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A Multi-Center Seamless Phase II-III Randomized Trial of High-dose Cytarabine in Initial Induction with Evaluation of Flow-cytometry-based Minimal Residual Disease for Children with de Novo Acute Myeloid Leukemia (AML-12) (AML-12)

AML-12 (AML-12)

387

Among the 387 patients registered to the trial, total 324 patients (ECM arm, N=168; HD-ECM arm, N=156) met the diffinition of full analysis set (FAS). Thus, baseline characteristics of the 324 FAS patients are listed as follows. Age at diagnosis (years): ECM-7.8 (mean), HD-ECM-7.8 (mean) Age group: younger than 1 year old ECM-11.3%, HD-ECM-10.9% 1 - 9 years old ECM-50.0%, HD-ECM-49.4% 10 years old or older ECM-38.7%, HD-ECM-39.7% Sex: ECM-Male 53.0%/Female 47.0%, HD-ECM-Male 55.8%/Female 44.2% WBC count at diagnosis (/microL): ECM-43830 (mean), HD-ECM-57629 (mean) Treating facilities: ECM-Selected 52.4%/Others 47.6%, HD-ECM-Selected 54.5%/Others 45.5% Risk group: CBF SR ECM-31.0%, HD-ECM-28.9% Non-CBF SR ECM-45.8%, HD-ECM-41.0% HR ECM-10.1%, HD-ECM-15.4% Others ECM-13.1%, HD-ECM-14.7%

This trial is a seamless Phase II-III clinical trial. Phase II part was initiated on March 1, 2014; 189 patients were registered from the selected institutions (eligible for randomized trial) and 37 patients were registered from the other institutions (not eligible for randomized trial). Phase III part was initiated on September 1, 2016; 161 patients were registerd (all patients are eligible for randomized trial). Trial registration ended on February 28, 2018, and follow-up was continued until April 30, 2021. Along with the enactment and enforcement of the Clinical Trials Act in Japan, this trial obtained approval as a specified clinical trial from the certified review board on December 7, 2018, and was released in jRCT on March 26, 2019.

From March 1, 2014 to March 25, 2019: Severe adverse events which required immediate report occurred in 7 patients. Cardiogenic shock, died (during Induction-2) Bronchospasm, died (before initiating Induction-1) Sepsis, died (during Induction-1) Intracranial hemorrhage, died (during Induction-1) Intracranial hemorrhage, died (during Induction-1) Sepsis, permanent optic nerve disorder (during Consolidation-2) Intracranial hemorrhage, died (during Induction-1) From March 26, 2019 to April 30, 2021 (after jRCT release as a specified clinical trial ): No severe adverse events requiring immediate report.

