Efficacy of Hypomethylating Agents vs. Intensive Chemotherapy in Acute Myeloid Leukemia Using 5hmC as a Blood-Based Minimal Residual Disease Marker

Not Applicable

Not yet recruiting

• Conditions: Acute Myeloid Leukemia (AML); Acute Myeloid Leukaemia (AML)
• Interventions: Diagnostic Test: 5hmC Biomarker; Drug: Venetoclax; Drug: Cytarabine (Ara-C); Drug: Decitabine 20 mg/m²/day for 5 days; Drug: Anthracycline; Drug: Azacitidine (AZA)

• Registration Number: NCT07060001
• Lead Sponsor: The Methodist Hospital Research Institute

Brief Summary

This is a therapeutic intervention trial evaluating the clinical utility of a novel blood-based epigenetic biomarker-genome-wide 5-hydroxymethylcytosine (5hmC) in cell-free DNA (cfDNA)-for assessing measurable residual disease (MRD) in patients with newly diagnosed acute myeloid leukemia (AML). The study compares the efficacy of hypomethylating agent (HMA)-based therapy versus intensive induction chemotherapy, using the 5hmC biomarker to guide post-induction treatment decisions. Approximately 112 adult patients will be enrolled and assigned to treatment arms based on a stratified sampling scheme. Blood samples will be collected at defined intervals to assess MRD status. Primary endpoints include minimal residual disease (MRD) negativity rate, duration of remission, event-free survival (EFS), and overall survival (OS).

Detailed Description

This is a therapeutic intervention trial evaluating the efficacy of a novel, blood epigenetic marker \[genome-wide 5 hydroxymethylcytosine (5hmC) of cell free DNA (cfDNA)\] for assessing measurable residual disease (MRD) in patients with acute myeloid leukemia (AML). Using the highly sensitive cfDNA 5hmC method, the trial will evaluate clinical efficacy of induction therapy and minimal residual disease (MRD) guided therapy in AML patients. Female or male patients aged 18 years, or older, with newly diagnosed de novo AML who will receive induction therapy with either hypomethylating agent (HMA) -based treatment or intensive chemotherapy will be eligible to participate in the trial. Patients will be assigned to one of the two treatment options based on a stratified sampling scheme. Approximately, 112 patients will be enrolled in the study. Informed consent will be obtained from all patients prior to participation.

The efficacy of HMA-based treatment versus intensive induction chemotherapy will be evaluated using the cfDNA 5hmC method in AML patients. The 5hmC marker will be used to determine treatment modality post-induction therapy. After Week 4 of standard-of-care therapy (either HMA-based treatment or intensive induction chemotherapy), 5hmC biomarker testing will be performed. If MRD is positive, patients will continue the same standard-of-care treatment or crossover to the other arm of the study. If MRD is negative, patients will proceed with consolidation (either HSCT or continue on same treatment).

For patients receiving HMA-based treatment, blood samples will be collected ± 5 days before and after 4 and 12 weeks of therapy. For patients receiving intensive chemotherapy blood samples will be collected ± 5 days before and after 4 and 12 weeks of therapy. The primary endpoints will be assessment of cfDNA 5hmC-MRD negativity rate, duration of remission, event-free survival (EFS), and overall survival (OS) in the two treatment groups. EFS will be assessed from the time of treatment initiation to the first occurrence of disease progression (\>5% blasts in blood or bone marrow) or death from any cause. All sample collections will be conducted in accordance with the patient's standard-of-care visits. Patient samples will be collected prospectively at Houston Methodist Hospital. At least 112 subjects will be enrolled.

The hypothesis is that the 5hmC method for MRD detection will be more sensitive in AML patients receiving HMA-based regimens compared with those receiving intensive induction chemotherapy.

Study Timeline

• Status Verified: 2025-06
• Study First Submitted: 2025-06-20
• Study Start: 2025-07-01
• Study First Submitted QC: 2025-07-01
• Last Update Submitted: 2025-07-01
• Study First Posted: 2025-07-11
• Last Update Posted: 2025-07-11
• Primary Completion: 2028-12
• Study Completion: 2029-12-01

Recruitment & Eligibility

• Status: NOT_YET_RECRUITING
• Sex: All
• Target Recruitment: 112

Inclusion Criteria

1. The patient (or legally acceptable representative if applicable) provides written informed consent for the trial. Spanish speaking patients will be included and translation services will be provided as needed.

2. Male or female, 18 years of age or older, on the day of informed consent signing.

3. Newly diagnosed de novo AML

4. Expected life expectancy of at least 6 months 6. Willing and able to comply with the protocol for the duration of the trial including undergoing treatment and scheduled visits and examinations. 7. Women with childbearing potential and men should practice at least one of the following methods of birth control throughout the study and for 6 for women and 3 months for men after the last dose of study therapy:

5. Total abstinence from sexual intercourse (periodic abstinence not acceptable);

6. Surgically sterile partner(s) including vasectomy, bilateral tubal ligation, bilateral oophorectomy, or hysterectomy;

7. Practicing 2 effective methods of contraception (at least 1 highly effective, method of contraception [See Appendix 4]). WOCBP should only be included after a confirmed negative serum pregnancy test.

