Update Posted:
    Jan 28, 2022
    Last Verified:
    Mar 1, 2021

    Study Results

    Participant Flow

    Recruitment Details
    Pre-assignment Detail
    Arm/Group Title Treatment (Combination Chemotherapy)
    Arm/Group Description 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. asparaginase: Given IM daunorubicin hydrochloride: Given IV cytarabine: Given IV or IT thioguanine: Given orally etoposide: Given IV laboratory biomarker analysis: Correlative studies
    Period Title: Overall Study
    STARTED 205
    COMPLETED 185
    NOT COMPLETED 20

    Baseline Characteristics

    Arm/Group Title Treatment (Combination Chemotherapy)
    Arm/Group Description 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. asparaginase: Given IM daunorubicin hydrochloride: Given IV cytarabine: Given IV or IT thioguanine: Given orally etoposide: Given IV laboratory biomarker analysis: Correlative studies
    Overall Participants 205
    Age (days) [Mean (Standard Deviation) ]
    Mean (Standard Deviation) [days]
    616.41
    (265.73)
    Age (Count of Participants)
    <=18 years
    205
    100%
    Between 18 and 65 years
    0
    0%
    >=65 years
    0
    0%
    Sex: Female, Male (Count of Participants)
    Female
    106
    51.7%
    Male
    99
    48.3%
    Race (NIH/OMB) (Count of Participants)
    American Indian or Alaska Native
    0
    0%
    Asian
    12
    5.9%
    Native Hawaiian or Other Pacific Islander
    2
    1%
    Black or African American
    28
    13.7%
    White
    141
    68.8%
    More than one race
    0
    0%
    Unknown or Not Reported
    22
    10.7%
    Ethnicity (NIH/OMB) (Count of Participants)
    Hispanic or Latino
    48
    23.4%
    Not Hispanic or Latino
    154
    75.1%
    Unknown or Not Reported
    3
    1.5%
    Region of Enrollment (participants) [Number]
    United States
    187
    91.2%
    Canada
    11
    5.4%
    Australia
    7
    3.4%

    Outcome Measures

    1. Primary Outcome
    Title Event-free Survival (EFS) at 3 Years
    Description
    Time Frame Time from study entry to induction failure, relapse, or death assessed at 3 years.

    Outcome Measure Data

    Analysis Population Description
    Ineligible patients are excluded from analyses of event free survival and overall survival.
    Arm/Group Title Treatment (Combination Chemotherapy)
    Arm/Group Description 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. asparaginase: Given IM daunorubicin hydrochloride: Given IV cytarabine: Given IV or IT thioguanine: Given orally etoposide: Given IV laboratory biomarker analysis: Correlative studies
    Measure Participants 204
    Number (95% Confidence Interval) [percentage]
    90.1
    2. Primary Outcome
    Title Overall Survival (OS) at 3 Years
    Description
    Time Frame Time from study entry to death, assessed at 3 years.

    Outcome Measure Data

    Analysis Population Description
    Ineligible patients are excluded from analyses of overall survival and event free survival.
    Arm/Group Title Treatment (Combination Chemotherapy)
    Arm/Group Description 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. asparaginase: Given IM daunorubicin hydrochloride: Given IV cytarabine: Given IV or IT thioguanine: Given orally etoposide: Given IV laboratory biomarker analysis: Correlative studies
    Measure Participants 204
    Number (95% Confidence Interval) [percentage]
    92.7
    3. Secondary Outcome
    Title Induction Remission Rate
    Description Proportion of participants with a remission after four courses of Induction therapy.
    Time Frame End of induction therapy (day 112)

    Outcome Measure Data

    Analysis Population Description
    Ineligible (n=1) patients are excluded. Patients who withdrew from therapy before completing 4 courses of Induction and did not die or relapse are not evaluable (n=9) for Induction remission rate.
    Arm/Group Title Treatment (Combination Chemotherapy)
    Arm/Group Description 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. asparaginase: Given IM daunorubicin hydrochloride: Given IV cytarabine: Given IV or IT thioguanine: Given orally etoposide: Given IV laboratory biomarker analysis: Correlative studies
    Measure Participants 195
    Number [Proportion of participants]
    0.984615
    0.5%
    4. Secondary Outcome
    Title 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
    Description Proportion of participants with at least one grade 3 or higher adverse event during therapy.
    Time Frame From the beginning of induction therapy to the end of intensification therapy

