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The Treatment of Down Syndrome Children With Acute Myeloid Leukemia (AML) and Myelodysplastic Syndromes (MDS) Under the Age of 4 Years


Phase 3
N/A
3 Years
Open (Enrolling)
Both
Leukemia, Myelodysplastic Syndromes

Thank you

Trial Information

The Treatment of Down Syndrome Children With Acute Myeloid Leukemia (AML) and Myelodysplastic Syndromes (MDS) Under the Age of 4 Years


OBJECTIVES:

Primary

- Determine the event-free survival (EFS) and overall survival rates in pediatric
patients with Down syndrome and acute myeloid leukemia or myelodysplastic syndromes
treated with induction therapy comprising cytarabine, daunorubicin hydrochloride,
thioguanine, and asparaginase followed by intensification therapy comprising cytarabine
and etoposide.

- 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.

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

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

Secondary

- Determine the type and degree of treatment-related toxicity in these patients.

- Determine the prevalence of leukemia phenotype and GATA1 mutations of DS patients < 4
years of age at diagnosis.

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

- 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.

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

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

- 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.

- Assess the effect of karyotypic abnormalities on survival.

- 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 1: 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 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 2: 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 3: Patients receive treatment as in course 1.

- Course 4: 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.

PROJECTED ACCRUAL: A total of 205 patients will be accrued for this study.

Inclusion Criteria


DISEASE CHARACTERISTICS:

- Diagnosis of Down syndrome (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

PATIENT CHARACTERISTICS:

- 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]) OR

- Creatinine clearance or radioisotope glomerular filtration rate at least 70 mL/min

- No evidence of dyspnea at rest

- No exercise intolerance

- Pulse oximetry > 94%

PRIOR CONCURRENT THERAPY:

- No prior chemotherapy, radiotherapy, or any antileukemic therapy

- Intrathecal cytarabine therapy given at diagnosis allowed

- Prior therapy for TMD allowed

Type of Study:

Interventional

Study Design:

Allocation: Non-Randomized, Primary Purpose: Treatment

Outcome Measure:

Event-free survival from the beginning of the study to the time to induction failure, relapse, or death

Safety Issue:

No

Principal Investigator

Jeffrey Taub, MD

Investigator Role:

Study Chair

Investigator Affiliation:

Children's Hospital of Michigan

Authority:

United States: Federal Government

Study ID:

CDR0000492776

NCT ID:

NCT00369317

Start Date:

March 2007

Completion Date:

Related Keywords:

  • Leukemia
  • Myelodysplastic Syndromes
  • de novo myelodysplastic syndromes
  • secondary myelodysplastic syndromes
  • untreated childhood acute myeloid leukemia and other myeloid malignancies
  • childhood acute minimally differentiated myeloid leukemia (M0)
  • secondary acute myeloid leukemia
  • childhood acute basophilic leukemia
  • childhood acute monocytic leukemia (M5b)
  • childhood acute eosinophilic leukemia
  • childhood acute erythroleukemia (M6)
  • childhood acute megakaryocytic leukemia (M7)
  • childhood acute myeloblastic leukemia with maturation (M2)
  • childhood acute myeloblastic leukemia without maturation (M1)
  • childhood acute myelomonocytic leukemia (M4)
  • childhood acute monoblastic leukemia (M5a)
  • childhood myelodysplastic syndromes
  • Down Syndrome
  • Leukemia
  • Leukemia, Myeloid, Acute
  • Leukemia, Myeloid
  • Myelodysplastic Syndromes
  • Preleukemia

