S0521, Combination Chemotherapy With or Without Gemtuzumab Followed By Tretinoin, Mercaptopurine, and Methotrexate or Observation in Treating Patients With Acute Promyelocytic Leukemia
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 05/27/10)
|Study Design:||Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
|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|
- Disease-free survival [ Time Frame: 5 years ] [ Designated as safety issue: No ]
- Overall survival [ Time Frame: 5 years ] [ Designated as safety issue: No ]
- Toxicity [ Time Frame: 5 years ] [ Designated as safety issue: Yes ]
|Study Start Date:||June 2007|
|Estimated Primary Completion Date:||September 2013 (Final data collection date for primary outcome measure)|
Experimental: 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.
Given orallyDrug: methotrexate
Given orallyDrug: tretinoin
No Intervention: 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 05/27/10)
- Compare disease-free survival in patients with previously untreated low- or intermediate-risk acute promyelocytic leukemia treated with induction and consolidation combination chemotherapy with or without gemtuzumab ozogamicin followed by maintenance therapy comprising tretinoin, mercaptopurine, and methotrexate vs observation.(Randomization and observation arm closed as of 05/27/10)
- Assess the toxicity of these regimens in these patients.
- Determine whether gene expression profiling assessed prior to treatment is predictive of resistance to remission induction chemotherapy and correlate with detectable minimal residual disease post-consolidation therapy.
- Determine the relapse-free survival of patients who respond to induction chemotherapy.
- Assess, preliminarily, the outcomes of patients who fail to achieve or maintain PCR-negative PML-RARα fusion gene after consolidation therapy when treated with gemtuzumab ozogamicin.
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 05/27/10)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 05/27/10) 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 05/27/10) 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.