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

ConditionsAcute Myeloid Leukemia (AML)Acute Myeloid Leukaemia (AML)
Trial statusRecruiting
Trial phasePhase 2
Trial typeInterventional
Biological sexAll
Age18+
SponsorThe Methodist Hospital Research Institute

About this trial

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).

Eligibility criteria

This trial does not accept healthy volunteers

Qualifiers

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.

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

Newly diagnosed de novo AML

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

Disqualifiers

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.

The patient has serious and/or uncontrolled preexisting medical condition(s) that, in the judgment of the investigator, would preclude participation in this study

Known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial.

Confirmed positive pregnancy test in WOCBP.

Trial design

Design model

Parallel

Treatments tested in this trial

  • 5hmC Biomarker

    Diagnostic test

    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.

  • Venetoclax

    Drug

    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.

  • Decitabine 20 mg/m²/day for 5 days

    Drug

    Decitabine is a nucleoside metabolic inhibitor that is administered as an intravenous infusion over a 1-3 hours.

  • Azacitidine (AZA)

    Drug

    Azacitidine can be given as a sub-cutaneous injection or intravenously.

  • Cytarabine (Ara-C)

    Drug

    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.

  • Anthracycline

    Drug

    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.

Treatment groups

112 Participants
are divided into 2 treatment groups
Group A: HMA- Based Treatment ArmActive comparator 4 interventions
Group B: Intensive Chemotherapy ArmActive comparator 3 interventions

Trial outcomes

Primary outcomes

1

5hmC Minimal Residual Disease Rates

cfDNA 5hmC-MRD negativity and positivity rates at the time of morphologic remission.

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.
2

Duration of Remission (DoR) Based on 5hmC-MRD Status

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.

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.
3

Event-Free Survival (EFS) by 5hmC-MRD Status

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.

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.
4

Overall Survival (OS) in Relation to 5hmC-MRD

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.

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.

Secondary outcomes

1

MRD Positivity Rate Across Detection Methods

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.

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.
2

Duration of Remission (DoR) in MRD-Positive and MRD-Negative Patients by Method

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.

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.
3

Event-Free Survival by MRD Detection Method

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.

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.
4

Overall Survival by MRD Detection Method

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.

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.

Other outcomes

Sponsors and contacts

Click on the lead sponsor to view all of their trials.

The Methodist Hospital Research Institute

Lead sponsor

Source ClinicalTrials.gov
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