Combination Chemotherapy in Treating Young Patients With Newly Diagnosed Acute Promyelocytic Leukemia

PRIMARY OBJECTIVES:

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

SECONDARY OBJECTIVES:

I. To assign treatment based on risk stratification by white blood cell count (WBC) at
diagnosis.

II. 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.

III. To monitor for cardiotoxicity in an idarubicin/mitoxantrone based regimen. IV. To
document the toxicity of a traditional chemotherapy/all-trans retinoic acid (ATRA)
(tretinoin) based regimen combined with arsenic trioxide therapy.

V. To study the relationship of Fms-like tyrosine kinase 3 (FLT3) mutations to clinical
features and outcome in APL.

VI. To study risk factors for pseudotumor cerebri in APL. VII. To study the relationship of
early progenitor cell involvement to treatment failure in FLT3 positive APL.

VIII. To compare the EFS of children enrolled on AAML0631 with the EFS of children enrolled
on C9710 who were between the ages of 2 and 21 and did not receive arsenic trioxide.

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

X. To estimate the proportion of patients with variant RARA partners. XI. 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 less than 10,000/mm^3] or high-risk [WBC 10,000/mm^3 or higher]).

INDUCTION THERAPY:

STANDARD-RISK: Patients receive tretinoin orally (PO) twice daily (BID) on days 1-30 and
idarubicin intravenously (IV) over 15 minutes once on days 3, 5, and 7.

HIGH-RISK: Patients receive tretinoin PO BID 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 tretinoin PO BID 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, tretinoin PO BID
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 1 week later or when blood counts recover.

CONSOLIDATION 3: Patients receive cytarabine IT on day 1, tretinoin PO BID 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,
tretinoin PO BID 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), tretinoin PO
BID on days 1-14, mercaptopurine PO once daily (QD) on days 1-84, methotrexate PO once on
days 1, 8, 15, 22, 29, 36, 43, 50, 57, 64, 71, and 78. Treatment repeats every 12 weeks for
9 courses.

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:

- Patients must be newly diagnosed with a clinical diagnosis of acute promyelocytic
leukemia initially by morphology (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; APL is considered a hematological emergency and
treatment should be initiated as quickly as possible without waiting for molecular or
cytogenetic/fluorescence in situ hybridization (FISH) confirmation; for patients who
are unable to begin receiving ATRA in a timely manner following a presumed diagnosis
of APL, consideration should be given to initiating ATRA and proceeding with
treatment outside of the AAML0631 protocol; if the RQ-PCR results are known at the
time of study enrollment, the patient must demonstrate PML-RARA and/or RARA-PML
transcripts by RQ-PCR to be eligible; 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 probes; NOTE: A lumbar puncture is not
required to be enrolled on study; if the diagnosis of APL is known or suspected,
extreme caution must be exercised in performing a lumbar puncture during active
coagulopathy; in addition a computed tomography (CT) or magnetic resonance imaging
(MRI) should be considered to rule out the possibility of an associated chloroma if
central nervous system (CNS) disease is suspected or proven; if CNS disease is
documented, patients are still eligible

- No minimal performance status criteria

- The patient must not have received systemic definitive treatment for APL or other
suspected leukemia, including cytotoxic chemotherapy, retinoids, or arsenic; prior
therapy with corticosteroids, hydroxyurea, or leukopheresis will not exclude the
patient; if a patient received intrathecal cytarabine prior to the diagnosis of APL
being known, the patient will still be eligible as long as they meet all other
eligibility requirements

Exclusion Criteria:

- Pregnant women or nursing mothers are excluded; treatment under this protocol would
expose an unborn child to significant risks; patients should not be pregnant or plan
to become pregnant while on treatment; women and men of reproductive potential should
agree to use an effective means of birth control; there is an extremely high risk of
fetal malformation if pregnancy occurs while on ATRA in any amount even for short
periods

- Patients with a pre-existing prolonged QT Syndrome will not be eligible for this
protocol due to the use of arsenic trioxide which can prolong the QT interval