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S0521, Combination Chemothera...

S0521, Combination Chemotherapy With or Without Gemtuzumab Followed By Tretinoin, Mercaptopurine, and Methotrexate or Observation in Treating Patients With Acute Promyelocytic Leukemia

Last Updated: 2023-01-10

Study Results

Results available

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Basic Information

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Recruitment Status

COMPLETED

Clinical Phase

PHASE3

Total Enrollment

105 participants

Study Classification

INTERVENTIONAL

Study Start Date

2007-06-01

Study Completion Date

2016-05-04

Brief Summary

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RATIONALE: 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. Monoclonal antibodies, such as gemtuzumab, can block cancer growth in different ways. Some block the ability of cancer cells to grow and spread. Others find cancer cells and help kill them or carry cancer-killing substances to them. Sometimes the cancer may not need more treatment until it progresses. In this case, observation may be sufficient. It is not yet known whether combination chemotherapy is more effective than observation when given as maintenance therapy in treating acute promyelocytic leukemia.

PURPOSE: This randomized phase III trial is studying tretinoin, mercaptopurine, and methotrexate to see how well they work when given as maintenance therapy compared with observation after combination chemotherapy in treating patients with acute promyelocytic leukemia. (Randomization and observation group closed as of 8/15/10)

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Detailed Description

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OBJECTIVES:

* Compare disease-free survival (DFS) among patients with previously untreated low and intermediate risk acute promyelocytic leukemia (APL) who are PCR-negative for Promyelocytic-retinoic acid receptor alpha (PML-RARα) after consolidation therapy and receive maintenance therapy versus patients who receive no maintenance therapy. (Randomization and observation arm closed as of 8/15/10)
* Assess the toxicity of induction, consolidation and maintenance in these patients.
* Test whether gene expression profiles assessed prior to treatment are predictive of resistance to remission induction chemotherapy and correlate with detectable minimal residual disease post-consolidation therapy. (Only one patient was not in molecular remission after receiving consolidation. Therefore, the predictive value of pre-treatment gene expression profiling could not be determined and is not reported here).
* Investigate in a preliminarily manner the outcomes of patients who fail to achieve or maintain PCR-negative PML-RARα fusion gene after consolidation therapy when treated with gemtuzumab ozogamicin. (Only one patient was treated with gemtuzumab ozogamicin as part of protocol treatment. Therefore, results for this objective are not reported).

OUTLINE: This is a randomized, multicenter study.

* Induction therapy: Patients receive oral tretinoin twice daily until morphologic complete remission (CR) or for a maximum of 90 days in the absence of disease progression or unacceptable toxicity. Patients also receive cytarabine IV continuously on days 3-9 and daunorubicin hydrochloride IV on days 3-6.
* Consolidation therapy: Patients who achieve CR, CR with incomplete blood count recovery (CRi), or partial remission (PR) after induction therapy receive arsenic trioxide IV over 2 hours 5 days a week for 5 weeks. After a 2-week rest period, patients receive a second course of arsenic trioxide. Within 14-30 days after blood count recovery, patients receive oral tretinoin twice daily on days 1-7 and daunorubicin hydrochloride IV on days 1-3. Patients receive a second course of tretinoin and daunorubicin hydrochloride after adequate blood count recovery.
* Post-consolidation therapy: Patients who do not achieve molecular CR (CRm), but do achieve CR or CRi and are still PML-RARα-positive after consolidation therapy, receive gemtuzumab ozogamicin IV over 2 hours on days 1 and 15. Treatment repeats every 14 days for up to 6 courses or until PML-RARα-negative by PCR. (closed as of 8/15/10)Patients are stratified according to age (18 to 60 years vs \> 60 years), acute promyelocytic leukemia (APL) risk group (low vs intermediate), and if the patient received consolidation therapy courses 3 or 4 (yes vs no) regardless of their CRm response. These patients are randomized to 1 of 2 treatment arms. (Randomization and observation arm closed as of 8/15/10) All patients are non-randomly assigned to receive post-consolidation therapy.