    Outcome Measure Data

    Analysis Population Description
    Ineligible patients (n=1) are excluded.
    Arm/Group Title Treatment (Combination Chemotherapy)
    Arm/Group Description 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. asparaginase: Given IM daunorubicin hydrochloride: Given IV cytarabine: Given IV or IT thioguanine: Given orally etoposide: Given IV laboratory biomarker analysis: Correlative studies
    Measure Participants 204
    Number [Proportion of participants]
    0.911765
    0.4%
    5. Secondary Outcome
    Title Prevalence of Leukemia Phenotype of DS Patients < 4 Years of Age at Diagnosis by Flow Cytometry
    Description Proportion of participants having megakaryoblastic subtype (AMkL) phenotype among patients with phenotype data available.
    Time Frame At the start of therapy

    Outcome Measure Data

    Analysis Population Description
    Ineligible patients (n=1) are excluded. Patients without available or evaluable phenotype data are excluded (n=40). Data are not available at end of therapy or relapse.
    Arm/Group Title Treatment (Combination Chemotherapy)
    Arm/Group Description 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. asparaginase: Given IM daunorubicin hydrochloride: Given IV cytarabine: Given IV or IT thioguanine: Given orally etoposide: Given IV laboratory biomarker analysis: Correlative studies
    Measure Participants 164
    Number [Proportion of participants]
    0.45122
    0.2%
    6. Secondary Outcome
    Title Prevalence of of GATA1 Mutations of DS Patients < 4 Years of Age at Diagnosis
    Description Proportion of participants having GATA1 mutation among patients with phenotype data available.
    Time Frame At baseline and at the end of therapy (intensification) or disease relapse

    Outcome Measure Data

    Analysis Population Description
    Ineligible patients (n=1) are excluded. Patients without available or evaluable phenotype data are excluded (n=158). Data are not available at end of therapy or relapse.
    Arm/Group Title Treatment (Combination Chemotherapy)
    Arm/Group Description 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. asparaginase: Given IM daunorubicin hydrochloride: Given IV cytarabine: Given IV or IT thioguanine: Given orally etoposide: Given IV laboratory biomarker analysis: Correlative studies
    Measure Participants 46
    Number [Proportion of participants]
    0.891304
    0.4%
    7. Secondary Outcome
    Title Proportions of Patients in Morphologic Remission With Positive MRD by Flow Cytometry
    Description Proportion of participants in complete remission by morphology and with positive MRD by flow cytometry among patients having evaluable remission and MRD assessment.
    Time Frame After Induction I therapy (day 28 from start of therapy)

    Outcome Measure Data

    Analysis Population Description
    Ineligible patients (n=1) are excluded. Patients without available MRD at end of Induction I (n=58) or not evaluable for morphologic remission assessment (n=7) are excluded. MRD data are not available at end of Induction IV or after completion of Intensification therapy.
    Arm/Group Title Treatment (Combination Chemotherapy)
    Arm/Group Description 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. asparaginase: Given IM daunorubicin hydrochloride: Given IV cytarabine: Given IV or IT thioguanine: Given orally etoposide: Given IV laboratory biomarker analysis: Correlative studies
    Measure Participants 139
    Number [Proportion of participants]
    0.0935254
    0%
    8. Secondary Outcome
    Title Cytarabine Drug Sensitivity by R-Strip (MicroMath) Curve Fitting Program
    Description Mean and standard deviation of peak plasma concentration. 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.
    Time Frame Days 1, 2, 8, and 9 of induction II

    Outcome Measure Data

    Analysis Population Description
    Ineligible patients (n=1) are excluded. Patients without available data from peak plasma concentration (n=146) are excluded.
    Arm/Group Title Treatment (Combination Chemotherapy)
    Arm/Group Description 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. asparaginase: Given IM daunorubicin hydrochloride: Given IV cytarabine: Given IV or IT thioguanine: Given orally etoposide: Given IV laboratory biomarker analysis: Correlative studies
    Measure Participants 58
    Mean (Standard Deviation) [Mean micromolar]
    32.69931
    (18.545798)
    9. Secondary Outcome
    Title Cytarabine Drug Sensitivity by R-Strip (MicroMath) Curve Fitting Program
    Description Mean and standard deviation of area under the concentration time curve. 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.
    Time Frame Days 1, 2, 8, and 9 of induction II

    Outcome Measure Data

    Analysis Population Description
    Ineligible patients (n=1) are excluded. Patients without available data for area under the concentration time curve (n=146) are excluded.
    Arm/Group Title Treatment (Combination Chemotherapy)
    Arm/Group Description 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. asparaginase: Given IM daunorubicin hydrochloride: Given IV cytarabine: Given IV or IT thioguanine: Given orally etoposide: Given IV laboratory biomarker analysis: Correlative studies
    Measure Participants 58
    Mean (Standard Deviation) [Mean micromolar x minutes]
    1337.279
    (1172.20853)
    10. Secondary Outcome
    Title Cytarabine Drug Sensitivity by R-Strip (MicroMath) Curve Fitting Program
    Description 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.
    Time Frame Days 1, 2, 8, and 9 of induction II

