Clinical Study of Induction Therapy Options Based on Molecular Subtyping and MRD in Children and Adolescents With AML

Study Results

Results pending

The study team has not published outcome measurements, participant flow, or safety data for this trial yet. Check back later for updates.

Basic Information

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Recruitment Status

RECRUITING

Clinical Phase

PHASE2

Total Enrollment

500 participants

Study Classification

INTERVENTIONAL

Study Start Date

2024-01-01

Study Completion Date

2029-12-31

Brief Summary

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The goal of this clinical trial is to estimate the rate (probability) of complete remission or complete remission with incomplete count recovery (CR/CRi) with negative MRD after induction I and II, event-free survival (EFS), and cumulative incidence (probability) of relapse (CIR), in patients receiving molecular/precision medicine and MRD-driven remission inductions, and to assess secondarily if there is an improvement over the AML2018 protocol.

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Detailed Description

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Advances in risk stratification and therapy, have improved the event-free survival (EFS) and overall survival (OS) for pediatric acute myeloid leukemia (AML) with current treatment strategies. Investigators previously conducted a multicenter, randomized controlled trial (AML18) to compare the efficacy and safety of low-dose chemotherapy versus standard-dose chemotherapy. The results showed that low-dose chemotherapy was non-inferior to standard-dose chemotherapy in terms of efficacy and had fewer adverse events. However, different subtypes exhibited varying treatment responses to both chemotherapy regimens. The MRD (Measurable Residual Disease) after induction therapy in both groups had an impact on prognosis. According to the backbone of the 2018 protocol, investigators decide whether to use low-dose or standard-dose for the first induction according to the patient's fusion gene, and the second induction and subsequent treatment are adjusted according to the treatment response. Patients with the following 5 fusion genes RUNX1: RUNX1T1, CBFβ: MYH11, KMT2A: MLLT3 (AF9), KMT2A: MLLT10 (AF10), KMT2A: MLLT4 (AF6) fusion or KIT mutation will be assigned to the standard dose remission induction regimen (HHT + Ara-C + VP16), others will be assigned to the standard dose regimen (Mitoxantrone/Idarubicin + Ara-C + G-CSF). At the same time, investigators will add targeted drugs such as venetoclax, avaptitinib, and gilteritinib/sorafenib to the chemotherapy regimen and assess their safety and efficacy. Post-induction consolidation consisted of 3 to 4 cycles of standard-dose chemotherapy according to risk classification. Patients classified as high-risk are candidates for allogeneic bone marrow transplantation after 1 or 2 courses of consolidation.

Conditions

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AML, Childhood Acute Myeloid Leukemia

Study Design

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Allocation Method

NON_RANDOMIZED

Intervention Model

FACTORIAL

Primary Study Purpose

TREATMENT

Blinding Strategy

NONE

Study Groups

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SDC group

Patients with CBF fusion gene (RUNX1: : RUNX1T1 and CBFB: : MYH11) or KMT2A: : MLLT3(AF9) , KMT2A: : MLLT10(AF10) , KMT2A: : MLLT4(AF6) fusion gene or KIT mutation will receive SDC regimen, including one course of HAE (Homoharringtonine, cytarabine, etoposide) in induction I. These patients will continue on the SDC (HAE) regimen in the second course if the MRD is \< 1% after induction I, otherwise venetoclax will be added to the SDC group sequentially on Day 2 after the end of HAE. FLT3-ITD will be given sorafenib or gilteritinib as early as possible, and patients with KIT mutations will be recommended to add avapritinib as appropriate. These targeted drugs will not be combined with venetoclax.

