Standard-dose vs Intermediate-dose Cytarabine Induction in the Treatment of Acute Myeloid Leukemia With RUNX1-RUNX1T1

Phase 3

Not yet recruiting

• Conditions: AML; RUNX1-RUNX1T1 Fusion Protein Expression
• Interventions: Drug: cytarabine; Drug: daunorubicin; Drug: idarubicin; Drug: cyclophosphamide

• Registration Number: NCT06744504
• Lead Sponsor: Institute of Hematology & Blood Diseases Hospital, China

Brief Summary

Leukemia is one of the common malignant tumors that threaten human health. Although the efficacy of AML treatment has improved significantly in recent years, it remains one of the major diseases threatening human health. Current research on AML treatment mainly has two directions. One is the addition of new targeted therapy drugs, and the other research direction is to enhance the intensity of AML chemotherapy, including the use of large doses of anthracycline drugs or the use of high-dose cytarabine treatment.

Since the 1990s, induction remission has been achieved by using anthracyclines in combination with high-dose cytarabine. The ECOG (Eastern Cooperative Oncology Group) contends that high-dose induction chemotherapy fails to enhance the bone marrow remission rate but elevates the chemotherapy-related mortality rate. Bradstock and the Australian Group also noted that although it does not increase the bone marrow remission rate, it can result in longer survival time and disease-free survival time. The clinical study from EORTC-GIMEMA AML-12 discovered that AML patients under the age of 45 could benefit from induction therapy incorporating high-dose cytarabine. In our previous randomized controlled clinical trials, it was found that the HAD and DA regimens containing intermediate-dose cytarabine could enhance the complete remission rate and improve the overall survival of adult AML. However, the degree of benefit varies among different AML subgroups.

The abnormalities of RUNX1-RUNX1T1 and CBFβ-MYH11 respectively involve a subunit of CBF (core binding factor), thus the two are collectively called CBF leukemia. Previous retrospective studies show that this type of leukemia benefits from intensified treatment regimens such as FLAG. However, at present, there is a lack of prospective randomized controlled clinical studies to confirm this. Therefore, in this study, we intend to further verify through a prospective randomized controlled clinical trial whether the induction treatment regimen containing intermediate-dose cytarabine can improve the long-term efficacy of adult RUNX1-RUNX1T1 acute myeloid leukemia.

Detailed Description

This study is a prospective, randomized, controlled phase III clinical trial that plans to enroll adult patients with AML who meet the WHO (2022) or ICC criteria for eligibility for intensive chemotherapy with RUNX1-RUNX1 fusion. For patients who meet the inclusion criteria and do not meet any exclusion criteria, they will be randomly assigned to either the A group, which receives standard-dose DA induction therapy, or the B group, which receives intermediate-dose DA induction therapy. Patients who do not achieve complete remission after one cycle of induction therapy will receive IAC reinduction therapy. Patients who achieve complete remission after one or two cycles of induction therapy will proceed to receive three cycles of high-dose cytarabine consolidation therapy. Patients who do not achieve complete remission after two cycles of induction therapy will be withdrawn from the treatment protocol. For patients whose fusion gene levels do not meet the criteria, allogeneic hematopoietic stem cell transplantation is recommended.

Study Timeline

• Status Verified: 2024-11
• Study First Submitted: 2024-12-17
• Study First Submitted QC: 2024-12-17
• Last Update Submitted: 2024-12-17
• Study First Posted: 2024-12-20
• Last Update Posted: 2024-12-20
• Study Start: 2024-12-25
• Primary Completion: 2027-12-01
• Study Completion: 2029-12-01

Recruitment & Eligibility

• Status: NOT_YET_RECRUITING
• Sex: All
• Target Recruitment: 300

Inclusion Criteria

1. AML conforming to WHO (2022) or ICC standards
2. Possessing the RUNX1::RUNX1T1 fusion gene
3. Age ranging from 14 to 60 years old, regardless of gender.
4. The performance status assessment of the Eastern Cooperative Oncology Group (ECOG-PS) being 0 - 2.
5. Meeting the requirements of the following laboratory examination indicators (conducted within 7 days before treatment):

1. Total bilirubin ≤ 1.5 times the upper limit of the normal value for the same age group; 2) AST and ALT ≤ 2.5 times the upper limit of the normal value for the same age group; 3) Serum creatinine < 2 times the upper limit of the normal value for the same age group; 4) Cardiac enzymes < 2 times the upper limit of the normal value for the same age group; 5) The cardiac ejection fraction determined by echocardiography (ECHO) > 50%. An informed consent form must be signed before the commencement of all specific research procedures, either by the patient themselves or their immediate relatives. Considering the patient's condition, if the patient's signature is not conducive to the treatment of the disease, the informed consent form shall be signed by the legal guardian or the immediate relatives of the patient.