Exclusion Criteria

1. Currently participating and receiving study therapy or has participated in a study of an investigational agent and received study therapy or used an investigational device within 3 weeks of trial treatment administration.
2. The patient has serious and/or uncontrolled preexisting medical condition(s) that, in the judgment of the investigator, would preclude participation in this study
3. Known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial.
4. Confirmed positive pregnancy test in WOCBP.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
HMA- Based Treatment Arm	5hmC Biomarker	Azacitidine or Decitabine with or without Venetoclax (HMA-based treatment): * Venetoclax is a BCL-2 inhibitor FDA Approved for the treatment of newly-diagnosed acute myeloid leukemia (AML) in adults who are age 75 years or older, or who have comorbidities that preclude use of intensive induction chemotherapy, in combination with azacitidine, decitabine or low-dose cytarabine in. * Decitabine is a nucleoside metabolic inhibitor that is administered as an intravenous infusion over a 1-3 hours. * Azacitidine can be given as a sub-cutaneous injection or intravenously. In AML, the most common adverse reactions (≥30%) in combination with azacitidine or decitabine or low-dose cytarabine were nausea, diarrhea, thrombocytopenia, constipation, neutropenia, febrile neutropenia, fatigue, vomiting, peripheral edema, pyrexia, pneumonia, dyspnea, hemorrhage, anemia, rash, abdominal pain, sepsis, back pain, myalgia, dizziness, cough, oropharyngeal pain, and hypotension.
HMA- Based Treatment Arm	Venetoclax	Azacitidine or Decitabine with or without Venetoclax (HMA-based treatment): * Venetoclax is a BCL-2 inhibitor FDA Approved for the treatment of newly-diagnosed acute myeloid leukemia (AML) in adults who are age 75 years or older, or who have comorbidities that preclude use of intensive induction chemotherapy, in combination with azacitidine, decitabine or low-dose cytarabine in. * Decitabine is a nucleoside metabolic inhibitor that is administered as an intravenous infusion over a 1-3 hours. * Azacitidine can be given as a sub-cutaneous injection or intravenously. In AML, the most common adverse reactions (≥30%) in combination with azacitidine or decitabine or low-dose cytarabine were nausea, diarrhea, thrombocytopenia, constipation, neutropenia, febrile neutropenia, fatigue, vomiting, peripheral edema, pyrexia, pneumonia, dyspnea, hemorrhage, anemia, rash, abdominal pain, sepsis, back pain, myalgia, dizziness, cough, oropharyngeal pain, and hypotension.
Intensive Chemotherapy Arm	5hmC Biomarker	Cytarabine with Anthracycline (standard intensive induction therapy): * Cytarabine is FDA approved chemotherapy (pyrimidine analog) infusion that is frequently used with other drug such as anthracycline to treat acute myeloid leukemia, acute lymphoblastic leukemia. Common side effects include low counts, immune suppression, nausea, neutropenic fever. * Anthracyclines are chemotherapy infusions which topoisomerase II inhibition. Other than having side effects similar to cytarabine, it may cause weakening of heart pumping function few years later. Both of these medications may cause a temporary loss of hair in some people. After treatment with cytarabine has ended, normal hair growth should return.
Intensive Chemotherapy Arm	Cytarabine (Ara-C)	Cytarabine with Anthracycline (standard intensive induction therapy): * Cytarabine is FDA approved chemotherapy (pyrimidine analog) infusion that is frequently used with other drug such as anthracycline to treat acute myeloid leukemia, acute lymphoblastic leukemia. Common side effects include low counts, immune suppression, nausea, neutropenic fever. * Anthracyclines are chemotherapy infusions which topoisomerase II inhibition. Other than having side effects similar to cytarabine, it may cause weakening of heart pumping function few years later. Both of these medications may cause a temporary loss of hair in some people. After treatment with cytarabine has ended, normal hair growth should return.
HMA- Based Treatment Arm	Decitabine 20 mg/m²/day for 5 days	Azacitidine or Decitabine with or without Venetoclax (HMA-based treatment): * Venetoclax is a BCL-2 inhibitor FDA Approved for the treatment of newly-diagnosed acute myeloid leukemia (AML) in adults who are age 75 years or older, or who have comorbidities that preclude use of intensive induction chemotherapy, in combination with azacitidine, decitabine or low-dose cytarabine in. * Decitabine is a nucleoside metabolic inhibitor that is administered as an intravenous infusion over a 1-3 hours. * Azacitidine can be given as a sub-cutaneous injection or intravenously. In AML, the most common adverse reactions (≥30%) in combination with azacitidine or decitabine or low-dose cytarabine were nausea, diarrhea, thrombocytopenia, constipation, neutropenia, febrile neutropenia, fatigue, vomiting, peripheral edema, pyrexia, pneumonia, dyspnea, hemorrhage, anemia, rash, abdominal pain, sepsis, back pain, myalgia, dizziness, cough, oropharyngeal pain, and hypotension.
HMA- Based Treatment Arm	Azacitidine (AZA)	Azacitidine or Decitabine with or without Venetoclax (HMA-based treatment): * Venetoclax is a BCL-2 inhibitor FDA Approved for the treatment of newly-diagnosed acute myeloid leukemia (AML) in adults who are age 75 years or older, or who have comorbidities that preclude use of intensive induction chemotherapy, in combination with azacitidine, decitabine or low-dose cytarabine in. * Decitabine is a nucleoside metabolic inhibitor that is administered as an intravenous infusion over a 1-3 hours. * Azacitidine can be given as a sub-cutaneous injection or intravenously. In AML, the most common adverse reactions (≥30%) in combination with azacitidine or decitabine or low-dose cytarabine were nausea, diarrhea, thrombocytopenia, constipation, neutropenia, febrile neutropenia, fatigue, vomiting, peripheral edema, pyrexia, pneumonia, dyspnea, hemorrhage, anemia, rash, abdominal pain, sepsis, back pain, myalgia, dizziness, cough, oropharyngeal pain, and hypotension.
Intensive Chemotherapy Arm	Anthracycline	Cytarabine with Anthracycline (standard intensive induction therapy): * Cytarabine is FDA approved chemotherapy (pyrimidine analog) infusion that is frequently used with other drug such as anthracycline to treat acute myeloid leukemia, acute lymphoblastic leukemia. Common side effects include low counts, immune suppression, nausea, neutropenic fever. * Anthracyclines are chemotherapy infusions which topoisomerase II inhibition. Other than having side effects similar to cytarabine, it may cause weakening of heart pumping function few years later. Both of these medications may cause a temporary loss of hair in some people. After treatment with cytarabine has ended, normal hair growth should return.