Primary endpoints of this trial were early mortality rate in the Phase II part and 3-year event-free survival rate (EFS) and rate of patients with positive flow-cytometric MRD (FCM-MRD) at end-of-Induction-1 in the Phase III part. The interim analysis (as of May 31, 2015) was performed for the 70 eligible patients (ECM arm, N=31; HD-ECM arm, N=24; others, N=5) who had met the FAS criteria (those with follow-up period of 42 days or longer after trial registration and those who had initiated Induction-1) out of the 87 registered patients. Early mortality rate was 0% for both the patients in ECM and HD-ECM arms. The main analyses of the Phase III part (including the patients registered at the selected institutes in Phase II part) were performed for the 324 patients (ECM arm, N=168; HD-ECM arm, N=156) defined as FAS. 3-year EFS: ECM 64.3% (95%CI, 56.5-71.0%), HD-ECM 61.2% (95%CI, 53.1-68.4%), p=0.551 Positive FCM-MRD rate at TP1: ECM 22.2% (95%CI, 15.5-30.2%), HD-ECM 25.2% (95%CI, 17.9-33.7%), p=0.682 Secondary endpoints included CR rate, early mortality rate, bone marrow remission rate after Induction-1, positive FCM-MRD rate at TP2, overall surival rate (OS), relapse, non-relapse death, incidence of sever adverese events (grade 3 or higher) during Induction-1 and -2. The results were as follows: CR rate: ECM 94.2% (95%CI, 89.3-97.3%), HD-ECM 93.8% (95%CI, 88.6-97.1%), p=0.998 Early mortality rate: ECM 0.6% (95%CI, 0.0-3.3%)), HD-ECM 0.6% (95%CI, 0.0-3.5%), p=0.949 M1 marrow rate after Induction-1: ECM 89.0% (95%CI, 83.2-93.4%), HD-ECM 90.1% (95%CI, 84.3-94.4%), p=0.753 Positive FCM-MRD rate at TP2: ECM 7.6% (95%CI, 3.7-13.5%), HD-ECM 18.3% (95%CI, 11.9-26.4%), p=0.021 3-year OS: ECM 84.4% (95%CI, 78.0-89.1%), HD-ECM 75.3% (95%CI, 67.7-81.4%), p=0.055 Relapse (number of events): ECM 49, HD-ECM 52, p=0.389 Non-relapse death (number of events): ECM 7, HD-ECM 8, p=0.782 Incidence of sever adverese events (grade 3 or higher) during Induction-1 and -2: Statistically significant differences were observed for DIC during Induction-1 (ECM 1.8%, HD-ECM 6.4%, p=0.046) and fever during Induction-1 (ECM 27.4%, HD-ECM: 14.7%, p=0.007). No differences were observed for other adverse events.

AML-12 is a multicenter phase II-III trial conducted by the JPLSG to compare the efficacy and safety of initial induction therapy with high-dose and continuous administration of cytarabine for previously untreated, newly diagnosed patients with AML at <18 years of age. Between March 1, 2014 and February 28, 2018, 346 eligible patients were registered and 324 patients were randomized. There was no difference in 3-year EFS and end-of induction MRD rate between the 2 arms.

Mar. 31, 2023

Nov. 06, 2023

https://doi.org/10.1038/s41375-023-02075-9

No

https://jrct.mhlw.go.jp/latest-detail/jRCTs041180128

Adachi Souichi

Kyoto University

54 Kawaharacho, Shogoin, Sakyo-ku Kyoto, JAPAN

adachiso@kuhp.kyoto-u.ac.jp

Adachi Souichi

Kyoto University

54 Kawaharacho, Shogoin, Sakyo-ku Kyoto, JAPAN

+81-75-751-3297

adachiso@kuhp.kyoto-u.ac.jp

Complete

Mar. 01, 2014

Interventional

randomized controlled trial

open(masking not used)

active control

parallel assignment

treatment purpose

1) AML [excluding APL, AML with Down syndrome (ML-DS), secondary AML, AML developed after MDS, NK/myeloid leukemia, and granulocytic sarcoma]
2) Age 0 year to 18 years old at diagnosis; for neonates aged 30 days or less, patients must be >= 36 weeks gestational age at the time of diagnosis
3) ECOG performance status (PS) score of 0-2; those with PS score 3 is eligible if that is derived from AML
4) newly diagnosed AML without history of previous chemotherapy or radiation therapy; those with history of steroid therapy, ATRA (because of suspicion of APL), or single intrathecal methotrexate therapy (because of suspicion of ALL) are eligible
5) Patients must have sufficient organ function satisfying the laboratory data listed below (should be evaluated within 7 days of study enrollment);
T-Bil: within 3x of the age-dependent normal range
Cre: within 3x of the age-dependent normal range
6) All patients and/or their parents or legal guardians must sign a written informed consent.

