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

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.

Inclusion criteria

• 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

• 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:

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

• 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.