    Outcome Measure Data

    Analysis Population Description
    Ineligible patients (n=1) are excluded. Patients without available data for half-life of elimination (n=146) are excluded.
    Arm/Group Title Treatment (Combination Chemotherapy)
    Arm/Group Description 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. asparaginase: Given IM daunorubicin hydrochloride: Given IV cytarabine: Given IV or IT thioguanine: Given orally etoposide: Given IV laboratory biomarker analysis: Correlative studies
    Measure Participants 58
    Mean (Standard Deviation) [Mean minutes]
    306.156034
    (307.042662)
    11. Secondary Outcome
    Title Gene Expression Profiles by Microarrays
    Description 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.
    Time Frame At baseline and at the time of relapse (if available)

    Outcome Measure Data

    Analysis Population Description
    The Microarray analysis secondary outcome is not available because the number of specimens with good quality wasn't sufficient to yield meaningful results.
    Arm/Group Title Treatment (Combination Chemotherapy)
    Arm/Group Description 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. asparaginase: Given IM daunorubicin hydrochloride: Given IV cytarabine: Given IV or IT thioguanine: Given orally etoposide: Given IV laboratory biomarker analysis: Correlative studies
    Measure Participants 0

    Adverse Events

    Time Frame
    Adverse Event Reporting Description SAE field contains NCI CTCAEs submitted via expedited reporting (NCI AdEERs / CAeRs). The AE field contains grade 3 and higher CTCAEs reported on study excluding those that were reported as SAEs.
    Arm/Group Title Treatment (Combination Chemotherapy)
    Arm/Group Description 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. asparaginase: Given IM daunorubicin hydrochloride: Given IV cytarabine: Given IV or IT thioguanine: Given orally etoposide: Given IV laboratory biomarker analysis: Correlative studies
    All Cause Mortality
    Treatment (Combination Chemotherapy)
    Affected / at Risk (%) # Events
    Total / (NaN)
    Serious Adverse Events
    Treatment (Combination Chemotherapy)
    Affected / at Risk (%) # Events
    Total 3/204 (1.5%)
    Gastrointestinal disorders
    Ascites 1/204 (0.5%)
    Typhlitis 1/204 (0.5%)
    Hepatobiliary disorders
    Hepatic failure 1/204 (0.5%)
    Immune system disorders
    Immune system disorders - Other 1/204 (0.5%)
    Respiratory, thoracic and mediastinal disorders
    Hypoxia 1/204 (0.5%)
    Respiratory, thoracic and mediastinal disorders - Other 1/204 (0.5%)
    Other (Not Including Serious) Adverse Events
    Treatment (Combination Chemotherapy)
    Affected / at Risk (%) # Events
    Total 185/204 (90.7%)
    Blood and lymphatic system disorders
    Anemia 2/204 (1%)
    Blood and lymphatic system disorders - Other 1/204 (0.5%)
    Disseminated intravascular coagulation 1/204 (0.5%)
    Febrile neutropenia 105/204 (51.5%)
    Cardiac disorders
    Cardiac arrest 1/204 (0.5%)
    Cardiac disorders - Other 4/204 (2%)
    Pericardial effusion 2/204 (1%)
    Sinus tachycardia 2/204 (1%)
    Eye disorders
    Photophobia 1/204 (0.5%)
    Gastrointestinal disorders
    Abdominal pain 2/204 (1%)
    Anal pain 1/204 (0.5%)
    Colitis 4/204 (2%)
    Diarrhea 18/204 (8.8%)
    Dysphagia 1/204 (0.5%)
    Esophagitis 1/204 (0.5%)
    Gastritis 1/204 (0.5%)
    Gastrointestinal disorders - Other 1/204 (0.5%)
    Malabsorption 1/204 (0.5%)
    Mucositis oral 20/204 (9.8%)
    Nausea 1/204 (0.5%)
    Oral hemorrhage 1/204 (0.5%)
    Oral pain 5/204 (2.5%)
    Typhlitis 2/204 (1%)
    Upper gastrointestinal hemorrhage 1/204 (0.5%)
    Vomiting 8/204 (3.9%)
    General disorders
    Fatigue 1/204 (0.5%)
    Fever 7/204 (3.4%)
