Alternate Title
Basic Trial Information
Objectives
Entry Criteria
Expected Enrollment
Outline
Published Results
Related Publications
Trial Contact Information
Registry Information

Alternate Title

Tretinoin, Cytarabine, and Daunorubicin With or Without Arsenic Trioxide Followed by Tretinoin With or Without Mercaptopurine and Methotrexate in Treating Patients With Acute Promyelocytic Leukemia

Basic Trial Information

Phase	Type	Status	Age	Sponsor	Protocol IDs
Phase III	Treatment	Closed	Any age	NCI	CALGB-C9710 CAN-NCIC-AL3, COG-C9710, ECOG-C9710, SWOG-C9710, CAN-NCIC-C9710, C9710, NCT00003934, AL3

Objectives

1. Compare the efficacy (event-free survival) and toxicity of tretinoin, cytarabine, and daunorubicin with or without arsenic trioxide as induction/consolidation therapy in patients with previously untreated acute promyelocytic leukemia.
2. Evaluate the efficacy (disease-free survival) and toxicity of intermittent tretinoin with or without mercaptopurine and methotrexate as maintenance therapy in these patients who achieve a complete response after induction/consolidation therapy.
3. Determine the relationship between CD56 expression at diagnosis and clinical outcomes in these patients treated with this regimen.
4. Evaluate the cardiac toxicity of intensive daunorubicin therapy in pediatric patients.

Entry Criteria

Disease Characteristics:

• Clinically diagnosed, previously untreated acute promyelocytic leukemia (APL) with proof of APL morphology (FAB-M3) confirmed by reverse transcriptase polymerase chain reaction
  • M3 characteristics by aspirate smear
  • At least 30% of cells must be abnormal promyelocytes with heavy granulation
  • Overall marrow cellularity must be normocellular or hypercellular
  • Microgranular variant (M3V) eligible

Prior/Concurrent Therapy:

Biologic therapy:

• No concurrent growth factors, except filgrastim (G-CSF) or sargramostim (GM-CSF) for life-threatening clinical deterioration (e.g., severe pneumonia, hypotension, multiorgan dysfunction, or fungal infection)

Chemotherapy:

• No prior cytotoxic chemotherapy for APL
• Prior hydroxyurea allowed

Endocrine therapy:

• Prior corticosteroids allowed

Radiotherapy:

• No concurrent palliative radiotherapy

Surgery:

• Not specified

Other:

• Prior leukapheresis allowed
• No prior retinoids for APL

Patient Characteristics:

Age:

• Any age

Performance status:

• Not specified

Life expectancy:

• Not specified

Hematopoietic:

• Not specified

Hepatic:

• Not specified

Renal:

• Not specified

Other:

• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception

Expected Enrollment

A total of 522 patients (456 adults and 66 pediatric) will be accrued for this study within 4.75 years.

Outline

This is a randomized, multicenter study. Patients are stratified according to age (under 15 vs 15 to 60 vs over 60) for the induction phase. Patients are stratified according to age, as in the induction phase, and the consolidation arm (with vs without arsenic trioxide) for the consolidation phase. Patients under age 5 do not receive arsenic trioxide.

• Induction: All patients receive oral tretinoin every 12 hours beginning on day 1 until complete response or for a maximum of 90 days. Patients also receive daunorubicin IV on days 3-6 and cytarabine IV continuously on days 3-9.



• Consolidation: All patients achieving complete response (CR), or partial response (PR) after completion of tretinoin, proceed to consolidation within 2 weeks of achieving CR or PR, but not prior to 30 days from the start of induction. Patients are randomized to 1 of 2 treatment arms.
  • Arm I: Patients receive oral tretinoin every 12 hours on days 1-7 and daunorubicin IV on days 1-2 or days 1-3, depending on age. Patients may receive an additional course. Treatment begins no earlier than 2 weeks and no later than 4 weeks after hematopoietic recovery.
  
  
  
  • Arm II: Patients receive arsenic trioxide IV over 2 hours daily 5 days a week for 5 weeks. After a 2-week rest, patients receive a second course of arsenic trioxide. Patients then receive tretinoin and daunorubicin as in arm I.
  
