Improving Risk Assessment of AML With a Precision Genomic Strategy to Assess Mutation Clearance

The investigators will prospectively determine whether the relapse-free and overall survival in patients who have cleared their leukemia-associated mutations treated with standard consolidation chemotherapy is superior to what is expected based on historical controls. The investigators will also prospectively determine the relapse-free and overall survival of patients who have not cleared their mutations. Because the relapse rate of patients with persistent mutations is expected to be high, treatment with either standard of care consolidation therapy alone or alloSCT will be permitted, at the discretion of the treating physician.

Study Overview

• Status: Active, not recruiting
• Conditions: Acute Myeloid Leukemia
• Intervention / Treatment: Drug: Cytarabine; Procedure: Allogeneic stem cell transplant; Procedure: Bone marrow aspiration; Procedure: Punch skin biopsy; Device: ClinSeq

• Study Type: Interventional
• Enrollment (Actual): 107
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Meagan Jacoby, M.D., Ph.D.; Phone Number: 314-454-8304; Email: mjacoby@wustl.edu

Study Locations

• United States
  • Florida
    • Gainesville, Florida, United States, 32608
      • University of Florida
  • Missouri
    • Saint Louis, Missouri, United States, 63110
      • Washington University School of Medicine
  • New York
    • Rochester, New York, United States, 14642
      • University of Rochester

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 60 years (Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Age 18-60 years.
• Considered to be suitable intensive (cytotoxic) induction candidates.
• Has previously untreated, de novo, non-M3 AML with intermediate-risk disease (Intermediate-I or Intermediate-II) as defined by ELN criteria OR normal cytogenetics with mutated NPM1 without FLT3-ITD. Monoallelic CEBPA mutations are not considered favorable risk and are therefore eligible.
• Has undergone cytotoxic induction therapy
• In a morphologic complete remission with incomplete blood count recovery, or morphologic complete remission post-induction after no more than 2 induction cycles as defined by revised IWG criteria
• Patients at Washington University must be enrolled in HRPO# 201011766 ("Tissue Acquisition for Analysis of Genetic Progression Factors in Hematologic Diseases").This is not a requirement for secondary sites. However, secondary sites must provide informed consent forms that document that permission for whole genome, whole exome, and/or genome wide sequencing, and data sharing among institutions, was obtained. Because we will be also be sequencing non-diseased (normal) tissue, the informed consent forms must explicitly ask if patients wish to be informed, (or in the case of their death, their next-of-kin) if a deleterious mutation is identified in their non-diseased tissue, as this may be heritable.
• Women of childbearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control, abstinence) prior to study entry and for the duration of study participation. Should a woman become pregnant or suspect she is pregnant while participating in this study, she must inform her treating physician immediately.
• Able to understand and willing to sign an IRB approved written informed consent document.

• Willing to comply with the treatment assignment:

  • Intent to proceed with HiDAC consolidation for LAM VAF <2.5%
  • Intent to proceed with either HiDAC consolidation or allogeneic stem cell transplantation, at the discretion of the treating physician, for LAM ≥2.5%

Exclusion Criteria:

