Trial Information

S0535, A Phase II Study of ATRA, Arsenic Trioxide and Gemtuzumab Ozogamicin in Patients With Previously Untreated High-Risk Acute Promyelocytic Leukemia

OBJECTIVES:

- To assess the event-free survival and death during the first six weeks in patients with
previously untreated, high-risk acute promyelocytic leukemia treated with a combined
regimen of tretinoin, arsenic trioxide, and gemtuzumab ozogamicin.

- To estimate the frequency and severity of toxicities of this regimen in this group of
patients.

- To investigate the molecular response rate utilizing this regimen in high-risk
patients.

OUTLINE:

- Induction chemotherapy: Patients receive oral tretinoin twice daily beginning on day 1
until CR (up to 90 days), gemtuzumab ozogamicin IV over 2 hours on day 1, and arsenic
trioxide IV over 2 hours 5 days a week beginning on day 10 until CR (up to 60 days) in
the absence of disease progression or unacceptable toxicity. Patients achieving A1 bone
marrow, B1 peripheral blood, and C1 extramedullary disease status proceed to
consolidation therapy after maintaining B1 peripheral blood status for ≥ 7 days.

- Consolidation therapy: Beginning between 2-8 weeks after documentation of complete
response (CR), patients receive consolidation therapy.

- Consolidation courses 1 and 2: Patients receive arsenic trioxide IV over 2 hours 5
days a week for 5 weeks. Treatment repeats every 7 weeks for up to 2 courses.
Patients remaining in A1 bone marrow, B1 peripheral blood, and C1 extramedullary
disease status continue with consolidation courses 3 and 4.

- Consolidation courses 3 and 4: Within 4 weeks of completing consolidation course
2, patients receive oral tretinoin twice daily on days 1-7 and daunomycin IV bolus
or over 1 hour on days 1-3. Within 2-8 weeks after recovery to B1 peripheral blood
status, patients receive consolidation course 4 as in course 3. Patients who
remain in B1 peripheral blood and C1 extramedullary disease status continue on
consolidation courses 5 and 6.

- Consolidation courses 5 and 6: Beginning between 2-8 weeks after recovery to B1
peripheral blood status, patients receive gemtuzumab IV over 2 hours on day 1.
Between 2-8 weeks after recovery to B1 peripheral blood status, patients receive
consolidation course 6 as in course 5. Patients who remain in A1 bone marrow, B1
peripheral blood, and C1 extramedullary disease status proceed to maintenance
therapy.

- Maintenance therapy: Beginning 2-8 weeks after recovery of blood counts, patients
receive oral tretinoin twice daily on days 1-7 every other week for 1 year, oral
mercaptopurine once daily for 1 year, and oral methotrexate once weekly for 1 year.

Patients undergo bone marrow aspirates and biopsies periodically during study. Samples are
analyzed for cytogenetics by fluorescence in situ hybridization (FISH) and for PML-RARα by
polymerase chain reaction (PCR).

After completion of study treatment, patients are evaluated at 3, 6, 9, 12, 18, 24, and 36
months.