Phase III Randomized Study of Concurrent Tretinoin and Chemotherapy With or Without Arsenic Trioxide (AS2O3) (NSC # 706363) as Initial Consolidation Therapy Followed by Maintenance Therapy With Intermittent Tretinoin Versus Intermittent Tretinoin Plus Mercaptopurine and Methotrexate for Patients With Untreated Acute Promyelocytic Leukemia

Trial Information

Phase III Randomized Study of Concurrent Tretinoin and Chemotherapy With or Without Arsenic Trioxide (AS2O3) (NSC # 706363) as Initial Consolidation Therapy Followed by Maintenance Therapy With Intermittent Tretinoin Versus Intermittent Tretinoin Plus Mercaptopurine and Methotrexate for Patients With Untreated Acute Promyelocytic Leukemia

PRIMARY OBJECTIVES:

i. To compare the efficacy (event-free survival) and toxicities of two
induction/consolidation therapies for patients with untreated APL: ATRA/ara-C/daunorubicin
with or without arsenic trioxide (As2O3).

II. To evaluate the efficacy (disease-free survival) and toxicities of maintenance therapy
with intermittent ATRA vs intermittent ATRA plus 6-MP/MTX for patients with APL who achieve
a complete response.

III. To explore the relationship between CD56 expression at diagnosis and clinical outcomes.

IV. To evaluate the cardiac toxicity of intensive daunorubicin therapy, as given in this
study, to pediatric patients.

OUTLINE: This is a randomized, multicenter study. Patients are stratified according to age
(under 15 vs 15 to 60 vs over 60) for the induction phase. Patients are stratified according
to age, as in the induction phase, and the consolidation arm (with vs without arsenic
trioxide) for the consolidation phase. Patients under age 5 do not receive arsenic trioxide.

Induction: All patients receive oral tretinoin every 12 hours beginning on day 1 until
complete response or for a maximum of 90 days. Patients also receive daunorubicin IV on days
3-6 and cytarabine IV continuously on days 3-9.

Consolidation: All patients achieving complete response (CR), or partial response (PR) after
completion of tretinoin, proceed to consolidation within 2 weeks of achieving CR or PR, but
not prior to 30 days from the start of induction. Patients are randomized to 1 of 2
treatment arms.

Arm I: Patients receive oral tretinoin every 12 hours on days 1-7 and daunorubicin IV on
days 1-2 or days 1-3, depending on age. Patients may receive an additional course. Treatment
begins no earlier than 2 weeks and no later than 4 weeks after hematopoietic recovery.

Arm II: Patients receive arsenic trioxide IV over 2 hours daily 5 days a week for 5 weeks.
After a 2-week rest, patients receive a second course of arsenic trioxide. Patients then
receive tretinoin and daunorubicin as in arm I.

Maintenance: Patients maintaining CR or PR after consolidation therapy proceed to
maintenance therapy, beginning no earlier than 2 weeks and no later than 4 weeks after
hematopoietic recovery. Patients are randomized to 1 of 2 treatment arms.

Arm I: Patients receive oral tretinoin every 12 hours for 7 days every other week for 1
year.

Arm II: Patients receive oral tretinoin as in arm I above. Patients also receive oral
mercaptopurine once a day and oral methotrexate once weekly for up to 1 year.

Maintenance therapy continues for up to 1 year in the absence of unacceptable toxicity.

Patients are followed every 2 months for 2 years, every 3 months for 1 year, every 6 months
for 2 years, and then annually for 5 years.

PROJECTED ACCRUAL: A total of 522 patients (456 adults and 66 pediatric) will be accrued for
this study within 4.75 years.