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

Official title

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

Overview

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.

Interventions

• 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 trea
• 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.
• 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.

Primary outcome measures

• 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.]
• 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.]
• 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.]
• 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.]

Secondary outcome measures (4)

• 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.]
• 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.]
• 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.]
• 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.]

Eligibility criteria

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

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:

• 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.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Non-randomized

Model

Parallel assignment

Masking

Open label

Primary purpose

Treatment

Study locations

United States · 1 center

• Houston Methodist Neal Cancer Center — Houston

Publications

• Krug U, Rollig C, Koschmieder A, Heinecke A, Sauerland MC, Schaich M, Thiede C, Kramer M, Braess J, Spiekermann K, Haferlach T, Haferlach C, Koschmieder S, Rohde C, Serve H, Wormann B, Hiddemann W, Ehninger G, Berdel WE, Buchner T, Muller-Tidow C; German Acute Myeloid Leukaemia Cooperative Group; Study Alliance Leukemia Investigators. Complete remission and early death after intensive chemotherapy PMID 21131036
• Appelbaum FR, Gundacker H, Head DR, Slovak ML, Willman CL, Godwin JE, Anderson JE, Petersdorf SH. Age and acute myeloid leukemia. Blood. 2006 May 1;107(9):3481-5. doi: 10.1182/blood-2005-09-3724. Epub 2006 Feb 2. PMID 16455952
• Camus V, Stamatoullas A, Mareschal S, Viailly PJ, Sarafan-Vasseur N, Bohers E, Dubois S, Picquenot JM, Ruminy P, Maingonnat C, Bertrand P, Cornic M, Tallon-Simon V, Becker S, Veresezan L, Frebourg T, Vera P, Bastard C, Tilly H, Jardin F. Detection and prognostic value of recurrent exportin 1 mutations in tumor and cell-free circulating DNA of patients with classical Hodgkin lymphoma. Haematologica PMID 27479820
• Armand P, Oki Y, Neuberg DS, Faham M, Cummings C, Klinger M, Weng L, Bhattar S, Lacasce AS, Jacobsen ED, Davids MS, Jacobson C, Fisher DC, Brown JR, Fowler NH, Alma Rodriguez M, Wallace MJ, Neelapu SS, Rodig S, Younes A, Freedman AS. Detection of circulating tumour DNA in patients with aggressive B-cell non-Hodgkin lymphoma. Br J Haematol. 2013 Oct;163(1):123-6. doi: 10.1111/bjh.12439. Epub 2013 J PMID 23795711
• Cuccaro A, Bartolomei F, Cupelli E, Galli E, Giachelia M, Hohaus S. Prognostic factors in hodgkin lymphoma. Mediterr J Hematol Infect Dis. 2014 Jul 5;6(1):e2014053. doi: 10.4084/MJHID.2014.053. eCollection 2014. PMID 25045461
• Schwarz AK, Stanulla M, Cario G, Flohr T, Sutton R, Moricke A, Anker P, Stroun M, Welte K, Bartram CR, Schrappe M, Schrauder A. Quantification of free total plasma DNA and minimal residual disease detection in the plasma of children with acute lymphoblastic leukemia. Ann Hematol. 2009 Sep;88(9):897-905. doi: 10.1007/s00277-009-0698-6. Epub 2009 Jan 23. PMID 19165483
• Nakamura S, Yokoyama K, Shimizu E, Yusa N, Kondoh K, Ogawa M, Takei T, Kobayashi A, Ito M, Isobe M, Konuma T, Kato S, Kasajima R, Wada Y, Nagamura-Inoue T, Yamaguchi R, Takahashi S, Imoto S, Miyano S, Tojo A. Prognostic impact of circulating tumor DNA status post-allogeneic hematopoietic stem cell transplantation in AML and MDS. Blood. 2019 Jun 20;133(25):2682-2695. doi: 10.1182/blood-2018-10-8806 PMID 30936070
• Bohers E, Viailly PJ, Dubois S, Bertrand P, Maingonnat C, Mareschal S, Ruminy P, Picquenot JM, Bastard C, Desmots F, Fest T, Leroy K, Tilly H, Jardin F. Somatic mutations of cell-free circulating DNA detected by next-generation sequencing reflect the genetic changes in both germinal center B-cell-like and activated B-cell-like diffuse large B-cell lymphomas at the time of diagnosis. Haematologica. PMID 25749829

Identifiers

NCT: NCT07060001 · PRO00038056 (HMCC-HM24-001)

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