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

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.

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