    Irritability 1/204 (0.5%)
    Pain 6/204 (2.9%)
    Immune system disorders
    Anaphylaxis 5/204 (2.5%)
    Infections and infestations
    Anorectal infection 1/204 (0.5%)
    Bladder infection 1/204 (0.5%)
    Catheter related infection 22/204 (10.8%)
    Conjunctivitis infective 1/204 (0.5%)
    Device related infection 1/204 (0.5%)
    Endocarditis infective 1/204 (0.5%)
    Enterocolitis infectious 13/204 (6.4%)
    Eye infection 1/204 (0.5%)
    Gum infection 1/204 (0.5%)
    Infections and infestations - Other 122/204 (59.8%)
    Lung infection 12/204 (5.9%)
    Otitis externa 1/204 (0.5%)
    Otitis media 2/204 (1%)
    Sepsis 8/204 (3.9%)
    Sinusitis 1/204 (0.5%)
    Skin infection 7/204 (3.4%)
    Small intestine infection 2/204 (1%)
    Soft tissue infection 2/204 (1%)
    Upper respiratory infection 11/204 (5.4%)
    Urinary tract infection 6/204 (2.9%)
    Vulval infection 1/204 (0.5%)
    Injury, poisoning and procedural complications
    Vascular access complication 1/204 (0.5%)
    Investigations
    Activated partial thromboplastin time prolonged 2/204 (1%)
    Alanine aminotransferase increased 23/204 (11.3%)
    Aspartate aminotransferase increased 9/204 (4.4%)
    Blood bilirubin increased 1/204 (0.5%)
    Electrocardiogram QT corrected interval prolonged 4/204 (2%)
    GGT increased 3/204 (1.5%)
    Investigations - Other 1/204 (0.5%)
    Lipase increased 2/204 (1%)
    Lymphocyte count decreased 2/204 (1%)
    Neutrophil count decreased 13/204 (6.4%)
    Platelet count decreased 4/204 (2%)
    Serum amylase increased 1/204 (0.5%)
    Weight loss 1/204 (0.5%)
    White blood cell decreased 5/204 (2.5%)
    Metabolism and nutrition disorders
    Acidosis 4/204 (2%)
    Alkalosis 1/204 (0.5%)
    Anorexia 24/204 (11.8%)
    Dehydration 4/204 (2%)
    Hyperglycemia 13/204 (6.4%)
    Hyperkalemia 8/204 (3.9%)
    Hypoalbuminemia 3/204 (1.5%)
    Hypocalcemia 11/204 (5.4%)
    Hypoglycemia 2/204 (1%)
    Hypokalemia 17/204 (8.3%)
    Hypomagnesemia 1/204 (0.5%)
    Hyponatremia 7/204 (3.4%)
    Hypophosphatemia 5/204 (2.5%)
    Metabolism and nutrition disorders - Other 1/204 (0.5%)
    Nervous system disorders
    Encephalopathy 1/204 (0.5%)
    Nervous system disorders - Other 1/204 (0.5%)
    Seizure 1/204 (0.5%)
    Renal and urinary disorders
    Acute kidney injury 1/204 (0.5%)
    Respiratory, thoracic and mediastinal disorders
    Adult respiratory distress syndrome 2/204 (1%)
    Apnea 1/204 (0.5%)
    Aspiration 2/204 (1%)
    Dyspnea 1/204 (0.5%)
    Epistaxis 2/204 (1%)
    Hypoxia 21/204 (10.3%)
    Laryngeal edema 1/204 (0.5%)
    Pharyngeal mucositis 1/204 (0.5%)
    Pleural effusion 2/204 (1%)
    Pneumonitis 2/204 (1%)
    Respiratory, thoracic and mediastinal disorders - Other 1/204 (0.5%)
    Stridor 1/204 (0.5%)
    Skin and subcutaneous tissue disorders
    Pain of skin 1/204 (0.5%)
    Purpura 1/204 (0.5%)
    Rash maculo-papular 3/204 (1.5%)
    Vascular disorders
    Hypertension 1/204 (0.5%)
    Hypotension 8/204 (3.9%)

    Limitations/Caveats

    [Not Specified]

    More Information

    Certain Agreements

    Principal Investigators are NOT employed by the organization sponsoring the study.

    Must obtain prior Sponsor approval.

    Results Point of Contact

    Name/Title Results Reporting Coordinator
    Organization Children's Oncology Group
    Phone 626-447-0064
    Email resultsreportingcoordintator@childrensoncologygroup.org
    Responsible Party:
    Children's Oncology Group
    ClinicalTrials.gov Identifier:
    NCT00369317
    Other Study ID Numbers:
    • AAML0431
    • NCI-2009-00318
    • CDR0000492776
    • COG-AAML0431
    • AAML0431
    • U10CA098543
    First Posted:
    Aug 29, 2006
    Last Update Posted:
    Jan 28, 2022
    Last Verified:
    Mar 1, 2021