Group Type EXPERIMENTAL

Homoharringtonine

Intervention Type DRUG

3mg/m2/day for weighing \>10kg, 0.1mg/kg/day for weighing ≤10kg, d1-7, ivgtt, qd, more than 6 hours

Cytarabine

Intervention Type DRUG

100mg/m2/q12h for weighing \>10kg, 3.3mg/kg/q12h for weighing ≤10kg, d1-7, ivgtt, q12h, more than 30 minutes in SDC group; 10mg/m2/q12h for weighing \>10kg, 0.33mg/kg/q12h for weighing ≤10kg, d1-10, s.c.,q12h (the first dose at 8 am) in the LDC group;

Etoposide

Intervention Type DRUG

100mg/m2/d for weighing \>10kg, 3.3mg/kg/d for weighing ≤ 10kg, d1-5, ivgtt, qd, more than 4 hours

Venetoclax

Intervention Type DRUG

100mg/m2/d for weighing \>10kg, 3.33mg/kg/d for weighing ≤10kg, d12-25, po, qd

Sorafenib

Intervention Type DRUG

100mg/m2/day for weighing \>10kg, 3.3mg/kg/day for weighing ≤10kg, from identification, po, qd

Gilteritinib

Intervention Type DRUG

20mg/m2/day for weighing \>10kg, 0.7mg/kg/day for weighing ≤ 10kg, from identification, po, qd

Avapritinib

Intervention Type DRUG

50mg/m2/day for weighing bodyweight \>10kg, 1.65mg/kg/day for weighing ≤ 10kg, po, qd

LDC group

Patients with the exception of the CBF fusion gene (RUNX1: : RUNX1T1 and CBFB: : MYH11) or those with the KMT2A: : MLLT3(AF9) , KMT2A: : MLLT10(AF10) , KMT2A: : MLLT4(AF6) fusion gene or KIT mutation will receive the LDC (MAG/IDAG+ venetoclax) regimen in induction I. Patients with MRD ≥1% or KIT mutations, assessed after induction I, will receive the HAE plus venetoclax (or targeted drugs) regimen, otherwise, they will receive MAG/IDAG + venetoclax. FLT3-ITD will be given sorafenib or gilteritinib as early as possible, and patients with KIT mutations will be recommended to add avapritinib as appropriate. These targeted drugs will not be combined with venetoclax.

Group Type EXPERIMENTAL

Cytarabine

Intervention Type DRUG

100mg/m2/q12h for weighing \>10kg, 3.3mg/kg/q12h for weighing ≤10kg, d1-7, ivgtt, q12h, more than 30 minutes in SDC group; 10mg/m2/q12h for weighing \>10kg, 0.33mg/kg/q12h for weighing ≤10kg, d1-10, s.c.,q12h (the first dose at 8 am) in the LDC group;

Mitoxantrone hydrochloride liposome

Intervention Type DRUG

5mg/m2/d for weighing \>10kg, 0.17mg/kg/d for weighing ≤ 10kg, d1, 3, 5, ivgtt, qod, more than 2 hours at 10 am.

Recombinant Human Granulocyte Colony-Stimulating Factor

Intervention Type DRUG

5ug/kg/d, d1-10, s.c., qd, at 1pm

Idarubicin Hydrochloride

Intervention Type DRUG

3mg/m2/day for weighing \>10kg, 0.1mg/kg/day for weighing ≤ 10kg, d1-7, ivgtt, qd, more than 6 hours.

Sorafenib

Intervention Type DRUG

100mg/m2/day for weighing \>10kg, 3.3mg/kg/day for weighing ≤10kg, from identification, po, qd

Gilteritinib

Intervention Type DRUG

20mg/m2/day for weighing \>10kg, 0.7mg/kg/day for weighing ≤ 10kg, from identification, po, qd

Avapritinib

Intervention Type DRUG

50mg/m2/day for weighing bodyweight \>10kg, 1.65mg/kg/day for weighing ≤ 10kg, po, qd

Interventions

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Homoharringtonine

3mg/m2/day for weighing \>10kg, 0.1mg/kg/day for weighing ≤10kg, d1-7, ivgtt, qd, more than 6 hours

Intervention Type DRUG

Cytarabine

100mg/m2/q12h for weighing \>10kg, 3.3mg/kg/q12h for weighing ≤10kg, d1-7, ivgtt, q12h, more than 30 minutes in SDC group; 10mg/m2/q12h for weighing \>10kg, 0.33mg/kg/q12h for weighing ≤10kg, d1-10, s.c.,q12h (the first dose at 8 am) in the LDC group;

