Trial Information

Risk Adapted Treatment of Newly Diagnosed Childhood Acute Promyelocytic Leukemia (APL) Using Arsenic Trioxide (Trisenox® IND #103331) During Consolidation

OBJECTIVES:

Primary

- To decrease the total anthracycline dose from the best current published results in
patients with standard-risk childhood acute promyelocytic leukemia (APL) while still
maintaining a comparable event-free survival (EFS).

Secondary

- To assign treatment based on risk stratification by WBC at diagnosis.

- To estimate the induction failure rate, toxic death rate, disease-free survival rate,
and overall survival rate in both standard- and high-risk APL patients.

- To monitor for cardiotoxicity in an idarubicin/mitoxantrone hydrochloride-based
regimen.

- To document the toxicity of a traditional chemotherapy/tretinoin-based regimen combined
with arsenic trioxide therapy.

- To compare the EFS of children enrolled on this study with the EFS of children enrolled
on CALGB-C9710 who were between the ages of 2 and 21 and did not receive arsenic
trioxide.

- To estimate the proportion of patients who carry a cryptic t(15;17), i.e., those who
are positive for a PML-RARA fusion transcript by PCR analysis but have normal
chromosomes.

- To estimate the proportion of patients with variant RARA partners.

- To compare the outcome of patients with only a t(15;17) with that of patients who carry
a t(15;17) and other chromosomal abnormalities.

OUTLINE: This is a multicenter study. Patients are treated based on risk factor
(standard-risk [WBC < 10,000/mm^3] or high-risk [WBC ≥ 10,000/mm^3]).

- Induction therapy:

- Standard-risk: Patients receive oral tretinoin twice daily on days 1-30 and
idarubicin IV over 15 minutes once on days 3, 5, and 7.

- High-risk: Patients receive oral tretinoin twice daily on days 1-30 and idarubicin
IV over 15 minutes once on days 1, 3, and 5.

Patients proceed to consolidation therapy one week later or when blood counts recover.

- Consolidation therapy:

- Consolidation 1: Patients receive arsenic trioxide IV over 2 hours on days 1-5,
8-12, 15-19, 22-26, and 29-33 and oral tretinoin twice daily on days 1-14.
Treatment repeats every 5 weeks for 2 courses, followed by a 2-week break, and
then treatment repeats for 2 more courses. Beginning 1 week later or when blood
counts recover, patients proceed to consolidation 2.

- Consolidation 2: Patients receive cytarabine intrathecally (IT) on day 1, oral
tretinoin twice daily on days 1-14, high-dose cytarabine IV over 3 hours every 12
hours on days 1-3, and mitoxantrone hydrochloride IV over 15-30 minutes once on
days 3 and 4. Patients proceed to consolidation 3 one week later or when blood
counts recover.

- Consolidation 3: Patients receive cytarabine IT on day 1, oral tretinoin twice
daily on days 1-14, and idarubicin IV over 15 minutes once daily on days 1, 3, and
5. High-risk patients and those standard-risk patients who are positive for
minimal residual disease by real-time quantitative (RQ)-PCR receive consolidation
4 one week later or when blood counts recover. All other standard-risk patients
proceed to maintenance therapy.

- Consolidation 4 (patients with high-risk cytology): Patients receive cytarabine IT
on day 1, oral tretinoin twice daily on days 1-14, high-dose cytarabine IV over 3
hours every 12 hours on days 1-3, and idarubicin IV over 15 minutes once on day 4.
Patients who demonstrate molecular complete remission (CR) and remain in
hematological CR proceed to maintenance therapy 1 week later or when blood counts
recover.

- Maintenance therapy: Patients receive cytarabine IT on day 1 (course 1 only), oral
tretinoin twice daily on days 1-14, oral mercaptopurine once daily on days 1-84, oral
methotrexate once on days 1, 8, 15, 22, 29, 36, 43, 50, 57, 64, 71, and 78. Treatment
repeats every 12 weeks for 9 courses.

Bone marrow or blood is collected at baseline and then periodically during the study for
RQ-PCR analysis. Tumor tissue is collected at baseline for cytogenetic analysis.

After completion of study treatment, patients are followed every month for 1 year, every 3
months for 2 years, every 6 months for 2 years, and then annually for 5 years.