Combination Chemotherapy in Treating Young Patients With Newly Diagnosed Acute Promyelocytic Leukemia

NCT ID: NCT00866918

Last Updated: 2022-10-25

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE3
• Total Enrollment: 106 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2009-03-09
• Study Completion Date: 2022-09-30

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.

Conditions

Childhood Acute Promyelocytic Leukemia With PML-RARA; Myeloid Neoplasm

Study Design

• Allocation Method: NON_RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Arm I (standard risk, combination chemotherapy)

See Detailed Description

Group Type: EXPERIMENTAL

Arsenic Trioxide

Intervention Type: DRUG

Given IV

Cytarabine

Intervention Type: DRUG

Given IT or IV

Diagnostic Laboratory Biomarker Analysis

Intervention Type: OTHER

Correlative studies

Idarubicin

Intervention Type: DRUG

Given IV

Mercaptopurine

Intervention Type: DRUG

Given orally

Methotrexate

Intervention Type: DRUG

Given orally

Mitoxantrone Hydrochloride

Intervention Type: DRUG

Given IV

Tretinoin

Intervention Type: DRUG

Given orally

Arm II (high risk, combination chemotherapy)

See Detailed Description.

Group Type: EXPERIMENTAL

Arsenic Trioxide

Intervention Type: DRUG

Given IV

Cytarabine

Intervention Type: DRUG

Given IT or IV

Diagnostic Laboratory Biomarker Analysis

Intervention Type: OTHER

Correlative studies

Idarubicin

Intervention Type: DRUG

Given IV

Mercaptopurine

Intervention Type: DRUG

Given orally

Methotrexate

Intervention Type: DRUG

Given orally

Mitoxantrone Hydrochloride

Intervention Type: DRUG

Given IV

Tretinoin

Intervention Type: DRUG

Given orally

Interventions

Arsenic Trioxide

Given IV

Intervention Type: DRUG

Cytarabine

Given IT or IV

Intervention Type: DRUG

Diagnostic Laboratory Biomarker Analysis

Correlative studies

Intervention Type: OTHER

Idarubicin

Given IV

Intervention Type: DRUG

Mercaptopurine

Given orally

Intervention Type: DRUG

Methotrexate

Given orally

Intervention Type: DRUG

Mitoxantrone Hydrochloride

Given IV

Intervention Type: DRUG

Tretinoin

Given orally

Intervention Type: DRUG

Other Intervention Names