  
  



• Maintenance: Patients maintaining CR or PR after consolidation therapy proceed to maintenance therapy, beginning no earlier than 2 weeks and no later than 4 weeks after hematopoietic recovery. Patients are randomized to 1 of 2 treatment arms.
  • Arm I: Patients receive oral tretinoin every 12 hours for 7 days every other week for 1 year.
  
  
  
  • Arm II: Patients receive oral tretinoin as in arm I above. Patients also receive oral mercaptopurine once a day and oral methotrexate once weekly for up to 1 year.
  
  
  

Maintenance therapy continues for up to 1 year in the absence of unacceptable toxicity.

Patients are followed every 2 months for 2 years, every 3 months for 1 year, every 6 months for 2 years, and then annually for 5 years.

Stock W, Najib K, Moser BK, et al.: High incidence of FLT3 mutations in adults with Acute Promyelocytic Leukemia (APL): correlation with diagnostic features and treatment outcome (CALGB 9710). [Abstract] J Clin Oncol 26 (Suppl 15): A-7002, 2008.

Powell BL, Moser B, Stock W, et al.: Effect of consolidation with arsenic trioxide (As2O3) on event-free survival (EFS) and overall survival (OS) among patients with newly diagnosed acute promyelocytic leukemia (APL): North American Intergroup Protocol C9710. [Abstract] J Clin Oncol 25 (Suppl 18): A-2, 2007.

Gallagher RE, Schachter-Tokarz EL, Moser BK, et al.: Frequent PML-RARα mutations in relapse patients on acute promyelocytic leukemia (APL) intergroup phase III trial C9710. [Abstract] Blood 108 (11): A-2342, 2006.

Powell BL, Moser B, Stock W, et al.: Preliminary results from the North American Acute Promyelocytic Leukemia (APL) study C9710. [Abstract] Blood 108 (11): A-566, 2006.

Stock W, Harvey R, Moser B, et al.: Minimal residual disease (MRD) and risk of relapse in acute promyelocytic leukemia (APL): insights from the North American Intergroup phase III trial C9710. [Abstract] Blood 108 (11): A-494, 2006.

Dvorak CC, Agarwal R, Dahl GV, et al.: Hematopoietic stem cell transplant for pediatric acute promyelocytic leukemia. Biol Blood Marrow Transplant 14 (7): 824-30, 2008.[PUBMED Abstract]

Paietta E, Goloubeva O, Neuberg D, et al.: A surrogate marker profile for PML/RAR alpha expressing acute promyelocytic leukemia and the association of immunophenotypic markers with morphologic and molecular subtypes. Cytometry B Clin Cytom 59B (1): 1-9, 2004.[PUBMED Abstract]

Paietta E, Goloubeva O, Bennett JM, et al.: A surrogate marker profile for acute promyelocytic leukemia (APL) and the association of immunophenotypic markers with morphologic and molecular subtypes of APL. [Abstract] Blood 100 (11 pt 2): A-4434, 2002.

Trial Contact Information

Trial Lead Organizations

Cancer and Leukemia Group B

Bayard Powell, MD, Protocol chair		Ph: 336-716-7970; 800-446-2255 Email: bpowell@wfubmc.edu

Eastern Cooperative Oncology Group

Martin Tallman, MD, Protocol chair		Ph: 312-695-0990

NCIC-Clinical Trials Group

Stephen Couban, MD, Protocol chair		Ph: 902-473-7006; 866-599-2267 Email: stephen.couban@cdha.nshealth.ca

Southwest Oncology Group

Steven Coutre, MD, Protocol chair		Ph: 650-723-5007 Email: coutre@stanford.edu

Children's Oncology Group

Bayard Powell, MD, Protocol chair		Ph: 336-716-7970; 800-446-2255 Email: bpowell@wfubmc.edu

Registry Information
Official Title		Phase III Randomized Study of Concurrent Tretinoin and Chemotherapy With or Without Arsenic Trioxide (As2O3) (NSC# 706363) as Initial Consolidation Therapy Followed by Intermittent Tretinoin Maintenance Therapy Versus Observation for Patients with Untreated Acute Promyelocytic Leukemia
Trial Start Date		1999-06-30
Registered in ClinicalTrials.gov		NCT00003934
Date Submitted to PDQ		1999-06-17
Information Last Verified		2004-11-17
NCI Grant/Contract Number		U10-CA31946

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