Molecular Subtype Combined with Early Minimal Residual Disease to Optimize the Treatment of Newly Diagnosed Acute Myeloid Leukemia

Molecular Subtype Combined with Early Minimal Residual Disease to Optimize the Treatment of Young Treatment-naive Acute Myeloid Leukemia: a Multicenter, Phase II Study

This study aims to investigate the safety and efficacy of drug "X" in combination with intensive chemotherapy in subjects with newly diagnosed AML (excluding APL and CBF-AML). "X" drugs included BCL-2 inhibitor venetoclax and FLT3 inhibitor Gilteritinib.

Subjects will receive standard intensive chemotherapy during induction and consolidation. Early induction response will be evaluated according to the results of peripheral blood blast clearance rate on the fifth day after induction therapy (D5-PBCR). Venetoclax will be added in D5-PBCR positive subjects. For subjects with FLT3 mutations, Gilteritinib will be combined.

Subjects will be stratified based on the genetic risk classification of 2022 European LeukemiaNet recommendations (ELN risk) and MRD status to receive specific consolidation therapy after the induction therapy.

Study Overview

• Status: Not yet recruiting
• Conditions: Acute Myeloid Leukemia (AML)
• Intervention / Treatment: Drug: D5-PBCR(-) IA arm; Drug: D5-PBCR(+) IA+Venetoclax arm

Detailed Description

Young patients with naïve AML (excluding APL and CBF-AML) were included in this study. 218 subjects who meet the eligibility criteria will receive the standard 3+7 intensive chemotherapy induction, containing cytarabine and idarubicin. On the basis of the IA induction regimen, the early chemotherapy response was evaluated according to the results of peripheral blood blast clearance rate on the fifth day after induction therapy (D5-PBCR). For D5-PBCR-positive patients, venetoclax will be added to conventional chemotherapy. For patients with FLT3 mutations, gilteritinib will be combined.

Subjects who achieve a composite complete remission (CRc) after induction therapy will receive further consolidation therapy, which regimen will be decided based on the ELN risk at diagnosis and MRD status detected by MFC and gene quantification after induction therapy.

The purpose of the study is to determine whether the addition of drug "X" to the standard induction regimen improves efficacy in the treatment of naïve AML.

Primary objective: To evaluate whether intensive IA combined with targeted drug (drug "X") regimens can improve the composite response rate (CRc) after 1 course of induction therapy in newly diagnosed young AML patients Secondary Objective: To evaluate whether intensive chemotherapy combined with drug "X" during induction and consolidation can improve overall response rates, overall survival, and event-free survival in newly diagnosed young AML patients Safety indicators: incidence of adverse reactions during treatment, recovery time of neutrophils and platelets

• Study Type: Interventional
• Enrollment (Estimated): 218
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Yunxiang Zhang; Phone Number: +86-13564516001; Email: zyx12103@rjh.com.cn
• Study Contact Backup: Name: Hongming Zhu; Phone Number: +86-15921512422; Email: zhm11931@rjh.com.cn

Study Locations

• China
  • Shanghai, China
    • Ruijin Hospital, Shanghai JiaoTong University School of Medicine
    • Contact: Yang Shen; Phone Number: +86-021-64370045; Email: sy_clinicaltrial@163.com

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Bone marrow morphology and immunology confirmed newly diagnosed AML patients (according to 2022 ICC criteria)
2. Exclude patients with APL and CBF-AML (according to fusion genes and chromosomes)
3. Performance status score 0-2 (ECOG score)
4. Age 18~59 years old
5. Liver and kidney function: blood bilirubin ≤ 35 μmol/L, AST/ALT below 2 times the upper limit of normal, creatinine ≤ 150 μmol/L
6. Normal cardiac function (EF ≥50%)
7. Obtained informed consent signed by the patient or family member

Exclusion Criteria:

