NCT00866918 · CITED IN SOURCE DOCUMENTS

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

An NCI or FDA source cites this study. A citation does not establish that it applies to an individual diagnosis.

Phase: PHASE3
Status at capture: COMPLETED
Registry last update: 2022-10-25

This phase III trial is studying combination chemotherapy to see how well it works in treating young patients with newly diagnosed acute promyelocytic leukemia. Drugs used in chemotherapy work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. Giving more than one drug (combination chemotherapy) may kill more cancer cells.

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What did the study report?

Outcomes, safety and baseline populations are separate source sections. Quality-of-life measures appear under their original outcome titles.

flow

Participant flow

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baseline

Baseline characteristics

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outcome · POSTED

Event-free Survival (EFS)

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outcome · POSTED

Hematologic Remission Rate

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outcome · POSTED

Hematologic, Molecular, and Cytogenetic Remission Rate

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outcome · POSTED

Overall Survival (OS)

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adverse events

Adverse events

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more info

Limitations, agreements, and source contact

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Who could take part

eligibility Criteria: 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
healthy Volunteers: false
maximum Age: 21 Years
minimum Age: 2 Years
sex: ALL
std Ages: CHILD
ADULT

Treatment arms and interventions

arm Groups

description
See Detailed Description
intervention Names
Drug: Arsenic Trioxide
Drug: Cytarabine
Other: Diagnostic Laboratory Biomarker Analysis
Drug: Idarubicin
Drug: Mercaptopurine
Drug: Methotrexate
Drug: Mitoxantrone Hydrochloride
Drug: Tretinoin
label
Arm I (standard risk, combination chemotherapy)
type
EXPERIMENTAL
description
See Detailed Description.
intervention Names
Drug: Arsenic Trioxide
Drug: Cytarabine
Other: Diagnostic Laboratory Biomarker Analysis
Drug: Idarubicin
Drug: Mercaptopurine
Drug: Methotrexate
Drug: Mitoxantrone Hydrochloride
Drug: Tretinoin
label
Arm II (high risk, combination chemotherapy)
type
EXPERIMENTAL

