Trial Information

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

OBJECTIVES:

- 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.