Name

Location

National Naval Medical CenterBethesda, Maryland  20889
Roswell Park Cancer InstituteBuffalo, New York  14263
Memorial Sloan-Kettering Cancer CenterNew York, New York  10021
Children's Hospital of PhiladelphiaPhiladelphia, Pennsylvania  19104
Mayo Clinic Cancer CenterRochester, Minnesota  55905
Cardinal Bernardin Cancer Center at Loyola University Medical CenterMaywood, Illinois  60153-5500
University of Chicago Cancer Research CenterChicago, Illinois  60637
Barbara Ann Karmanos Cancer InstituteDetroit, Michigan  48201
Hurley Medical CenterFlint, Michigan  48503
Medical City Dallas HospitalDallas, Texas  75230
University of Texas Health Science Center at San AntonioSan Antonio, Texas  78284-7811
Presbyterian - St. Luke's Medical CenterDenver, Colorado  80218
Van Elslander Cancer Center at St. John Hospital and Medical CenterGrosse Pointe Woods, Michigan  48236
CCOP - MeritCare HospitalFargo, North Dakota  58122
Sanford Cancer Center at Sanford USD Medical CenterSioux Falls, South Dakota  57117-5039
Vanderbilt-Ingram Cancer CenterNashville, Tennessee  37232-6838
Marshfield Clinic - Marshfield CenterMarshfield, Wisconsin  54449
Newark Beth Israel Medical CenterNewark, New Jersey  07112
New York Medical CollegeValhalla, New York  10595
Lineberger Comprehensive Cancer Center at University of North Carolina - Chapel HillChapel Hill, North Carolina  27599-7570
Sidney Kimmel Comprehensive Cancer Center at Johns HopkinsBaltimore, Maryland  21231-2410
Cancer Research Center of HawaiiHonolulu, Hawaii  96813
Cleveland Clinic Taussig Cancer CenterCleveland, Ohio  44195
Brooke Army Medical CenterFort Sam Houston, Texas  78234-6200
Sutter Cancer CenterSacramento, California  95816
Children's Hospital of Orange CountyOrange, California  92668
Children's National Medical CenterWashington, District of Columbia  20010-2970
Children's Mercy HospitalKansas City, Missouri  64108
Children's Hospital and Regional Medical Center - SeattleSeattle, Washington  98105
Nemours Children's ClinicJacksonville, Florida  32207
All Children's HospitalSt. Petersburg, Florida  33701
Children's Memorial Hospital - ChicagoChicago, Illinois  60614
Saint Jude Midwest AffiliatePeoria, Illinois  61637
St. Christopher's Hospital for ChildrenPhiladelphia, Pennsylvania  19134-1095
St. Jude Children's Research HospitalMemphis, Tennessee  38105-2794
Driscoll Children's HospitalCorpus Christi, Texas  78466
Cook Children's Medical Center - Fort WorthFort Worth, Texas  76104
Inova Fairfax HospitalFalls Church, Virginia  22042-3300
Fletcher Allen Health Care - University Health Center CampusBurlington, Vermont  05401
Phoenix Children's HospitalPhoenix, Arizona  85016-7710
Southern California Permanente Medical GroupDowney, California  90242
Children's Hospital Central CaliforniaMadera, California  93638-8762
Kosair Children's HospitalLouisville, Kentucky  40202-3830
Brooklyn Hospital CenterBrooklyn, New York  11201
Palmetto Health South Carolina Cancer CenterColumbia, South Carolina  29203
East Tennessee Children's HospitalKnoxville, Tennessee  37901
Covenant Children's HospitalLubbock, Texas  79410
Children's Hospital of the King's DaughtersNorfolk, Virginia  23507
Midwest Children's Cancer Center at Children's Hospital of WisconsinMilwaukee, Wisconsin  53226
Arizona Cancer Center at University of Arizona Health Sciences CenterTucson, Arizona  85724
Arkansas Cancer Research Center at University of Arkansas for Medical SciencesLittle Rock, Arkansas  72205