interventions

arm Group Labels
Arm I (standard risk, combination chemotherapy)
Arm II (high risk, combination chemotherapy)
description
Given IV
name
Arsenic Trioxide
other Names
Arsenic (III) Oxide
Arsenic Sesquioxide
Arsenous Acid
Arsenous Acid Anhydride
Arsenous Oxide
ATO
Trisenox
White Arsenic
type
DRUG
arm Group Labels
Arm I (standard risk, combination chemotherapy)
Arm II (high risk, combination chemotherapy)
description
Given IT or IV
name
Cytarabine
other Names
.beta.-Cytosine arabinoside
1-.beta.-D-Arabinofuranosyl-4-amino-2(1H)pyrimidinone
1-.beta.-D-Arabinofuranosylcytosine
1-Beta-D-arabinofuranosyl-4-amino-2(1H)pyrimidinone
1-Beta-D-arabinofuranosylcytosine
1.beta.-D-Arabinofuranosylcytosine
2(1H)-Pyrimidinone, 4-Amino-1-beta-D-arabinofuranosyl-
2(1H)-Pyrimidinone, 4-amino-1.beta.-D-arabinofuranosyl-
Alexan
Ara-C
ARA-cell
Arabine
type
DRUG
arm Group Labels
Arm I (standard risk, combination chemotherapy)
Arm II (high risk, combination chemotherapy)
description
Correlative studies
name
Diagnostic Laboratory Biomarker Analysis
type
OTHER
arm Group Labels
Arm I (standard risk, combination chemotherapy)
Arm II (high risk, combination chemotherapy)
description
Given IV
name
Idarubicin
other Names
4-Demethoxydaunomycin
4-Demethoxydaunorubicin
4-DMDR
type
DRUG
arm Group Labels
Arm I (standard risk, combination chemotherapy)
Arm II (high risk, combination chemotherapy)
description
Given orally
name
Mercaptopurine
other Names
3H-Purine-6-thiol
6 MP
6 Thiohypoxanthine
6 Thiopurine
6-Mercaptopurine
6-Mercaptopurine Monohydrate
6-MP
6-Purinethiol
6-Thiopurine
6-Thioxopurine
6H-Purine-6-thione, 1,7-dihydro- (9CI)
7-Mercapto-1,3,4,6-tetrazaindene
type
DRUG
arm Group Labels
Arm I (standard risk, combination chemotherapy)
Arm II (high risk, combination chemotherapy)
description
Given orally
name
Methotrexate
other Names
Abitrexate
Alpha-Methopterin
Amethopterin
Brimexate
CL 14377
CL-14377
Emtexate
Emthexat
Emthexate
Farmitrexat
Fauldexato
Folex
type
DRUG
arm Group Labels
Arm I (standard risk, combination chemotherapy)
Arm II (high risk, combination chemotherapy)
description
Given IV
name
Mitoxantrone Hydrochloride
other Names
CL 232315
DHAD
DHAQ
Dihydroxyanthracenedione Dihydrochloride
Mitoxantrone Dihydrochloride
Mitoxantroni Hydrochloridum
Mitozantrone Hydrochloride
Mitroxone
Neotalem
Novantrone
Onkotrone
Pralifan
type
DRUG
arm Group Labels
Arm I (standard risk, combination chemotherapy)
Arm II (high risk, combination chemotherapy)
description
Given orally
name
Tretinoin
other Names
2,4,6,8-Nonatetraenoic acid, 3, 7-dimethyl-9-(2,6,6-trimethyl-1-cyclohexen-1-yl)-, (all-E)-
Aberel
Airol
Aknoten
all trans-Retinoic acid
All-trans Retinoic Acid
All-trans Vitamin A Acid
all-trans-Retinoic acid
all-trans-Vitamin A acid
ATRA
Avita
beta-Retinoic Acid
type
DRUG

Study design

allocation

NON_RANDOMIZED

intervention Model

PARALLEL

masking Info

masking: NONE

primary Purpose

TREATMENT

Enrollment

count: 106
type: ACTUAL

Registered outcome plans (not posted results)

primary Outcomes

description
EFS - time from study entry until failure to achieve complete remission during consolidation, relapse, or death. For further clarification see definitions provided in the protocol.
measure
Event-free Survival (EFS)
time Frame
At 3 years from study entry

secondary Outcomes

description
Proportion of patients in hematologic remission at end of consolidation, course 1 are reported.
measure
Hematologic Remission Rate
time Frame
End of consolidation, course 1: up to 5 months
description
Proportion of patients in hematologic, molecular, and cytogenetic remission at end of consolidation, course 3 and 4 are reported. Patients were determined to be in remission by all three criteria.
measure
Hematologic, Molecular, and Cytogenetic Remission Rate
time Frame
End of consolidation, course 3; up to 7 months (for Standard Risk) or end of consolidation, course 4; up to 9 months (for High Risk)
description
OS - time from study entry to death.
measure
Overall Survival (OS)
time Frame
At 3 years from study entry

Full study description

brief Summary: This phase III trial is studying combination chemotherapy to see how well it works in treating young patients with newly diagnosed acute promyelocytic leukemia. Drugs used in chemotherapy work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. Giving more than one drug (combination chemotherapy) may kill more cancer cells.
detailed Description: 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 assigned to 1 of 2 arms based on risk factor (standard-risk \[WBC less than 10,000/mm\^3\] or high-risk \[WBC 10,000/mm\^3 or higher\]). ARM I (STANDARD-RISK): INDUCTION THERAPY: 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. 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. 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. ARM II (HIGH-RISK): INDUCTION THERAPY: 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: Patients receive consolidation 1, 2, and 3 as in Arm I. CONSOLIDATION 4: 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 maintenance therapy as in Arm I. 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.

Source references