Trial Information

Phase II Study of Combined All-Trans Retinoic Acid and Arsenic Trioxide for Acute Promyelocytic Leukemia Followed by Risk-Adapted Postremission Therapy

OBJECTIVES:

Primary

- To determine the rate of molecular remission after induction therapy comprising
tretinoin (ATRA) and arsenic trioxide (ATO) (along with idarubicin in patients with
leukocytosis) in patients with acute promyelocytic leukemia (APL).

Secondary

- To determine the rate of clinical complete remission and the time to remission after
induction therapy.

- To determine the proportion of patients in molecular remission after each course of
postremission therapy and to use these findings to direct the number of consolidation
courses with ATRA and idarubicin that are administered.

- To determine the disease-free survival and overall survival of patients treated with
this regimen.

- To determine the toxicity of this treatment regimen, including the number and length of
hospitalizations, the incidence of secondary myelodysplastic syndromes or acute myeloid
leukemia, and the effects of treatment on LVEF.

- To characterize the differentiation of APL cells during treatment with combined ATRA
and ATO using serial immunophenotyping studies of peripheral blood and bone marrow.

- To compare the results of quantitative real-time reverse transcriptase-polymerase chain
reaction (RT-PCR) assays performed on bone marrow and peripheral blood.

OUTLINE:

- Induction therapy: Patients receive tretinoin orally twice daily and arsenic trioxide
IV over 1-4 hours once daily until a marrow remission is documented or for 60 days,
whichever comes first. Patients with leukocytosis (WBC > 10,000/μL) also receive
idarubicin IV over 10-15 minutes beginning on day 2 and continuing every other day for
4 doses. Patients who achieve a clinical complete remission (CR) proceed to
consolidation therapy. If a marrow remission is not achieved after 60 days, the patient
is removed from the study.

- Consolidation therapy:

- Consolidation courses 1, 2, and 3: Beginning 3-6 weeks after documentation of
clinical CR, patients receive consolidation therapy comprising tretinoin orally
twice daily for 15 days and arsenic trioxide IV over 1-4 hours once daily 5 days a
week for 5 weeks. Consolidation therapy repeats every 3-6 weeks for 3 courses.

Patients who have a negative PML-RARα transcript by reverse transcriptase-polymerase chain
reaction (RT-PCR) assay after consolidation course 2 proceed to maintenance therapy after
receiving consolidation course 3. Patients who have a negative PML-RARα transcript by RT-PCR
assay after consolidation course 3, proceed to consolidation course 4 followed by
maintenance therapy. Patients who have a positive PML-RARα transcript by RT-PCR assay after
consolidation courses 2 and 3 proceed to consolidation courses 4 and 5.

- Consolidation course 4: Beginning 3-6 weeks after completion of consolidation course 3,
patients receive tretinoin orally twice daily for 15 days and idarubicin IV over 10-15
minutes once daily for 4 days.

- Consolidation course 5: Beginning 3-6 weeks after completion of consolidation course 4,
patients receive tretinoin orally twice daily for 15 days and idarubicin IV over 10-15
minutes once daily for 3 days.

Patients who remain positive for the PML-RARα transcript after 5 courses of consolidation
therapy are removed from the study. Patients who have a negative PML-RARα transcript after 5
courses of consolidation therapy proceed to maintenance therapy.

- Maintenance therapy: Beginning approximately 3 months after completion of the final
consolidation course, patients receive tretinoin orally twice daily for 15 days.
Treatment repeats every 3 months for up to 2 years.

Disease status will be monitored with serial analyses of bone marrow and peripheral blood
samples using RT-PCR for PML-RARα mRNA. Patients will be followed until relapse, death, loss
to follow-up, or removal from study.