Exclusion Criteria

1. Acute promyelocytic leukemia accompanied by PML-RARA fusion gene.
2. Acute myeloid leukemia featuring BCR-ABL fusion gene.
3. Patients undergoing retreatment (but can receive cytoreductive therapy with hydroxyurea and cytarabine).
4. Individuals concurrently having malignant tumors in other organs (requiring treatment).
5. Active cardiac disorders, defined as one or more of the following:

1. A history of uncontrolled or symptomatic angina pectoris; 2) Myocardial infarction less than 6 months from study enrollment; 3) A history of significant arrhythmia requiring medication or presenting with severe clinical symptoms; 4) Uncontrolled or symptomatic congestive heart failure (> NYHA Class 2)

6. Severe infectious diseases (untreated tuberculosis, pulmonary aspergillosis).

7. Individuals deemed ineligible for enrollment by the investigator.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
standard-dose Cytarabine	cytarabine	Induction therapy: Cytarabine (Ara-c) 100mg/ m2/ day, day 1-7; Daunorubicin (DNR) 60mg/m2/ day, day 1-3; Those who did not meet CR were treated with IAC regimen. IAC: IDA 8 mg/m2/d, D1-3; Ara-c 100 mg/m2, D1-7; CTX 350mg/m2, D2,5; Post-remission treatment options: High dose Ara-C(HDAC) : 3 cycles Ara-C 3g/㎡/q12h, days 1, 3 and 5 For patietns RUNX1-RUNX1 MRD reduction \< 3 logs after 2 courses, allo-transplantation is recommended if donor is available.
standard-dose Cytarabine	daunorubicin	Induction therapy: Cytarabine (Ara-c) 100mg/ m2/ day, day 1-7; Daunorubicin (DNR) 60mg/m2/ day, day 1-3; Those who did not meet CR were treated with IAC regimen. IAC: IDA 8 mg/m2/d, D1-3; Ara-c 100 mg/m2, D1-7; CTX 350mg/m2, D2,5; Post-remission treatment options: High dose Ara-C(HDAC) : 3 cycles Ara-C 3g/㎡/q12h, days 1, 3 and 5 For patietns RUNX1-RUNX1 MRD reduction \< 3 logs after 2 courses, allo-transplantation is recommended if donor is available.
standard-dose Cytarabine	idarubicin	Induction therapy: Cytarabine (Ara-c) 100mg/ m2/ day, day 1-7; Daunorubicin (DNR) 60mg/m2/ day, day 1-3; Those who did not meet CR were treated with IAC regimen. IAC: IDA 8 mg/m2/d, D1-3; Ara-c 100 mg/m2, D1-7; CTX 350mg/m2, D2,5; Post-remission treatment options: High dose Ara-C(HDAC) : 3 cycles Ara-C 3g/㎡/q12h, days 1, 3 and 5 For patietns RUNX1-RUNX1 MRD reduction \< 3 logs after 2 courses, allo-transplantation is recommended if donor is available.
standard-dose Cytarabine	cyclophosphamide	Induction therapy: Cytarabine (Ara-c) 100mg/ m2/ day, day 1-7; Daunorubicin (DNR) 60mg/m2/ day, day 1-3; Those who did not meet CR were treated with IAC regimen. IAC: IDA 8 mg/m2/d, D1-3; Ara-c 100 mg/m2, D1-7; CTX 350mg/m2, D2,5; Post-remission treatment options: High dose Ara-C(HDAC) : 3 cycles Ara-C 3g/㎡/q12h, days 1, 3 and 5 For patietns RUNX1-RUNX1 MRD reduction \< 3 logs after 2 courses, allo-transplantation is recommended if donor is available.
Intermediate-dose Cytarabine	cytarabine	Induction therapy: Cytarabine (Ara-c) 100mg/ m2/ day, day 1-4; 1g/㎡/q12h, day 5-7; Daunorubicin (DNR) 60mg/m2/ day, day 1-3; Those who did not meet CR were treated with IAC regimen. IAC: IDA 8 mg/m2/d, D1-3; Ara-c 100 mg/m2, D1-7; CTX 350mg/m2, D2,5; Post-remission treatment options: High dose Ara-C(HDAC) : 3 cycles; Ara-C 3g/㎡/q12h, days 1, 3 and 5. For patietns RUNX1-RUNX1 MRD reduction \< 3 logs after 2 courses, allo-transplantation is recommended if donor is available.
Intermediate-dose Cytarabine	daunorubicin	Induction therapy: Cytarabine (Ara-c) 100mg/ m2/ day, day 1-4; 1g/㎡/q12h, day 5-7; Daunorubicin (DNR) 60mg/m2/ day, day 1-3; Those who did not meet CR were treated with IAC regimen. IAC: IDA 8 mg/m2/d, D1-3; Ara-c 100 mg/m2, D1-7; CTX 350mg/m2, D2,5; Post-remission treatment options: High dose Ara-C(HDAC) : 3 cycles; Ara-C 3g/㎡/q12h, days 1, 3 and 5. For patietns RUNX1-RUNX1 MRD reduction \< 3 logs after 2 courses, allo-transplantation is recommended if donor is available.
Intermediate-dose Cytarabine	idarubicin	Induction therapy: Cytarabine (Ara-c) 100mg/ m2/ day, day 1-4; 1g/㎡/q12h, day 5-7; Daunorubicin (DNR) 60mg/m2/ day, day 1-3; Those who did not meet CR were treated with IAC regimen. IAC: IDA 8 mg/m2/d, D1-3; Ara-c 100 mg/m2, D1-7; CTX 350mg/m2, D2,5; Post-remission treatment options: High dose Ara-C(HDAC) : 3 cycles; Ara-C 3g/㎡/q12h, days 1, 3 and 5. For patietns RUNX1-RUNX1 MRD reduction \< 3 logs after 2 courses, allo-transplantation is recommended if donor is available.
Intermediate-dose Cytarabine	cyclophosphamide	Induction therapy: Cytarabine (Ara-c) 100mg/ m2/ day, day 1-4; 1g/㎡/q12h, day 5-7; Daunorubicin (DNR) 60mg/m2/ day, day 1-3; Those who did not meet CR were treated with IAC regimen. IAC: IDA 8 mg/m2/d, D1-3; Ara-c 100 mg/m2, D1-7; CTX 350mg/m2, D2,5; Post-remission treatment options: High dose Ara-C(HDAC) : 3 cycles; Ara-C 3g/㎡/q12h, days 1, 3 and 5. For patietns RUNX1-RUNX1 MRD reduction \< 3 logs after 2 courses, allo-transplantation is recommended if donor is available.