Arsenic (III) Oxide; Arsenic Sesquioxide; Arsenous Acid; Arsenous Acid Anhydride; Arsenous Oxide; ATO; Trisenox; White Arsenic; .beta.-Cytosine arabinoside; 1-.beta.-D-Arabinofuranosyl-4-amino-2(1H)pyrimidinone; 1-.beta.-D-Arabinofuranosylcytosine; 1-Beta-D-arabinofuranosyl-4-amino-2(1H)pyrimidinone; 1-Beta-D-arabinofuranosylcytosine; 1.beta.-D-Arabinofuranosylcytosine; 2(1H)-Pyrimidinone, 4-Amino-1-beta-D-arabinofuranosyl-; 2(1H)-Pyrimidinone, 4-amino-1.beta.-D-arabinofuranosyl-; Alexan; Ara-C; ARA-cell; Arabine; Arabinofuranosylcytosine; Arabinosylcytosine; Aracytidine; Aracytin; Aracytine; Beta-Cytosine Arabinoside; CHX-3311; Cytarabinum; Cytarbel; Cytosar; Cytosine Arabinoside; Cytosine-.beta.-arabinoside; Cytosine-beta-arabinoside; Erpalfa; Starasid; Tarabine PFS; U 19920; U-19920; Udicil; WR-28453; 4-Demethoxydaunomycin; 4-Demethoxydaunorubicin; 4-DMDR; 3H-Purine-6-thiol; 6 MP; 6 Thiohypoxanthine; 6 Thiopurine; 6-Mercaptopurine; 6-Mercaptopurine Monohydrate; 6-MP; 6-Purinethiol; 6-Thiopurine; 6-Thioxopurine; 6H-Purine-6-thione, 1,7-dihydro- (9CI); 7-Mercapto-1,3,4,6-tetrazaindene; Alti-Mercaptopurine; Azathiopurine; Bw 57-323H; Flocofil; Ismipur; Leukerin; Leupurin; Mercaleukim; Mercaleukin; Mercaptina; Mercaptopurinum; Mercapurin; Mern; NCI-C04886; Puri-Nethol; Purimethol; Purine, 6-mercapto-; Purine-6-thiol (8CI); Purine-6-thiol, monohydrate; Purinethiol; Purinethol; U-4748; WR-2785; Abitrexate; Alpha-Methopterin; Amethopterin; Brimexate; CL 14377; CL-14377; Emtexate; Emthexat; Emthexate; Farmitrexat; Fauldexato; Folex; Folex PFS; Lantarel; Ledertrexate; Lumexon; Maxtrex; Medsatrexate; Metex; Methoblastin; Methotrexate LPF; Methotrexate Methylaminopterin; Methotrexatum; Metotrexato; Metrotex; Mexate; Mexate-AQ; MTX; Novatrex; Rheumatrex; Texate; Tremetex; Trexeron; Trixilem; WR-19039; CL 232315; DHAD; DHAQ; Dihydroxyanthracenedione Dihydrochloride; Mitoxantrone Dihydrochloride; Mitoxantroni Hydrochloridum; Mitozantrone Hydrochloride; Mitroxone; Neotalem; Novantrone; Onkotrone; Pralifan; 2,4,6,8-Nonatetraenoic acid, 3, 7-dimethyl-9-(2,6,6-trimethyl-1-cyclohexen-1-yl)-, (all-E)-; Aberel; Airol; Aknoten; all trans-Retinoic acid; All-trans Retinoic Acid; All-trans Vitamin A Acid; all-trans-Retinoic acid; all-trans-Vitamin A acid; ATRA; Avita; beta-Retinoic Acid; Cordes Vas; Dermairol; Epi-Aberel; Eudyna; Renova; Retin-A; Retin-A MICRO; Retin-A-Micro; Retinoic Acid; Retisol-A; Ro 5488; Stieva-A; Stieva-A Forte; Trans Retinoic Acid; Trans Vitamin A Acid; trans-Retinoic Acid; Tretinoinum; Vesanoid; Vitamin A Acid; Vitamin A acid, all-trans-; Vitinoin

Eligibility Criteria

Inclusion Criteria

• 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

Exclusion Criteria

• 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

• Minimum Eligible Age: 2 Years
• Maximum Eligible Age: 21 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

National Cancer Institute (NCI)