1. FAB classification is M3, or confirmed APL at the molecular level
2. CBF-AML
3. Patients who have already been treated
4. Comfirmed central nervous system leukemia
5. Allergy to any of the drugs involved in the protocol
6. Medical condition or organ system dysfunction that precludes the inability to swallow capsules or tablets, or has a disease that significantly affects gastrointestinal function and/or inhibits small bowel absorption (including malabsorption syndrome, small bowel resection, or poorly controlled inflammatory bowel disease)
7. Cardiac function and disease consistent with one of the following: a) long QTc syndrome or QTc interval >480 ms; b) second- or third-degree atrioventricular block; Severe, uncontrolled cardiac arrhythmias requiring medication; c) United States New York College of Cardiology Grade ≥ III; d) Ventricular ejection fraction (LVEF) less than 50%; e) History of myocardial infarction, unstable angina, severe unstable ventricular arrhythmia or any other arrhythmia requiring treatment, history of clinically severe pericardial disease, or ECG evidence of acute ischemic or active conduction abnormalities within 6 months prior to recruitment
8. Previous or present concomitant malignancies (except for basal cell carcinoma of the skin that have been effectively controlled as non-melanoma, carcinoma in situ of the breast/cervix, and other malignancies that have not been effectively controlled for more than 6 months, and patients who have been receiving long-term non-chemotherapy treatments such as hormonal therapy)
9. Significant abnormalities in liver and kidney function (serum bilirubin, aspartate aminotransferase, alanine aminotransferase or serum creatinine more than 2 times the upper limit of normal reference values; Excluded from AML-related as judged by the investigator)
10. Patients who have previously used other drugs for the treatment of AML (except hydroxyurea and cytarabine for cell count control), including but not limited to BCL2, FLT3, IDH1, IDH2 inhibitors, or other drugs in clinical trials
11. Coagulopathy not associated with AML
12. HIV infection, syphilis infection, HCV infection, active HBV infection (HBsAg positive, or HBsAg negative but HBcAb positive with HBV DNA > 1.0 ×ULN)
13. Other uncontrolled active infection (as judged by the investigator)
14. Pregnant or lactating women
15. Inability to understand or follow the study protocol
16. Participation in other relevant clinical studies within 30 days (except diagnostic clinical studies)
17. Patients who in the opinion of the investigator, are not suitable to participate in this study

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Sequential Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: D5-PBCR(-); On day five of IA induction, D5-PBCR will be tested according to protocol. For D5-PBCR (-) patients, no additional of venetoclax is needed.	Drug: D5-PBCR(-) IA arm; Induction: IA Drug: idarubicin, intravenously, 10 mg/m^2 on D1-3 Drug: cytarabine, intravenously, 100 mg/m^2 on D1-7 Consolidation: Subjects who achieve composite complete remission (CRc) proceed with consolidation therapy. In consolidation therapy phase, subjects in the group with favorable/intermediate risk and MRD negetive, will receive cytarabine intravenously at 2g/m^2/q12h*6 doses. Subjects in the group with adverse risk or MRD positive will receive cytarabine intravenously at 2g/m^2/q12h*6 doses together with venetoclax 400mg on D4-10. Dose ramp-up of venetoclax is not required. After two cycles of consolidation, a multi-disciplinary team will discuss whether the patient need allogeneic hematopoietic stem-cell transplant (allo-HSCT) according to ELN risk stratification and MRD status.
Experimental: D5-PBCR(+); On day five of induction, D5-PBCR will be tested according to protocol. D5-PBCR (+) patients, will receive induction therapy consisting of venentoclax combined with IA regimen.	Drug: D5-PBCR(+) IA+Venetoclax arm; Induction: IA+Ven Drug: idarubicin, intravenously, 10 mg/m^2, on D1-3, Drug: cytarabine, intravenously, 100 mg/m^2 on D1-7 For D5-PBCR (+) patients, Venetoclax will be combined. Drug: Venetoclax. Orally once daily, on D6-14. A 3-day dose ramp-up is required for the first induction (100mg D6, 200mg D7, 400mg D8-14) If a second induction is needed, the dose of IA is the same as the first cycle, and dose ramp-up of venetoclax is not required. Consolidation: Subjects who achieve composite complete remission (CRc) proceed with consolidation therapy. In consolidation therapy phase, subjects in the group will receive cytarabine intravenously at 2g/m^2/q12h*6 doses together with venetoclax 400mg on D4-10. Dose ramp-up of venetoclax is not required. After two cycles of consolidation, a multi-disciplinary team will discuss whether the patient need allogeneic hematopoietic stem-cell transplant (allo-HSCT) according to ELN risk stratification and MRD status.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Composite complete remission rate	Complete remission/complete remission with partial hematological recovery/complete remission with incomplete hematological recovery	At the end of cycle one (up to 42 days from the start of cycle 1）