1) Patients with severe CNS hemorrhage (grade 3 or higher in CTCAE ver4.0)
2) Patients with uncontrollable infection (including those with active tuberculosis or positive HIV antibody)
3) Patients who are pregnant or breast-feeding mother
4) Patients with history of primary or acquired immunodeficiency
5) Patients with uncontrollable heart failure; presence of heart anomaly itself is not an exclusion criteria
6) Patients with any other inappropriate status judged by physician

Both

Acute Myeloid Leukemia

<Standard Arm>
Induction-1A (ECM): In the Phase II study, patients in the "selected" institutions will be randomly assigned to either high-dose cytarabine (Ara-C) induction (HD-ECM) or standard-dose Ara-C induction (ECM). Patients in the "other" institutions will be non-randomly assigned to the ECM induction. In Phase III study, all the patients will be randomly assigned to either HD-ECM or ECM. Standard arm "Induction-1A (ECM)" consists of standard dose Ara-C, mitoxantrone (MIT), etoposide (VP-16), and triple intrathecal therapy [TIT; Ara-C, methotrexate (MTX), and hydrocortisone (HDC)].

Induction-2 (HCEI): All the patients will receive HCEI consisted of high-dose Ara-C, VP-16, idarubicin (IDA), and TIT.

Post-remission therapies: All the patients who achieved CR after 2 course of induction chemotherapy (Induction-1 and Induction-2) will be stratified to either of the three risk groups (SR/CBF, SR/non-CBF, or HR) and undergo risk stratified multiple chemotherapy courses with or without hematopoietic stem cell transplantation (HSCT) in first remission. HSCT is indicated only for the HR group. Chemotherapy is consisted of Ara-C, MIT or IDA, VP-16, and TIT.
<Experimental Arm>
Induction-1B (HD-ECM): In the Phase II study, patients in the "selected" institutions will be randomly assigned to either high-dose cytarabine (Ara-C) induction (HD-ECM) or standard-dose Ara-C induction (ECM). Patients in the "other" institutions will be non-randomly assigned to the ECM induction. In Phase III study, all the patients will be randomly assigned to either HD-ECM or ECM. Experimental arm "Induction-1B (HD-ECM)" consists of high-dose Ara-C, mitoxantrone (MIT), etoposide (VP-16), and triple intrathecal therapy [TIT; Ara-C, methotrexate (MTX), and hydrocortisone (HDC)].

Induction-2 (HCEI): All the patients will receive HCEI consisted of high-dose Ara-C, VP-16, idarubicin (IDA), and TIT.

Post-remission therapies: All the patients who achieved CR after 2 course of induction chemotherapy (Induction-1 and Induction-2) will be stratified to either of the three risk groups (SR/CBF, SR/non-CBF, or HR) and undergo risk stratified multiple chemotherapy courses with or without hematopoietic stem cell transplantation (HSCT) in first remission. HSCT is indicated only for the HR group. Chemotherapy is consisted of Ara-C, MIT or IDA, VP-16, and TIT.

<Phase II study>
Early death rate

<Phase III study>
1) 3-year event-free survival (EFS) rate
2) Positive rate of flow-cytometry-based minimal residual disease (FCM-MRD) after initial induction course (TP-1)

1) Overall response (CR+CRi) rate, CR rate, CRi rate, non-CR rate, early death rate, and bone marrow response after Induction-1
2) Rate of severe adverse events (grade 3 or higher) defined by Common Terminology Criteria for Adverse Events (CTCAE) ver4.0
3) Positive rate of FCM-MRD in TP-2 and TP-3
4) 3-year and 5-year EFS and overall survival (OS) rate
5) Relapse rate, non-relapse mortality
6) Comparison of FCM-MRD and MRD measuring WT1 mRNA expression
7) Subgroup analyses on all the endpoints; for the whole study cohort including "other" institutions in the Phase II study (except endpoints regarding MRD analyses) and according to the risk groups, MRD levels on TP-1 and TP-2, and other prognostic factors [age and WBC at diagnosis, WHO classification (ver4.0), cytogenetics (all the risk-stratifying factors, complex karyotype, FLT3-ITD allelic ratio, 11q23/MLL gene abnormalities, CEBPA mutation, NPM1 mutation, KIT mutation, and others]
8) For the high risk (HR) group, 3-year and 5-year post-transplantation EFS and OS for those transplanted in first remission (including subgroup analyses according to the donor type and conditioning regimen received)

+81-52-951-1111

Dec. 07, 2018

none