A Study for Improving the Outcome of Childhood Acute Promyeloid Leukemia

Study Overview
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Brief Summary
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Outcome of acute promyelocytic leukemia (APL) has greatly improved since the introduction of all-trans-retinoic acid (ATRA). Treatment with ATRA and anthracycline-based chemotherapy (ATRA + chemotherapy) decreases relapses of the disease as well as early hemorrhagic deaths. Nowadays patients with APL have an event-free survival (EFS) of up to 80%. However, there remains a subset of the patients in whom the disease relapses. Recently, a randomized prospective study showed that the addition of ATO to ATRA + chemotherapy treatment protocol had a significantly higher EFS in patients with APL than those treated with ATRA + chemotherapy protocol. The patients treated with ATO + ATRA + chemotherapy had a five years EFS of 89.2%. Moreover, a recent study showed that Indigo naturalis formula (RIF), a traditional Chinese medicine with tetraarsenic tetrasulfide (As4S4), indirubin, and tanshinone IIA as major active ingredients, yielded synergy in the treatment of a murine APL model in vivo and in the induction of APL cell differentiation in vitro . It is about 20 years since RIF was used to treat ALP in China. Clinical studies showed that this agent was effective against APL. Compared to ATO, RIF is relatively inexpensive and can be taken orally, resulting in reducing the number of hospital days and the treatment cost. However, there is no report comparing treatment outcomes of ATO + ATRA + chemotherapy and RIF + ATRA + chemotherapy protocols in children with APL so far. For this purpose, therefore, investigators are going to conduct a multicenter and randomized prospective study in children with APL.

Detailed Description
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OBJECTIVES: Determine the safety and efficacy of ATO/RIF + ATRA + less intensive chemotherapy protocol in children with acute promyelocytic leukemia (APL). Compare the safety，efficacy and treatment cost of RIF + ATRA + less intensive chemotherapy with ATO + ATRA + less intensive chemotherapy protocol in children with APL. Determine if ATO can be substituted by RIF. OUTLINE: This is a multicenter and randomized prospective study. PROJECTED ACCRUAL: A total of 162 patients will be accrued for this study.

Official Title
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A Multicenter and Randomized Prospective Study for Improving the Outcome of Childhood Acute Promyeloid Leukemia

Conditions
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Childhood Acute Promyelocytic Leukemia

Intervention / Treatment
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* Drug: ATO
* Drug: RIF
* Drug: ATRA
* Drug: mitoxantrone
* Drug: Ara-C
* Drug: MTX
* Drug: 6MP
* Other: intrathecal injection


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients less than 16 years old with newly diagnosed PML-RARa positive acute promyelocytic leukemia. Exclusion Criteria: Patients who have coma, convulsion or paralysis due to intracranial hemorrhage or central nervous system leukemia at diagnosis.

Ages Eligible for Study
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Maximum Age: 16 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: ATO and chemotherapy<br>Induction: ATRA 25mg/m2 d1-CR ≯42 days; ATO 0.16mg/kg d5-CR ≯42 days; mitoxantrone (MA) 10mg/m2 d3, or 7mg/m2 d2-4 (high risk). Consolidation 1: ATRA 25mg/m2 d1-15; MA 10mg/m2 d1-2; Intrathecal injection (IT)：Ara-C 15mg (age < 1 year), or 20 mg (1-3 years), or 30 mg ( > 3 years), dexamethasone 2mg. Consolidation 2: ATRA 25mg/m2 d1-15; ATO 0.16mg/kg d1-15; Ara-C 1g/m2 q12h d1-2 (high risk); IT. Consolidation 3: ATRA 25mg/m2 d1-15; ATO 0.16mg/kg d1-15; MA 10mg/m2 d1; Ara-C 1g/m2 q12h d1-2 (high risk); IT. Maintenance: ① ATO 0.16mg/kg.d w1-2; ATRA 25mg/m2.d w1-2; MTX 20mg/m2 qw w3-12; 6MP 50mg/m2 qn w3-12. ② ATRA 25mg/m2.d w1-2; MTX 20mg/m2 qw w3-12; 6MP 50mg/m2 qn w3-12. Rotation between ① and ② until the end of maintenance. | Drug: ATO<br>* Given IV<br>* Other names: arsenic trioxide;Drug: ATRA<br>* Given orally<br>* Other names: all-trans retinoic acid;Drug: mitoxantrone<br>* Given IV<br>* Other names: novantrone;Drug: Ara-C<br>* Given IV<br>* Other names: cytosine arabinoside;Drug: MTX<br>* Given orally<br>* Other names: methotrexate;Drug: 6MP<br>* Given orally<br>* Other names: mercaptopurine;Other: intrathecal injection<br>* Ara-C and dexamethasone<br>* Other names: IT;|
| Experimental: RIF and chemotherapy<br>Induction: ATRA 25mg/m2 d1-CR ≯42 days; RIF 0.135/kg d5-CR ≯42 days; mitoxantrone (MA) 10mg/m2 d3, or 7mg/m2 d2-4 (high risk). Consolidation 1: ATRA 25mg/m2 d1-15; MA 10mg/m2 d1-2; Intrathecal injection (IT)：Ara-C 15mg (age < 1 year), or 20mg (age 1-3 years), or 30mg (age > 3 years), dexamethasone 2mg. Consolidation 2: ATRA 25mg/m2 d1-15; RIF 0.135/kg d1-15; Ara-C 1g/m2 q12h d1-2 (high risk); IT. Consolidation 3: ATRA 25mg/m2 d1-15; RIF 0.135/kg d1-15; MA 10mg/m2 d1; Ara-C 1g/m2 q12h d1-2 (high risk); IT. Maintenance: ① RIF 0.135/kg.d w1-2; ATRA 25mg/m2.d w1-2; MTX 20mg/m2 qw w3-12; 6MP 50mg/m2 qn w3-12. ② ATRA 25mg/m2.d w1-2; MTX 20mg/m2 qw w3-12; 6MP 50mg/m2 qn w3-12. Rotation between ① and ② until the end of maintenance treatment. | Drug: RIF<br>* Given orally<br>* Other names: Realgar-Indigo naturalis formula;Drug: ATRA<br>* Given orally<br>* Other names: all-trans retinoic acid;Drug: mitoxantrone<br>* Given IV<br>* Other names: novantrone;Drug: Ara-C<br>* Given IV<br>* Other names: cytosine arabinoside;Drug: MTX<br>* Given orally<br>* Other names: methotrexate;Drug: 6MP<br>* Given orally<br>* Other names: mercaptopurine;Other: intrathecal injection<br>* Ara-C and dexamethasone<br>* Other names: IT;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| event-free survival |  | 5 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| hospitalization cost | The cost mainly includes the fees of hospital bed, drugs, therapies and blood products. Time frame: from the beginning of induction therapy to the end of maintenance treatment. | 2 years |