NIH

Sponsor Role: collaborator

Children's Oncology Group

NETWORK

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

John J Gregory

Role: PRINCIPAL_INVESTIGATOR

Children's Oncology Group

Locations

Children's Hospital of Alabama

Birmingham, Alabama, United States

University of Alabama at Birmingham Cancer Center

Birmingham, Alabama, United States

Phoenix Childrens Hospital

Phoenix, Arizona, United States

Arkansas Children's Hospital

Little Rock, Arkansas, United States

University of Arkansas for Medical Sciences

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

Children's Hospital Los Angeles

Los Angeles, California, United States

UCLA / Jonsson Comprehensive Cancer Center

Los Angeles, California, United States

Valley Children's Hospital

Madera, California, United States

UCSF Benioff Children's Hospital Oakland

Oakland, California, United States

Children's Hospital of Orange County

Orange, California, United States

Lucile Packard Children's Hospital Stanford University

Palo Alto, California, United States

Rady Children's Hospital - San Diego

San Diego, California, United States

UCSF Medical Center-Mount Zion

San Francisco, California, United States

UCSF Medical Center-Parnassus

San Francisco, California, United States

Harbor-University of California at Los Angeles Medical Center

Torrance, California, United States

Children's Hospital Colorado

Aurora, Colorado, United States

University of Connecticut

Farmington, Connecticut, United States

Connecticut Children's Medical Center

Hartford, Connecticut, United States

Alfred I duPont Hospital for Children

Wilmington, Delaware, United States

MedStar Georgetown University Hospital

Washington D.C., District of Columbia, United States

Children's National Medical Center

Washington D.C., District of Columbia, United States

Lee Memorial Health System

Fort Myers, Florida, United States

Golisano Children's Hospital of Southwest Florida

Fort Myers, Florida, United States

Nemours Children's Clinic-Jacksonville

Jacksonville, Florida, United States

AdventHealth Orlando

Orlando, Florida, United States

Nemours Children's Clinic - Orlando

Orlando, Florida, United States

Orlando Health Cancer Institute

Orlando, Florida, United States

Nemours Children's Clinic - Pensacola

Pensacola, Florida, United States

Sacred Heart Hospital

Pensacola, Florida, United States

Johns Hopkins All Children's Hospital

St. Petersburg, Florida, United States

Saint Joseph's Hospital/Children's Hospital-Tampa

Tampa, Florida, United States

Saint Mary's Hospital

West Palm Beach, Florida, United States

Children's Healthcare of Atlanta - Egleston

Atlanta, Georgia, United States

Emory University Hospital/Winship Cancer Institute

Atlanta, Georgia, United States

Memorial Health University Medical Center

Savannah, Georgia, United States

University of Hawaii Cancer Center

Honolulu, Hawaii, United States

Lurie Children's Hospital-Chicago

Chicago, Illinois, United States

Loyola University Medical Center

Maywood, Illinois, United States

Advocate Children's Hospital-Oak Lawn

Oak Lawn, Illinois, United States

Saint Jude Midwest Affiliate

Peoria, Illinois, United States

Southern Illinois University School of Medicine

Springfield, Illinois, 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

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

Eastern Maine Medical Center

Bangor, Maine, United States

Sinai Hospital of Baltimore

Baltimore, Maryland, United States

Johns Hopkins University/Sidney Kimmel Cancer Center

Baltimore, Maryland, United States

Dana-Farber Cancer Institute

Boston, Massachusetts, United States

Baystate Medical Center

Springfield, Massachusetts, United States

UMass Memorial Medical Center - University Campus

Worcester, Massachusetts, United States

C S Mott Children's Hospital

Ann Arbor, Michigan, United States

Wayne State University/Karmanos Cancer Institute

Detroit, Michigan, United States

Ascension Saint John Hospital

Detroit, Michigan, United States

Michigan State University Clinical Center

East Lansing, Michigan, United States

Helen DeVos Children's Hospital at Spectrum Health

Grand Rapids, Michigan, United States

Spectrum Health at Butterworth Campus

Grand Rapids, Michigan, United States

Children's Hospitals and Clinics of Minnesota - Minneapolis

Minneapolis, Minnesota, United States

Mayo Clinic in Rochester

Rochester, Minnesota, United States

University of Mississippi Medical Center

Jackson, Mississippi, United States

Children's Mercy Hospitals and Clinics

Kansas City, Missouri, United States

Cardinal Glennon Children's Medical Center

St Louis, Missouri, United States

Washington University School of Medicine

St Louis, Missouri, United States

Nevada Cancer Research Foundation NCORP

Las Vegas, Nevada, United States

Hackensack University Medical Center

Hackensack, New Jersey, United States

Morristown Medical Center

Morristown, New Jersey, United States

Rutgers Cancer Institute of New Jersey-Robert Wood Johnson University Hospital

New Brunswick, New Jersey, United States

Saint Joseph's Regional Medical Center

Paterson, New Jersey, United States

Overlook Hospital

Summit, New Jersey, United States

University of New Mexico Cancer Center

Albuquerque, New Mexico, United States

Roswell Park Cancer Institute

Buffalo, New York, United States

NYP/Columbia University Medical Center/Herbert Irving Comprehensive Cancer Center