Blumenthal Cancer Center at Carolinas Medical CenterCharlotte, North Carolina  28232-2861
Overlook HospitalSummit, New Jersey  07902-0220
Loma Linda University Cancer Institute at Loma Linda University Medical CenterLoma Linda, California  92354
Jonathan Jaques Children's Cancer Center at Miller Children's HospitalLong Beach, California  90801
Kaiser Permanente Medical Center - OaklandSacramento, California  95825
Lee Cancer Care of Lee Memorial Health SystemFort Myers, Florida  33901
Broward General Medical Center Cancer CenterFt. Lauderdale, Florida  33316
University of Florida Shands Cancer CenterGainesville, Florida  32610-0232
Nemours Children's Clinic - OrlandoOrlando, Florida  32806
Florida Hospital Cancer Institute at Florida Hospital OrlandoOrlando, Florida  32803-1273
St. Joseph's Cancer Institute at St. Joseph's HospitalTampa, Florida  33607
Kaplan Cancer Center at St. Mary's Medical CenterWest Palm Beach, Florida  33407
St. Vincent Indianapolis HospitalIndianapolis, Indiana  46260
Blank Children's HospitalDes Moines, Iowa  50309
Alvin and Lois Lapidus Cancer Institute at Sinai HospitalBaltimore, Maryland  21215
Breslin Cancer Center at Ingham Regional Medical CenterLansing, Michigan  48910
Hackensack University Medical Center Cancer CenterHackensack, New Jersey  07601
Stony Brook University Cancer CenterStony Brook, New York  11794-8174
SUNY Upstate Medical University HospitalSyracuse, New York  13210
Presbyterian Cancer Center at Presbyterian HospitalCharlotte, North Carolina  28233-3549
Wake Forest University Comprehensive Cancer CenterWinston-Salem, North Carolina  27157-1096
Cincinnati Children's Hospital Medical CenterCincinnati, Ohio  45229-3039
Rainbow Babies and Children's HospitalCleveland, Ohio  44106-5000
Rhode Island Hospital Comprehensive Cancer CenterProvidence, Rhode Island  02903
Hollings Cancer Center at Medical University of South CarolinaCharleston, South Carolina  29425
Texas Tech University Health Sciences Center School of Medicine - AmarilloAmarillo, Texas  79106
Simmons Comprehensive Cancer Center at University of Texas Southwestern Medical Center - DallasDallas, Texas  75390
Baylor University Medical Center - HoustonHouston, Texas  77030-2399
Methodist Children's Hospital of South TexasSan Antonio, Texas  78229-3993
Primary Children's Medical CenterSalt Lake City, Utah  84113-1100
Saint Peter's University HospitalNew Brunswick, New Jersey  08901-1780
James P. Wilmot Cancer Center at University of Rochester Medical CenterRochester, New York  14642
UNMC Eppley Cancer Center at the University of Nebraska Medical CenterOmaha, Nebraska  68198-7680
Memorial Cancer Institute at Memorial Regional HospitalHollywood, Florida  33021
Samuel Oschin Comprehensive Cancer Institute at Cedars-Sinai Medical CenterLos Angeles, California  90048-1865
Jonsson Comprehensive Cancer Center at UCLALos Angeles, California  90095-1781
Childrens Hospital Los AngelesLos Angeles, California  90027
Children's Hospital and Research Center OaklandOakland, California  94609
Lucile Packard Children's Hospital at Stanford University Medical CenterPalo Alto, California  95798
Rady Children's Hospital - San DiegoSan Diego, California  92123-4282
UCSF Helen Diller Family Comprehensive Cancer CenterSan Francisco, California  94115
Alfred I. duPont Hospital for ChildrenWilmington, Delaware  19803
Lombardi Comprehensive Cancer Center at Georgetown University Medical CenterWashington, District of Columbia  20007
AFLAC Cancer Center and Blood Disorders Service of Children's Healthcare of Atlanta - Egleston CampusAtlanta, Georgia  30322