Primary Outcome Measures

Name	Time	Method
overall survival	up to 2 years after the date of the last enrolled participants	Used to evaluate all patients who enter clinical trials. From the date of entry into the trial until the date of patient death (including any cause) or last survival follow-up.

Secondary Outcome Measures

Name	Time	Method
Complete remission (CR)/CR with partial hematologic recovery (CRh)/CR with incomplete hematologic recovery (CRi) rate	up to12 months after the date of the last enrolled participants	the ratio of patients achieved CR/CRh/CRi
Complete remission (CR)/CR with partial hematologic recovery (CRh)/CR with incomplete hematologic recovery (CRi) rate after induction therapy	up to 3 months after the date of the last enrolled participants	The ratio of patients achieved CR/CRh/CRi after induction therapy.
RUNX1::RUNX1T1 minimal residual disease (MRD) reduction >3 logs after 2 courses	up to 2 years after the date of the last enrolled participants	RUNX1::RUNX1T1 MRD is measured by real-time PCR.
RUNX1::RUNX1T1 molecular MRD undectable rate	up to 2 years after the date of the last enrolled participants	MRD levels monitored by polymerase chain reaction are associated with outcomes in acute myeloid leukemia with RUNX1-RUNX1T1.
Relapse-free survival (RFS)	up to 2 years after the date of the last enrolled participants	Defined only for patients achieving CRc; measured from the date of achievement of remission until the date of hematologic relapse or death from any cause; patients not known to have relapsed or died at last follow-up are censored on the date they were last known to be alive
Event-free survival (EFS)	up to 2 years after the date of the last enrolled participants	All patients definitions for the trial; From the date of enrollment to the time of treatment failure after two courses of induction therapy, recurrence after CRc, date of all-cause death, or the date of last survival follow-up.
30-day mortality	within 30 days of the date of the last enrolled participants	Percentage of patients who died within 30 days from enrollment.
60-day mortality	within 60 days of the date of the last enrolled participants	Percentage of patients who died within 60 days from enrollment