• Diagnosis acute promyelocytic leukemia (APL) with t(15;17)(q22;q12); PML-RARA.
• Therapy-related AML (defined as occurrence of AML due to prior exposure to chemotherapy or radiation for malignancy).
• Secondary AML (defined as development of AML in patients with an antecedent hematological malignancy).
• Has a medical or psychosocial conditions that would prevent study compliance.
• Known seropositivity for or active viral infection with human immunodeficiency virus (HIV), hepatitis B virus (HBV), or hepatitis C virus (HCV). Patients who are seropositive because of hepatitis B vaccine are eligible.
• History of allergic reaction to compounds of similar chemical or biologic composition to cytarabine.
• Pregnant and/or breastfeeding. Women of childbearing potential must have a negative pregnancy test within 3 days of signing consent.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Cohort A: HiDAC; At the time of diagnostic bone marrow biopsy, samples will be clinically sequenced via ClinSeq; Patients who have clearance of their leukemia-associated mutations, defined as a LAM VAF <2.5% will be assigned to the high-dose cytarabine consolidation (HiDAC) arm.; HiDAC = Standard regimen of cytarabine 1.5 g/m^2 or 3 g/m^2 over 2-3 hours twice a day on Days 1, 3, & 5 of each 28 day cycle for 3-4 cycles. Can be replaced by Onureg with permission from PI.; For patients with the FLT3-ITD or a FLT3-TKD mutation, therapy with the FDA-approved FLT3 inhibitor midostaurin is permitted at the discretion of the treating physician.	Drug: Cytarabine; Other Names: Ara-C; Cytosar-U; AraC; Tarabine-PFS; Procedure: Bone marrow aspiration; Baseline; Approximately 30 days after cytotoxic induction therapy; End of treatment; Procedure: Punch skin biopsy; The first will be obtained with the initial blood and bone marrow collections, whenever possible.; The second will be obtained at the time of re-biopsy to confirm remission.; Device: ClinSeq; Clinical Sequencing to determine clearance or persistence of leukemia-associate mutations performed at MGI CLIA lab
Experimental: Cohort B: Investigator's choice (HiDAC, AlloSCT); At the time of diagnostic bone marrow biopsy, samples will be clinically sequenced via ClinSeq; Patients who have persistent leukemia-associated mutations, defined as a LAM VAF ≥2.5% will be assigned to the investigator's choice arm.; Patients assigned to this arm may received either HiDAC or AlloSCT.; HiDAC = Standard regimen of cytarabine 1.5 g/m^2 or 3 g/m^2 over 2-3 hours twice a day on Days 1, 3, & 5 of each 28 day cycle for 3-4 cycles. Can be replaced by Onureg with permission from PI.; The source of stem cell product, donor selection, conditioning regimen, graft-versus-host-prophylaxis, and supportive care will be at the discretion of the treatment physician; For patients with the FLT3-ITD or a FLT3-TKD mutation, therapy with the FDA-approved FLT3 inhibitor midostaurin is permitted at the discretion of the treating physician.	Drug: Cytarabine; Other Names: Ara-C; Cytosar-U; AraC; Tarabine-PFS; Procedure: Allogeneic stem cell transplant; Other Names: AlloSCT; Procedure: Bone marrow aspiration; Baseline; Approximately 30 days after cytotoxic induction therapy; End of treatment; Procedure: Punch skin biopsy; The first will be obtained with the initial blood and bone marrow collections, whenever possible.; The second will be obtained at the time of re-biopsy to confirm remission.; Device: ClinSeq; Clinical Sequencing to determine clearance or persistence of leukemia-associate mutations performed at MGI CLIA lab