New York, New York, United States

State University of New York Upstate Medical University

Syracuse, New York, United States

Montefiore Medical Center - Moses Campus

The Bronx, New York, United States

UNC Lineberger Comprehensive Cancer Center

Chapel Hill, North Carolina, United States

Carolinas Medical Center/Levine Cancer Institute

Charlotte, North Carolina, United States

Novant Health Presbyterian Medical Center

Charlotte, North Carolina, United States

Duke University Medical Center

Durham, North Carolina, United States

Wake Forest University Health Sciences

Winston-Salem, North Carolina, United States

Sanford Broadway Medical Center

Fargo, North Dakota, United States

Cincinnati Children's Hospital Medical Center

Cincinnati, Ohio, 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

Dayton Children's Hospital

Dayton, Ohio, United States

ProMedica Toledo Hospital/Russell J Ebeid Children's Hospital

Toledo, Ohio, United States

University of Oklahoma Health Sciences Center

Oklahoma City, Oklahoma, United States

Oregon Health and Science University

Portland, Oregon, United States

Penn State Milton S Hershey Medical Center

Hershey, Pennsylvania, United States

Penn State Children's Hospital

Hershey, Pennsylvania, United States

Children's Hospital of Philadelphia

Philadelphia, Pennsylvania, United States

Children's Oncology Group

Philadelphia, Pennsylvania, United States

Children's Hospital of Pittsburgh of UPMC

Pittsburgh, Pennsylvania, United States

Prisma Health Richland Hospital

Columbia, South Carolina, United States

BI-LO Charities Children's Cancer Center

Greenville, South Carolina, United States

Greenville Cancer Treatment Center

Greenville, South Carolina, United States

T C Thompson Children's Hospital

Chattanooga, Tennessee, United States

Saint Jude Children's Research Hospital

Memphis, Tennessee, United States

Driscoll Children's Hospital

Corpus Christi, Texas, United States

Cook Children's Medical Center

Fort Worth, Texas, 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

Primary Children's Hospital

Salt Lake City, Utah, United States

Seattle Children's Hospital

Seattle, Washington, United States

Saint Vincent Hospital Cancer Center Green Bay

Green Bay, Wisconsin, United States

Marshfield Medical Center-Marshfield

Marshfield, Wisconsin, United States

Children's Hospital of Wisconsin

Milwaukee, Wisconsin, United States

British Columbia Children's Hospital

Vancouver, British Columbia, Canada

CancerCare Manitoba

Winnipeg, Manitoba, Canada

IWK Health Centre

Halifax, Nova Scotia, Canada

McMaster Children's Hospital at Hamilton Health Sciences

Hamilton, Ontario, Canada

Children's Hospital of Eastern Ontario

Ottawa, Ontario, Canada

Hospital for Sick Children

Toronto, Ontario, Canada

Centre Hospitalier Universitaire Sainte-Justine

Montreal, Quebec, Canada

Centre Hospitalier Universitaire de Quebec

Québec, , Canada

San Jorge Children's Hospital

San Juan, , Puerto Rico

Countries

United States; Canada; Puerto Rico

Related Links

https://nctn-data-archive.nci.nih.gov/

Data Available: Select individual patient-level data from this trial can be requested from the NCTN/NCORP Data Archive

Other Identifiers

NCI-2011-01904

Identifier Type: REGISTRY

Identifier Source: secondary_id

CDR0000637184

Identifier Type: -

Identifier Source: secondary_id

AAML0631

Identifier Type: OTHER

Identifier Source: secondary_id

AAML0631

Identifier Type: OTHER

Identifier Source: secondary_id

U10CA098543

Identifier Type: NIH

Identifier Source: secondary_id

View Link

AAML0631

Identifier Type: -

Identifier Source: org_study_id