S0521, Combination Chemotherapy With or Without Gemtuzumab Followed By Tretinoin, Mercaptopurine, and Methotrexate or Observation in Treating Patients With Acute Promyelocytic Leukemia
Condition: Leukemia
MeSH terms: Leukemia; Leukemia, Promyelocytic, Acute
Study type: Interventional
Phase: Phase 3

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.
    

Intervention name(s): mercaptopurine; methotrexate; tretinoin
Intervention type(s): Drug; Drug; Drug
Intervention description(s): Given orally; Given orally; Given orally
Intervention MeSH terms: Methotrexate; Mercaptopurine; Tretinoin
Allocation: Non-Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: adult acute myeloid leukemia with t(15;17)(q22;q12); adult acute promyelocytic leukemia (M3); untreated adult acute myeloid leukemia