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
EFS	event free survival rate	2-year
Total composite complete remission rate	Complete remission/complete remission with partial hematological recovery/complete remission with incomplete hematological recovery	At the end of induction cycle 2 (up to 42 days from the start of cycle 2)
OS	overall survival rate	2-year
AE	Adverse Events (AEs), Serious Adverse Events (SAEs) Based on NCI-CTCAE 5.0 Assessment	Throughout the entire study period, an average of 1 year
Recovery time for neutrophils and platelets	The time from the first day of induction therapy to the recovery of neutrophils to a count greater than 0.5*10^9/L and platelets to greater than 20*10^9/L	During induction cycle one (up to 42 days from the start of cycle 1)

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
The complete remission rate of MRD negative	The complete remission rate of MRD negative	at the end of induction (up to 42 days from the start of induction cycle 2) and consolidation stage (after two cycles of consolidation, up to 42 days from the start of consolidation cycle 2)
biomarkers of apoptosis	Level of apoptosis biomarkers such as BCL-2, BCL-xL and MCL-1	Throughout the entire study period, an average of 1 year

Collaborators and Investigators

• Sponsor: Ruijin Hospital
• Investigators: Principal Investigator: Yang Shen, Ruijin Hospital

Publications and helpful links

General Publications

• Zhang Y, Li X, Weng X, Shen Y, Chen Y, Zheng Y, Zhao H, You J, Mao Y, Wang L, Wu M, Sheng Y, Wu J, Hu J, Chen Q, Li J. Optimization of idarubicin and cytarabine induction regimen with homoharringtonine for newly diagnosed acute myeloid leukemia patients based on the peripheral blast clearance rate: A single-arm, phase 2 trial (RJ-AML 2014). Am J Hematol. 2022 Jan 1;97(1):43-51. doi: 10.1002/ajh.26386. Epub 2021 Nov 1.
• Yu C, Kong QL, Zhang YX, Weng XQ, Wu J, Sheng Y, Jiang CL, Zhu YM, Cao Q, Xiong SM, Li JM, Xi XD, Chen SJ, Chen B. Clinical significance of day 5 peripheral blast clearance rate in the evaluation of early treatment response and prognosis of patients with acute myeloid leukemia. J Hematol Oncol. 2015 May 10;8:48. doi: 10.1186/s13045-015-0145-1.

Study record dates

Study Major Dates

• Study Start (Estimated): October 30, 2024
• Primary Completion (Estimated): October 31, 2026
• Study Completion (Estimated): June 30, 2027

Study Registration Dates

• First Submitted: October 15, 2024
• First Submitted That Met QC Criteria: October 21, 2024
• First Posted (Actual): October 22, 2024

Study Record Updates

• Last Update Posted (Actual): October 22, 2024
• Last Update Submitted That Met QC Criteria: October 21, 2024
• Last Verified: October 1, 2024

More Information

Terms related to this study

• Keywords: venetoclax; Acute myeloid leukemia; gilteritinib; Risk-stratified; D5-PBCR
• Additional Relevant MeSH Terms: Pathologic Processes; Neoplasms; Neoplasms by Histologic Type; Hematologic Diseases; Neoplastic Processes; Leukemia; Leukemia, Myeloid; Leukemia, Myeloid, Acute; Neoplasm, Residual; Antineoplastic Agents; Venetoclax
• Other Study ID Numbers: IA+X 2024

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No