Primary Outcome Measures

Name	Time	Method
5hmC Minimal Residual Disease Rates	From date of initial treatment until progression, unacceptable toxicity, treating physician's discretion, or patient withdraws, whichever comes first, assessed up to 30 months.	cfDNA 5hmC-MRD negativity and positivity rates at the time of morphologic remission.
Duration of Remission (DoR) Based on 5hmC-MRD Status	From date of initial treatment until progression, unacceptable toxicity, treating physician's discretion, or patient withdraws, whichever comes first, assessed up to 30 months.	Time from initial treatment to disease relapse or progression, stratified by 5-hydroxymethylcytosine minimal residual disease (5hmC-MRD) status (positive vs. negative). This measure evaluates the impact of 5hmC-MRD on the sustainability of remission.
Event-Free Survival (EFS) by 5hmC-MRD Status	From date of initial treatment until progression, unacceptable toxicity, treating physician's discretion, or patient withdraws, whichever comes first, assessed up to 30 months.	Time from treatment initiation to the occurrence of any treatment failure event, including relapse, progression, or death from any cause, compared between patients with positive and negative 5hmC-MRD. This outcome assesses the prognostic value of 5hmC-MRD in predicting treatment durability.
Overall Survival (OS) in Relation to 5hmC-MRD	From date of initial treatment until progression, unacceptable toxicity, treating physician's discretion, or patient withdraws, whichever comes first, assessed up to 30 months.	Time from diagnosis or treatment start to death from any cause, analyzed by 5hmC-MRD status. This outcome measure determines whether 5hmC-MRD positivity is associated with reduced overall survival.

Secondary Outcome Measures

Name	Time	Method
MRD Positivity Rate Across Detection Methods	From date of initial treatment until progression, unacceptable toxicity, treating physician's discretion, or patient withdraws, whichever comes first, assessed up to 30 months.	Proportion of patients identified as MRD-positive following induction therapy using 5hmC, multiparameter flow cytometry (MFC), RT-PCR, and next-generation sequencing (NGS). This outcome compares the sensitivity and concordance of MRD detection methods.
Duration of Remission (DoR) in MRD-Positive and MRD-Negative Patients by Method	From date of initial treatment until progression, unacceptable toxicity, treating physician's discretion, or patient withdraws, whichever comes first, assessed up to 30 months.	Time from initial treatment to relapse or progression, stratified by MRD status (positive vs. negative) as determined by 5hmC, MFC, RT-PCR, and NGS. This outcome evaluates the prognostic value of each method in predicting remission durability.
Event-Free Survival by MRD Detection Method	From date of initial treatment until progression, unacceptable toxicity, treating physician's discretion, or patient withdraws, whichever comes first, assessed up to 30 months.	Event-free survival (EFS) measured from treatment initiation, stratified by MRD status as determined by each method (5hmC, MFC, RT-PCR, NGS). This outcome assesses the predictive utility of each MRD method for long-term clinical outcomes.
Overall Survival by MRD Detection Method	From date of initial treatment until progression, unacceptable toxicity, treating physician's discretion, or patient withdraws, whichever comes first, assessed up to 30 months.	Overall survival (OS) measured from treatment initiation, stratified by MRD status as determined by each method (5hmC, MFC, RT-PCR, NGS). This outcome assesses the predictive utility of each MRD method for long-term clinical outcomes.

Trial Locations

Locations (1)

Houston Methodist Neal Cancer Center; 🇺🇸 Houston, Texas, United States