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

Study Overview
=================
Brief Summary
-----------------
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)

Detailed Description
-----------------
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.

Official Title
-----------------
S0521, A Randomized Trial of Maintenance Versus Observation for Patients With Previously Untreated Low and Intermediate Risk Acute Promyelocytic Leukemia (APL), Phase III

Conditions
-----------------
Leukemia

Intervention / Treatment
-----------------
* Drug: mercaptopurine
* Drug: methotrexate
* Drug: tretinoin


Participation Criteria
=================
Eligibility 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

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 120 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Post-consolidation therapy arm I<br>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. | Drug: mercaptopurine<br>* Given orally<br>Drug: methotrexate<br>* Given orally<br>Drug: tretinoin<br>* Given orally<br>|
| No Intervention: Post-consolidation therapy arm II<br>Patients receive no further chemotherapy. Patients are followed every 3 months for 1 year. (Randomization and observation arm closed as of 8/15/10) | |

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 3-year Disease-free Survival (DFS) Rate | DFS measured from date of post-consolidation randomization until relapse of any kind or death from any cause. Observation censored at date of last follow-up for patients last known to be alive without report of relapse. Relapse from CR/CRi is occurrence of marrow blasts ≥ 5% or presence of Auer rods or presence of neoplastic promyelocytes; (re)appearance of leukemic blasts or neoplastic promyelocytes in the peripheral blood; or (re)appearance of extramedullary disease. Relapse from PR is sum of marrow blasts and promyelocytes ≥ 20%, or sum of marrow blasts and promyelocytes 6-19% with Auer rods and/or neoplastic promyelocytes; or (re)appearance of leukemic blasts or neoplastic promyelocytes in the peripheral blood; or (re)appearance of extramedullary disease. Relapse from CRc is reappearance of t(15;17) in cytogenetic analysis. Relapse from CRm/PRm is reappearance of PML-RARα by RT-PCR as defined by a normalized quotient > 10^-5 based on RT-PCR performed at appropriate central lab. | Up to 3 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Patients With Grade 3 Through 5 Adverse Events That Are Related to Study Drug | Any CTCAE 3.0 event of Grade 3 (severe), Grade 4 (life threatening), or Grade 5 (fatal) which were deemed to be related to protocol treatment are included. Only adverse events that are possibly, probably, or definitely related to study drug are reported. | Up to 5 years | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
untreated adult acute myeloid leukemia, adult acute myeloid leukemia with t(15;17)(q22;q12), adult acute promyelocytic leukemia (M3)