* Arm I: Beginning 14-30 days after blood count recovery, patients receive oral tretinoin twice daily on days 1-7, oral mercaptopurine once daily on days 1-14, and oral methotrexate on day 1. Treatment repeats every 2 weeks for up to 1 year.
* Arm II: Patients receive no further chemotherapy. Patients are followed every 3 months for 1 year. (Randomization and observation arm closed as of 8/15/10) Patients undergo blood collection periodically for cytogenetic studies. Samples are analyzed for PML-RARα fusion gene via reverse transcriptase-polymerase chain reaction (RT-PCR) assay and gene expression profiling.

After completion of study treatment, patients are followed every 3 months for 1 year, every 6 months for 1 year, and then annually for 3 years.

Conditions

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Leukemia

Study Design

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Allocation Method

NON_RANDOMIZED

Intervention Model

PARALLEL

Primary Study Purpose

TREATMENT

Blinding Strategy

NONE

Study Groups

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Post-consolidation therapy arm I

Patients receive oral tretinoin twice daily on days 1-7, oral mercaptopurine once daily on days 1-14, and oral methotrexate on day 1. Treatment repeats every 2 weeks for up to 1 year.

Group Type EXPERIMENTAL

mercaptopurine

Intervention Type DRUG

Given orally

methotrexate

Intervention Type DRUG

Given orally

tretinoin

Intervention Type DRUG

Given orally

Post-consolidation therapy arm II

Patients receive no further chemotherapy. Patients are followed every 3 months for 1 year. (Randomization and observation arm closed as of 8/15/10)

Group Type NO_INTERVENTION

No interventions assigned to this group

Interventions

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mercaptopurine

Given orally

Intervention Type DRUG

methotrexate

Given orally

Intervention Type DRUG

tretinoin

Given orally

Intervention Type DRUG

Eligibility Criteria

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Inclusion Criteria

DISEASE CHARACTERISTICS:

* Cytologically confirmed acute promyelocytic leukemia (APL) or the variant form of APL

* Previously untreated disease
* Low- or intermediate-risk disease

* Low-risk disease, defined as white blood cell (WBC) ≤ 10,000/mm\^3 and platelet count \> 40,000/mm\^3
* Intermediate-risk disease, defined as WBC ≤ 10,000/mm\^3 and platelet count ≤ 40,000/mm\^3
* WBC and platelet count confirming low- or intermediate-risk disease must be obtained within 48 hours prior to study registration unless the patient received tretinoin therapy prior to study registration in which case the WBC and platelet count must be obtained within 48 hours prior to study therapy
* PML-RARα fusion gene positive by reverse transcriptase-polymerase chain reaction (RT-PCR) assay
* No recurrent disease
* Must be registered on clinical trials SWOG-9007 and SWOG-S9910

* Specimens must be collected prior to tretinoin therapy and may be collected after tretinoin therapy

PATIENT CHARACTERISTICS:

* Zubrod performance status 0-3
* Not pregnant or nursing
* Negative pregnancy test
* Fertile patients must use effective contraception for ≥ 1 month prior to, during, and for 2 months after completion of study treatment
* No unstable cardiac arrhythmia or unstable angina
* No other malignancy within the past 5 years except for the following:

* Adequately treated basal cell or squamous cell skin cancer
* Carcinoma in situ of the cervix
* Adequately treated stage I or II cancer (except for highly aggressive malignancies with a high rate of early relapse) currently in complete remission

PRIOR CONCURRENT THERAPY:

* See Disease Characteristics
* No more than 1 prior dose of intrathecal chemotherapy for acute leukemia
* No prior systemic chemotherapy, hydroxyurea, or leukapheresis for acute leukemia

* Prior tretinoin at a dose of ≤ 45 mg/m\^2/day allowed provided it was received ≤ 5 days prior to study registration

