AML, Childhood, Acute Myeloid Leukemia
Conditions
Keywords
AML, Childhood, Molecular subtyping, MRD
Brief summary
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.
Detailed description
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.
Interventions
3mg/m2/day for weighing \>10kg, 0.1mg/kg/day for weighing ≤10kg, d1-7, ivgtt, qd, more than 6 hours
DRUGCytarabine
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;
DRUGEtoposide
100mg/m2/d for weighing \>10kg, 3.3mg/kg/d for weighing ≤ 10kg, d1-5, ivgtt, qd, more than 4 hours
DRUGVenetoclax
100mg/m2/d for weighing \>10kg, 3.33mg/kg/d for weighing ≤10kg, d12-25, po, qd
DRUGMitoxantrone 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.
DRUGRecombinant Human Granulocyte Colony-Stimulating Factor
5ug/kg/d, d1-10, s.c., qd, at 1pm
3mg/m2/day for weighing \>10kg, 0.1mg/kg/day for weighing ≤ 10kg, d1-7, ivgtt, qd, more than 6 hours.
DRUGSorafenib
100mg/m2/day for weighing \>10kg, 3.3mg/kg/day for weighing ≤10kg, from identification, po, qd
DRUGGilteritinib
20mg/m2/day for weighing \>10kg, 0.7mg/kg/day for weighing ≤ 10kg, from identification, po, qd
DRUGAvapritinib
50mg/m2/day for weighing bodyweight \>10kg, 1.65mg/kg/day for weighing ≤ 10kg, po, qd
Sponsors
Children's Hospital of Soochow University
Study design
Allocation
NON_RANDOMIZED
Intervention model
FACTORIAL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
No minimum to 18 Years
Healthy volunteers
No
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; * 9、Having any significant abnormal concurrent disease or mental illness that impacts the life safety and compliance of the patient and impacts informed consent, study participation, follow-up, or interpretation of results. In this case, all the participating units are required to report directly to the responsible person for this project to jointly decide whether they meet the
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Rate of CR/CRi with negative MRD | Day 26 (HAE group) and Day 32 (MAG+Ven group) for remission induction 1 and 2 are the necessary time points for response evaluation. | CR/CRi with negative MRD was defined as less than 5% blasts in bone marrow and MRD \<0.1%. |
| Event-free survival | From date of treatment until the date of the occurrence of the event, whichever comes first, assessed up to 72 months. Patients remaining event-free are censored at the last follow-up time. | Events/failures of EFS include any-cause death, relapse, second malignancy, no CR after Indiction II and off-therapy due to abandonment or attending physician's decision. Induction II and off-therapy due to abandonment or attending physician's decision. |
| Cumulative incidence of relapse | From date of treatment until the date of when a failure of CIR occurs, whichever comes first, assessed up to 72 months. | Failures of CIR only include relapse and no CR after Induction 2. Other failures including death in resission (before repalse), second malignancy, and off-therapy due to abandonment or attending physician's decision are considered competing risk. |
Countries
China
Contacts
Primary ContactShaoyan Hu, MD, PhD
Backup ContactLi Gao, MD
Outcome results
None listed