Intervention Type DRUG

Etoposide

100mg/m2/d for weighing \>10kg, 3.3mg/kg/d for weighing ≤ 10kg, d1-5, ivgtt, qd, more than 4 hours

Intervention Type DRUG

Venetoclax

100mg/m2/d for weighing \>10kg, 3.33mg/kg/d for weighing ≤10kg, d12-25, po, qd

Intervention Type DRUG

Mitoxantrone hydrochloride liposome

5mg/m2/d for weighing \>10kg, 0.17mg/kg/d for weighing ≤ 10kg, d1, 3, 5, ivgtt, qod, more than 2 hours at 10 am.

Intervention Type DRUG

Recombinant Human Granulocyte Colony-Stimulating Factor

5ug/kg/d, d1-10, s.c., qd, at 1pm

Intervention Type DRUG

Idarubicin Hydrochloride

3mg/m2/day for weighing \>10kg, 0.1mg/kg/day for weighing ≤ 10kg, d1-7, ivgtt, qd, more than 6 hours.

Intervention Type DRUG

Sorafenib

100mg/m2/day for weighing \>10kg, 3.3mg/kg/day for weighing ≤10kg, from identification, po, qd

Intervention Type DRUG

Gilteritinib

20mg/m2/day for weighing \>10kg, 0.7mg/kg/day for weighing ≤ 10kg, from identification, po, qd

Intervention Type DRUG

Avapritinib

50mg/m2/day for weighing bodyweight \>10kg, 1.65mg/kg/day for weighing ≤ 10kg, po, qd

Intervention Type DRUG

Other Intervention Names

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Homoharringtonine injection Cytosar Etoposide injection Venclexta Mitoxantrone hydrochloride liposome injection Recombinant Human Granulocyte Colony-Stimulating Factor Injection Idarubicin hydrochloride injection Nexavar Xospata Pill AYVAKIT

Eligibility Criteria

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Inclusion Criteria

* 1、Newly diagnosed, untreated AML；
* 2、Under 18 years old;
* 3、Patients who have used hydroxyurea or cytarabine before diagnosis, but the dosage of cytarabine does not exceed 5 days, and the total dose does not exceed 500 mg/m2 (50 mg/m2, q12h × 5d)；
* 4、 Liver function：Tbil≤2×ULN, ALT/AST≤3×ULN, creatinine clearance ≥50ml/min；Cardiac NYHA grading\<3；SaO2\>92%;
* 5、No active infection (symptoms resolved for more than 3 days if infected)
* 6、ECOG\<2;
* 7、Expected survival time greater than 12 weeks;
* 9、Obtain the consent of the child and/or guardian and sign the informed consent form.

Exclusion Criteria

* 1、Acute megakaryocytic leukemia (AMKL)；
* 2、Acute promyelocytic leukemia (APL);
* 3、Treatment-related secondary AML and AML with definite MDS transformation；
* 4、Myeloproliferative neoplasm (such as Juvenile myelomonocytic leukemia, JMML);
* 5、AML secondary to congenital bone marrow failure (such as AML secondary to Fanconi anemia (FA)；
* 6、AML secondary to Down syndrome;
* 7、Only temporary chemotherapy, radiotherapy, or immunotherapy, but not systematic treatment according to the treatment plan;
* 8、 Temporary chemotherapy, radiotherapy, or immunotherapy only, not systemic therapy per protocol;
* 10、Patients with very poor nutritional status, severe infection, cardiac insufficiency, and intolerance to chemotherapy;
* 11、Relapsed AML at any time；
* 12、The attending physician considers that the patient is not suitable for entering the study protocol based on the patient's physical condition, economic status, and other factors.

Maximum Eligible Age

18 Years

Eligible Sex

ALL

Accepts Healthy Volunteers

No

Responsible Party

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Shaoyan Hu

Study Chair

Responsibility Role PRINCIPAL_INVESTIGATOR

Principal Investigators

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Shaoyan Hu, MD, PhD

Role: STUDY_CHAIR

Children 's Hospital of Soochow University

Locations

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