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

Phase 3
2 Years
21 Years
Open (Enrolling)

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Trial Information

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



- 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).


- 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

- 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

- 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

- 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

- 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.

Inclusion Criteria


- New clinically and morphologically confirmed diagnosis of acute promyelocytic
leukemia (APL) (bone marrow or peripheral blood)

- Bone marrow is highly preferred but in cases where marrow cannot be obtained at
diagnosis, peripheral blood will be accepted

- If the real-time quantitative (RQ)-PCR results are known, the patient must
demonstrate PML-RARA and/or RARA-PML transcripts by RQ-PCR

- Patients without evidence of APL by bone marrow or peripheral blood morphology but
with isolated myeloid sarcoma (myeloblastoma; chloroma, including leukemia cutis) are
eligible provided that the t(15;17) translocation is documented on either marrow or
tumor tissue by cytogenetics, FISH, or PCR prior to study enrollment (in this
situation, touch preps from the tumor site can be evaluated by FISH with PML-RARA


- No minimal performance status criteria

- Not pregnant or nursing

- Fertile patients must use effective contraception

- No pre-existing prolonged QT syndrome


- Prior intrathecal cytarabine prior to the diagnosis of acute promyelocytic leukemia
(APL) allowed

- Prior corticosteroids, hydroxyurea, and leukapheresis allowed

- No prior systemic definitive treatment for APL or other suspected leukemia, including
cytotoxic chemotherapy, retinoids, or arsenic

Type of Study:


Study Design:

Endpoint Classification: Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Event-free survival

Outcome Description:

The Kaplan-Meier method will be used to estimate the EFS of children enrolled on AAML0631 and the EFS of children enrolled on C9710 who were between the ages of 2 and 21 at the time of diagnosis and did not receive arsenic. A test of the difference in EFS will be performed using the log-rank test. Log-rank tests will be used to compare OS and EFS for those with and without FLT3 mutations.

Outcome Time Frame:

Time from on study to failure to achieve hematological CR after Consolidation 1, relapse, or death, assessed up to 10 years

Safety Issue:


Principal Investigator

John J. Gregory, MD

Investigator Role:

Study Chair

Investigator Affiliation:

Goryeb Children's Hospital at Morristown Memorial Hospital


United States: Federal Government

Study ID:




Start Date:

March 2009

Completion Date:

Related Keywords:

  • Leukemia
  • childhood acute promyelocytic leukemia (M3)
  • Leukemia
  • Leukemia, Promyelocytic, Acute



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