Minimum Eligible Age

18 Years

Maximum Eligible Age

120 Years

Eligible Sex

ALL

Accepts Healthy Volunteers

Responsible Party

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Responsibility Role SPONSOR

Principal Investigators

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Steven E. Coutre, MD

Role: STUDY_CHAIR

Stanford University

Locations

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Mayo Clinic Scottsdale

Scottsdale, Arizona, United States

Site Status

Sutter Cancer Center at Roseville Medical Center

Roseville, California, United States

Site Status

Sutter Cancer Center

Sacramento, California, United States

Site Status

Stanford Cancer Center

Stanford, California, United States

Site Status

Tunnell Cancer Center at Beebe Medical Center

Lewes, Delaware, United States

Site Status

CCOP - Christiana Care Health Services

Newark, Delaware, United States

Site Status

Lombardi Comprehensive Cancer Center at Georgetown University Medical Center

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

Site Status

Hematology Oncology Associates of Illinois - Berwyn

Berwyn, Illinois, United States

Site Status

Illinois CancerCare - Bloomington

Bloomington, Illinois, United States

Site Status

St. Joseph Medical Center

Bloomington, Illinois, United States

Site Status

Graham Hospital

Canton, Illinois, United States

Site Status

Illinois CancerCare - Canton

Canton, Illinois, United States

Site Status

Illinois CancerCare - Carthage

Carthage, Illinois, United States

Site Status

Memorial Hospital

Carthage, Illinois, United States

Site Status

Robert H. Lurie Comprehensive Cancer Center at Northwestern University

Chicago, Illinois, United States

Site Status

Hematology and Oncology Associates

Chicago, Illinois, United States

Site Status

University of Chicago Cancer Research Center

Chicago, Illinois, United States

Site Status

Decatur Memorial Hospital Cancer Care Institute

Decatur, Illinois, United States

Site Status

Eureka Community Hospital

Eureka, Illinois, United States

Site Status

Illinois CancerCare - Eureka

Eureka, Illinois, United States

Site Status

Galesburg Clinic, PC

Galesburg, Illinois, United States

Site Status

Illinois CancerCare - Galesburg

Galesburg, Illinois, United States

Site Status

Illinois CancerCare - Havana

Havana, Illinois, United States

Site Status

Mason District Hospital

Havana, Illinois, United States

Site Status

Kellogg Cancer Care Center

Highland Park, Illinois, United States

Site Status

Midwest Center for Hematology/Oncology

Joliet, Illinois, United States

Site Status

Illinois CancerCare - Kewanee Clinic

Kewanee, Illinois, United States

Site Status

North Shore Oncology and Hematology Associates, Limited - Libertyville

Libertyville, Illinois, United States

Site Status

Illinois CancerCare - Macomb

Macomb, Illinois, United States

Site Status

McDonough District Hospital

Macomb, Illinois, United States

Site Status

Cardinal Bernardin Cancer Center at Loyola University Medical Center

Maywood, Illinois, United States

Site Status

Illinois CancerCare - Monmouth

Monmouth, Illinois, United States

Site Status

La Grange Oncology Associates - Geneva

Naperville, Illinois, United States

Site Status

Cancer Care and Hematology Specialists of Chicagoland - Niles

Niles, Illinois, United States

Site Status

BroMenn Regional Medical Center

Normal, Illinois, United States

Site Status

Community Cancer Center

Normal, Illinois, United States

Site Status

Illinois CancerCare - Community Cancer Center

Normal, Illinois, United States

Site Status

Community Hospital of Ottawa

Ottawa, Illinois, United States

Site Status

Oncology Hematology Associates of Central Illinois, PC - Ottawa

Ottawa, Illinois, United States

Site Status

Cancer Treatment Center at Pekin Hospital

Pekin, Illinois, United States

Site Status

Illinois CancerCare - Pekin

Pekin, Illinois, United States

Site Status

Proctor Hospital

Peoria, Illinois, United States

Site Status

CCOP - Illinois Oncology Research Association

Peoria, Illinois, United States

Site Status

Oncology Hematology Associates of Central Illinois, PC - Peoria

Peoria, Illinois, United States

Site Status

Methodist Medical Center of Illinois

Peoria, Illinois, United States

Site Status

OSF St. Francis Medical Center

Peoria, Illinois, United States

Site Status

Illinois CancerCare - Peru

Peru, Illinois, United States

Site Status

Illinois Valley Community Hospital

Peru, Illinois, United States

Site Status

Illinois CancerCare - Princeton

Princeton, Illinois, United States

Site Status

Perry Memorial Hospital

Princeton, Illinois, United States

Site Status

Hematology Oncology Associates - Skokie

Skokie, Illinois, United States

Site Status

Illinois CancerCare - Spring Valley

Spring Valley, Illinois, United States

Site Status

Regional Cancer Center at Memorial Medical Center

Springfield, Illinois, United States

Site Status

Fort Wayne Medical Oncology and Hematology

Fort Wayne, Indiana, United States

Site Status

McFarland Clinic, PC

Ames, Iowa, United States

Site Status