Mountain States Tumor Institute at St. Luke's Regional Medical CenterBoise, Idaho  83712-6297
Keyser Family Cancer Center at Advocate Hope Children's HospitalOak Lawn, Illinois  60453
Advocate Lutheran General Cancer Care CenterPark Ridge, Illinois  60068-1174
Simmons Cooper Cancer InstituteSpringfield, Illinois  62794-9677
Lucille P. Markey Cancer Center at University of KentuckyLexington, Kentucky  40536-0093
Tulane Cancer Center Office of Clinical ResearchAlexandria, Louisiana  71315-3198
CancerCare of Maine at Eastern Maine Medical CenterBangor, Maine  04401
Dana-Farber/Harvard Cancer Center at Dana-Farber Cancer InstituteBoston, Massachusetts  02115
C.S. Mott Children's Hospital at University of Michigan Medical CenterAnn Arbor, Michigan  48109-0286
Masonic Cancer Center at University of MinnesotaMinneapolis, Minnesota  55455
Children's Hospitals and Clinics of Minnesota - MinneapolisMinneapolis, Minnesota  55404
University of Mississippi Cancer ClinicJackson, Mississippi  39216-4505
Children's HospitalOmaha, Nebraska  68114-4113
CCOP - Nevada Cancer Research FoundationLas Vegas, Nevada  89109-2306
Cancer Institute of New Jersey at UMDNJ - Robert Wood Johnson Medical SchoolNew Brunswick, New Jersey  08903
University of New Mexico Cancer CenterAlbuquerque, New Mexico  87131-5636
Albany Medical Center HospitalAlbany, New York  12208-3419
Maimonides Cancer Center at Maimonides Medical CenterBrooklyn, New York  11219
Herbert Irving Comprehensive Cancer Center at Columbia University Medical CenterNew York, New York  10032
Akron Children's HospitalAkron, Ohio  44308-1062
Nationwide Children's HospitalColumbus, Ohio  43205-2696
Dayton Children's - DaytonDayton, Ohio  45404-1815
Tod Children's HospitalYoungstown, Ohio  44501
Oklahoma University Cancer InstituteOklahoma City, Oklahoma  73104
Knight Cancer Institute at Oregon Health and Science UniversityPortland, Oregon  97239-3098
Legacy Emanuel Hospital and Health Center and Children's HospitalPortland, Oregon  97227
Geisinger Cancer Institute at Geisinger HealthDanville, Pennsylvania  17822-0001
Penn State Children's HospitalHershey, Pennsylvania  17033-0850
Children's Hospital of Pittsburgh of UPMCPittsburgh, Pennsylvania  15213
Dell Children's Medical Center of Central TexasAustin, Texas  78723
Virginia Commonwealth University Massey Cancer CenterRichmond, Virginia  23298-0037
Carilion Medical Center for Children at Roanoke Community HospitalRoanoke, Virginia  24014
Madigan Army Medical Center - TacomaTacoma, Washington  98431
Mary Bridge Children's Hospital and Health Center - TacomaTacoma, Washington  98405
West Virginia University Health Sciences Center - CharlestonCharleston, West Virginia  25302
Riley's Children Cancer Center at Riley Hospital for ChildrenIndianapolis, Indiana  46202-5225
UAB Comprehensive Cancer CenterBirmingham, Alabama  35294
University of Miami Sylvester Comprehensive Cancer Center - MiamiMiami, Florida  33136
Lehigh Valley Hospital - MuhlenbergBethlehem, Pennsylvania  18017
Duke Cancer InstituteDurham, North Carolina  27710
Greenville Hospital Cancer CenterGreenville, South Carolina  29605
Connecticut Children's Medical CenterHartford, Connecticut  06106
Children's Hospital Colorado Center for Cancer and Blood DisordersAurora, Colorado  80045
Nemours Children's Clinic - PensacolaPensacola, Florida  32504
Helen DeVos Children's Hospital at Spectrum HealthGrand Rapids, Michigan  49503
Mercy Children's HospitalToledo, Ohio  43608