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

March 5, 2026 updated by: The Methodist Hospital Research Institute

Evaluation of the Efficacy of Hypomethylating Agent Versus Standard Intensive Chemotherapy Induction Based on 5hmC - a Novel, Blood Epigenetic Marker for Assessing Measurable Residual Disease in Patients With Acute Myeloid Leukemia

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).

Study Overview

Status

Not yet recruiting

Conditions

Intervention / Treatment

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 Type

Interventional

Enrollment (Estimated)

112

Phase

  • Phase 2

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Contact Backup

Study Locations

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

  • Adult
  • Older Adult

Accepts Healthy Volunteers

No

Description

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

5. 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:

  1. Total abstinence from sexual intercourse (periodic abstinence not acceptable);
  2. Surgically sterile partner(s) including vasectomy, bilateral tubal ligation, bilateral oophorectomy, or hysterectomy;
  3. 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 Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

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

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Active Comparator: HMA- Based Treatment Arm

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.
Diagnostic test: 5hmC Biomarker
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.
Drug: Venetoclax
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.
Drug: Decitabine 20 mg/m²/day for 5 days
Decitabine is a nucleoside metabolic inhibitor that is administered as an intravenous infusion over a 1-3 hours.
Drug: Azacitidine (AZA)
Azacitidine can be given as a sub-cutaneous injection or intravenously.
Active Comparator: Intensive Chemotherapy Arm

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.
Diagnostic test: 5hmC Biomarker
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.
Drug: Cytarabine (Ara-C)
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.
Drug: Anthracycline
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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
5hmC Minimal Residual Disease Rates
Time Frame: 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.
From date of initial treatment until progression, unacceptable toxicity, treating physician's discretion, or patient withdraws, whichever comes first, assessed up to 30 months.
Duration of Remission (DoR) Based on 5hmC-MRD Status
Time Frame: 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.
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) by 5hmC-MRD Status
Time Frame: 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.
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) in Relation to 5hmC-MRD
Time Frame: 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.
From date of initial treatment until progression, unacceptable toxicity, treating physician's discretion, or patient withdraws, whichever comes first, assessed up to 30 months.

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
MRD Positivity Rate Across Detection Methods
Time Frame: 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.
From date of initial treatment until progression, unacceptable toxicity, treating physician's discretion, or patient withdraws, whichever comes first, assessed up to 30 months.
Duration of Remission (DoR) in MRD-Positive and MRD-Negative Patients by Method
Time Frame: 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.
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 by MRD Detection Method
Time Frame: 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.
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 by MRD Detection Method
Time Frame: 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.
From date of initial treatment until progression, unacceptable toxicity, treating physician's discretion, or patient withdraws, whichever comes first, assessed up to 30 months.

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

The Methodist Hospital Research Institute

Investigators

  • Principal Investigator: Shilpan Shah, MD, Houston Methodist Neal Cancer Center

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Estimated)

April 1, 2026

Primary Completion (Estimated)

December 1, 2028

Study Completion (Estimated)

December 1, 2029

Study Registration Dates

First Submitted

June 20, 2025

First Submitted That Met QC Criteria

July 1, 2025

First Posted (Actual)

July 11, 2025

Study Record Updates

Last Update Posted (Actual)

March 6, 2026

Last Update Submitted That Met QC Criteria

March 5, 2026

Last Verified

March 1, 2026

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • PRO00038056 (HMCC-HM24-001)

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

YES

IPD Plan Description

De-identified data sets regarding the correlation between minimal residual disease using the 5hmC biomarker and the type of standard of care treatment may be used by researchers at Houston Methodist and/or shared with other researchers, the government, and other institutions for use in future research.

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

Yes

Studies a U.S. FDA-regulated device product

No

product manufactured in and exported from the U.S.

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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