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Relapse free survival of Cohort A compared to intermediate risk historical control group	Relapse-free survival is the time from study enrollment (morphologic complete remission (CR) or morphologic complete remission with incomplete blood count recovery (CRi) is required) until documented disease relapse, or death from any cause.; CR=Defined as morphologic leukemia-free state, defined as less than 5% blasts in aspirate with marrow spicules and a count of ≥200 nucleated cells and no blasts with Auer rods or any persistence of extramedullary disease. In addition, ANC >1000/μl and platelet count of ≥100,000/μl. Patient must be independent of transfusions. No duration requirement for this designation.; CRi=Defined as morphologic complete recovery with the exception of neutropenia <1000/μl or thrombocytopenia <100,000/μl.	Up to 5 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall survival (OS) of Cohort A compared intermediate risk historical control group	Overall survival is the time from enrollment on study until death from any cause.	Up to 5 years
Relapse free survival (RFS) of Cohort B	Relapse-free survival is the time from study enrollment (morphologic complete remission (CR) or morphologic complete remission with incomplete blood count recovery (CRi) is required) until documented disease relapse, or death from any cause.; CR=Defined as morphologic leukemia-free state, defined as less than 5% blasts in aspirate with marrow spicules and a count of ≥200 nucleated cells and no blasts with Auer rods or any persistence of extramedullary disease. In addition, ANC >1000/μl and platelet count of ≥100,000/μl. Patient must be independent of transfusions. No duration requirement for this designation.; CRi=Defined as morphologic complete recovery with the exception of neutropenia <1000/μl or thrombocytopenia <100,000/μl.	Up to 5 years
Overall survival (OS) of Cohort B	Overall survival is the time from enrollment on study until death from any cause.	Up to 5 years
Compare relapse free survival of Cohort A to Cohort B	Relapse-free survival is the time from study enrollment (morphologic complete remission (CR) or morphologic complete remission with incomplete blood count recovery (CRi) is required) until documented disease relapse, or death from any cause.; CR=Defined as morphologic leukemia-free state, defined as less than 5% blasts in aspirate with marrow spicules and a count of ≥200 nucleated cells and no blasts with Auer rods or any persistence of extramedullary disease. In addition, ANC >1000/μl and platelet count of ≥100,000/μl. Patient must be independent of transfusions. No duration requirement for this designation.; CRi=Defined as morphologic complete recovery with the exception of neutropenia <1000/μl or thrombocytopenia <100,000/μl.	Up to 5 years
Compare overall survival of Cohort A to Cohort B	Overall survival is the time from enrollment on study until death from any cause.	Up to 5 years
Compare relapse free survival of Cohort A to Cohort B	Relapse-free survival is the time from study enrollment (morphologic complete remission (CR) or morphologic complete remission with incomplete blood count recovery (CRi) is required) until documented disease relapse, or death from any cause.; CR=Defined as morphologic leukemia-free state, defined as less than 5% blasts in aspirate with marrow spicules and a count of ≥200 nucleated cells and no blasts with Auer rods or any persistence of extramedullary disease. In addition, ANC >1000/μl and platelet count of ≥100,000/μl. Patient must be independent of transfusions. No duration requirement for this designation.; CRi=Defined as morphologic complete recovery with the exception of neutropenia <1000/μl or thrombocytopenia <100,000/μl.	1 year
Compare overall survival of Cohort A to Cohort B	Overall survival is the time from enrollment on study until death from any cause.	1 year
Relapse free survival of Cohort B patients who receive alloSCT	Relapse-free survival is the time from study enrollment (morphologic complete remission (CR) or morphologic complete remission with incomplete blood count recovery (CRi) is required) until documented disease relapse, or death from any cause.; CR=Defined as morphologic leukemia-free state, defined as less than 5% blasts in aspirate with marrow spicules and a count of ≥200 nucleated cells and no blasts with Auer rods or any persistence of extramedullary disease. In addition, ANC >1000/μl and platelet count of ≥100,000/μl. Patient must be independent of transfusions. No duration requirement for this designation.; CRi=Defined as morphologic complete recovery with the exception of neutropenia <1000/μl or thrombocytopenia <100,000/μl.	Up to 5 years
Overall survival of Cohort B patients who receive alloSCT	Overall survival is the time from enrollment on study until death from any cause.	Up to 5 years
Relapse free survival of Cohort B patients who do not receive alloSCT	Relapse-free survival is the time from study enrollment (morphologic complete remission (CR) or morphologic complete remission with incomplete blood count recovery (CRi) is required) until documented disease relapse, or death from any cause.; CR=Defined as morphologic leukemia-free state, defined as less than 5% blasts in aspirate with marrow spicules and a count of ≥200 nucleated cells and no blasts with Auer rods or any persistence of extramedullary disease. In addition, ANC >1000/μl and platelet count of ≥100,000/μl. Patient must be independent of transfusions. No duration requirement for this designation.; CRi=Defined as morphologic complete recovery with the exception of neutropenia <1000/μl or thrombocytopenia <100,000/μl.	Up to 5 years
Overall survival of Cohort B patients who do not receive alloSCT	Overall survival is the time from enrollment on study until death from any cause.	Up to 5 years
Relapse free survival of patients with a LAM VAF <1.0% treated in Cohort A compared to intermediate risk historical control group	LAM VAF = Leukemia Associated Mutations variant allele frequency; Relapse-free survival is the time from study enrollment (morphologic complete remission (CR) or morphologic complete remission with incomplete blood count recovery (CRi) is required) until documented disease relapse, or death from any cause.; CR=Defined as morphologic leukemia-free state, defined as less than 5% blasts in aspirate with marrow spicules and a count of ≥200 nucleated cells and no blasts with Auer rods or any persistence of extramedullary disease. In addition, ANC >1000/μl and platelet count of ≥100,000/μl. Patient must be independent of transfusions. No duration requirement for this designation.; CRi=Defined as morphologic complete recovery with the exception of neutropenia <1000/μl or thrombocytopenia <100,000/μl.	Up to 5 years
Overall survival of patients with a LAM VAF <1.0% treated in Cohort A compared to intermediate risk historical control group	--LAM VAF = Leukemia Associated Mutations variant allele frequency -Overall survival is the time from enrollment on study until death from any cause.	Up to 5 years

Collaborators and Investigators

• Sponsor: Washington University School of Medicine
• Collaborators: The Leukemia and Lymphoma Society; American Society of Hematology
• Investigators: Principal Investigator: Meagan Jacoby, M.D., Ph.D., Washington University School of Medicine

Publications and helpful links

Helpful Links

• Alvin J. Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine

Study record dates

Study Major Dates

• Study Start (Actual): July 6, 2016
• Primary Completion (Estimated): July 31, 2033
• Study Completion (Estimated): July 31, 2033

Study Registration Dates

• First Submitted: April 27, 2016
• First Submitted That Met QC Criteria: April 27, 2016
• First Posted (Estimated): April 29, 2016

Study Record Updates

• Last Update Posted (Actual): April 2, 2024
• Last Update Submitted That Met QC Criteria: April 1, 2024
• Last Verified: April 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Cytarabine
• Other Study ID Numbers: 201606003

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: Yes
• product manufactured in and exported from the U.S.: No