Mutation Clearance in Improving Risk Assessment for Patients with Acute Myeloid Leukemia in Remission
This phase II trial studies mutation clearance in improving risk assessment for patients with acute myeloid leukemia with a decrease or disappearance of the signs and symptoms of cancer. Studying the number and type of genetic mutations that remain after a patient’s first routine treatment may help guide further treatment.
Inclusion Criteria
- Age 18-60 years
- Considered to be suitable intensive (cytotoxic) induction candidates
- Has previously untreated, de novo, non-M3 acute myeloid leukemia (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 International Working Group (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 the study will 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 Institutional Review Board (IRB) approved written informed consent document
- Willing to comply with the treatment assignment: * Intent to proceed with high-dose cytarabine (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); promyelocytic leukemia-retinoic acid receptor alpha (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 sponsor and potential other locations can be found on ClinicalTrials.gov for NCT02756962.
PRIMARY OBJECTIVE:
I. To determine whether the relapse-free survival of patients who have cleared all leukemia-associated mutations post-induction (leukemia-associated mutation [LAM] variant allele frequency [VAF] < 2.5 %) treated with high dose cytarabine alone (Cohort A) is significantly higher than expected from an intermediate risk group.
SECONDARY OBJECTIVES:
I. To determine whether the overall survival of patients who have cleared all leukemia-associated mutations post-induction (LAM VAF < 2.5 %) treated with high dose cytarabine alone (Cohort A) is significantly higher than expected from an intermediate risk group.
II. To determine the relapse-free and overall survival of patients with persistent mutations (LAM VAF >= 2.5 %) (Cohort B).
III. To compare the relapse-free and overall survival between patients who have cleared all leukemia-associated mutations post-induction (LAM VAF < 2.5 %) (Cohort A) and those with persistent mutations (LAM VAF >= 2.5 %) (Cohort B).
IV. To compare the relapse-free survival between patients who have cleared all leukemia-associated mutations post-induction (LAM VAF < 2.5 %) (Cohort A) and those with persistent mutations (LAM VAF >= 2.5 %) (Cohort B) at one year.
V. To determine the relapse–free and overall survival of patients with persistent mutations (LAM >= 2.5% VAF) who receive allogeneic stem cell transplant (alloSCT) (Cohort B1).
VI. To determine the relapse-free survival and overall survival of patients with persistent mutations post-induction (LAM >= 2.5% VAF) who do not receive alloSCT (Cohort B2).
VII. To determine whether the relapse-free survival and overall survival of patients who have cleared all leukemia-associated mutations post-induction to a LAM VAF < 1.0 % treated with high dose cytarabine alone (Cohort A) is significantly higher than expected from an intermediate risk group.
EXPLORATORY OBJECTIVES:
I. To compare the relapse-free survival and overall survival between patients with persistent mutations post-induction (LAM > 2.5% VAF) who receive alloSCT (Cohort B1) and those who do not (Cohort B2).
II. To perform minimal residual disease testing by multi-color flow cytometry in post-induction bone-marrow samples, and correlate these data with relapse-free and overall survival.
III. To perform minimal residual disease testing by multi-color flow cytometry in post-induction bone-marrow samples, and correlate these data with clearance or persistence of leukemia-associated mutations.
IV. To compare risk assessment based on European LeukemiaNet (ELN) criteria, LAM clearance, and multi-color flow, and to compare their impact on clinical outcome.
V. To compare the relapse-free survival and overall survival between patients with post-induction LAM VAF < 1% and >= 1%.
OUTLINE: Patients undergo LAM VAF analysis and are assigned to 1 of 2 treatment cohorts based on the results.
COHORT A (LAM VAF < 2.5%): Patients who have clearance of their leukemia-associated mutations receive cytarabine intravenously (IV) over 2-3 hours twice daily (BID) on days 1, 3, and 5. Treatment repeats every 28 days for up to 4 cycles in the absence of disease progression or unacceptable toxicity.
COHORT B (LAM VAF >= 2.5%): Patients who have persistent leukemia-associated mutations either undergo alloSCT (Cohort B1) or receive cytarabine (Cohort B2) as in Cohort A at the discretion of the treating physician.
After completion of study treatment, patients are followed up every 1-3 months for 2 years, and then every 3-6 months for 5 years.
Trial PhasePhase II
Trial Typetreatment
Lead OrganizationSiteman Cancer Center at Washington University
Principal InvestigatorMeagan Jacoby
- Primary ID201606003
- Secondary IDsNCI-2016-00863
- ClinicalTrials.gov IDNCT02756962