Acute Myeloid Leukemia (AML)
Conditions
Brief summary
Most patients with acute myeloid leukemia (AML) achieve complete remission (CR) following induction chemotherapy. However, a large majority subsequently relapse and succumb to the disease. Currently, cytogenetics and molecular aberrations are the best prognostic indicators; however, these factors cannot prognosticate accurately for individual patients. Overall, the majority of patients with favorable or intermediate-risk AML will experience relapse. Prognosis after relapse is dismal with a five-year overall survival rate of less than 10%. A leukemia stem cell (LSC) paradigm may explain this failure of CR to reliably translate into cure. This study is undertaken to determine whether the presence of LSCs has prognostic value as well as to determine whether the presence of LSCs has predictive value. This study has an observational component, whereby we intent evaluate whether the presence or absence of LSCs is prognostic. This study also has an interventional component in which it uses LSC status to determine whether favorable and intermediate risk AML patients in CR receive consolidation with chemotherapy or allogeneic HCT.
Interventions
PROCEDUREAllogeneic HCT
Allogeneic HCT
Cytarabine-based consolidation chemotherapy
Sponsors
Wake Forest University Health Sciences
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Must have previously signed the specimen procurement protocol consent associated with the leukemia stem cell assay (Step 1 informed consent) prior to starting AML therapy. 2. Age 18 years and older 3. New diagnosis of AML, other than APL, confirmed by bone marrow aspirate/biopsy and reviewed by an institutional hematopathologist 4. Completion of induction therapy, as defined by the Investigator and post-induction bone marrow biopsy.
Exclusion criteria
1. Any debilitating medical or psychiatric illness that would preclude ability to follow study procedures. 2. Indeterminate leukemia stem cell assay results at diagnosis.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 2 Year Relapse Free Survival (RFS) | 2 years | Comparison of 2 year RFS in patient with detectable LSCs in the marrow at the end of consolidation to the 2 year RFS of patients without detectable LSCs. IWG Criteria (Cheson 2003) was utilized to classify relapse, with relapse defined as ≥ 5% blasts in the marrow or peripheral blood, extramedullary disease, or disease presence determined by a physician upon clinical assessment. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Evaluable Cohort - Transplant Arm Standard of Care Consolidation (HCT)
Enrolled subjects that will contribute to the population of subjects who are evaluable for the primary and secondary objectives. This will not include any subjects who end up in either observational cohort. To be included in the evaluable cohort, the subject must meet the following requirements:
1. Complete remission (CR1) from standard cytarabine or HMA-based induction therapy per standard clinical criteria (Cheson Criteria)
2. Have confirmed presence of CD34+CD38-ALDHint population by flow cytometry at the diagnostic LSC assay (LSC0)
3. Cytarabine-based induction subjects: Are candidates for (as determined by the investigator) and receive consolidation therapy (cytarabine-based chemotherapy or HCT); HMA-based induction subjects: Are candidates for (as determined by the investigator) and receive HCT
Consolidation chemotherapy: Cytarabine-based consolidation chemotherapy | 1 |
| Evaluable Cohort - Consolidation Chemo Arm Standard of Care Consolidation (cytarabine-based chemo)
Enrolled subjects that will contribute to the population of subjects who are evaluable for the primary and secondary objectives. This will not include any subjects who end up in either observational cohort. To be included in the evaluable cohort, the subject must meet the following requirements:
1. Complete remission (CR1) from standard cytarabine or HMA-based induction therapy per standard clinical criteria (Cheson Criteria)
2. Have confirmed presence of CD34+CD38-ALDHint population by flow cytometry at the diagnostic LSC assay (LSC0)
3. Cytarabine-based induction subjects: Are candidates for (as determined by the investigator) and receive consolidation therapy (cytarabine-based chemotherapy or HCT)
Consolidation chemotherapy: Cytarabine-based consolidation chemotherapy | 6 |
| Observational Cohort 1 Enrolled subjects who do not achieve a CR to induction therapy, regardless of diagnostic phenotype. Following completion of induction therapy and remission bone marrow aspirate, if a subject is determined to not have achieved a complete remission to induction therapy, he or she would be included in observational cohort 1. | 4 |
| Observational Cohort 2 Enrolled subjects who achieve a CR to induction therapy but meet one or more of the following criteria:
* Lack the immunophenotype of interest,
* Cytarabine based induction subjects: Are not candidates for \[as determined by the investigator (e.g. unfit or refusal)\] and do not receive consolidation therapy (cytarabine-based chemotherapy or HCT)
* HMA-based induction subjects: Are not candidates for \[as determined by the investigator (e.g. unfit, lack of donor, refusal)\] and do not receive HCT
Final investigator determination of fit-ness can occur at any time until the start of consolidation therapy.
HMA-based induction subjects will not receive consolidation cytarabine-based chemotherapy as part of the evaluable cohort if they do not receive HCT. | 7 |
| Total | 18 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Death | 0 | 1 | 0 | 4 |
| Overall Study | Early Study Termination | 1 | 5 | 4 | 3 |
Baseline characteristics
| Characteristic | Evaluable Cohort - Transplant Arm | Evaluable Cohort - Consolidation Chemo Arm | Observational Cohort 1 | Observational Cohort 2 | Total |
|---|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 1 Participants | 0 Participants | 1 Participants | 2 Participants |
| Age, Categorical Between 18 and 65 years | 1 Participants | 5 Participants | 4 Participants | 6 Participants | 16 Participants |
| Age, Continuous | 35.0 years | 44.3 years STANDARD_DEVIATION 14.7 | 51.0 years STANDARD_DEVIATION 14.5 | 46.3 years STANDARD_DEVIATION 15.6 | 46.1 years STANDARD_DEVIATION 14.2 |
| AML Risk Level (prior to induction) Favorable Risk | 0 Participants | 6 Participants | 1 Participants | 4 Participants | 11 Participants |
| AML Risk Level (prior to induction) Intermediate Risk | 0 Participants | 0 Participants | 2 Participants | 1 Participants | 3 Participants |
| AML Risk Level (prior to induction) Unfavorable Risk | 1 Participants | 0 Participants | 1 Participants | 2 Participants | 4 Participants |
| Deletion 5 or 5q Negative | 1 Participants | 6 Participants | 4 Participants | 7 Participants | 18 Participants |
| Deletion 5 or 5q Positive | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Deletion 5 or 5q Uninterpretable results | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Deletion 7 or 7q Negative | 1 Participants | 6 Participants | 4 Participants | 7 Participants | 18 Participants |
| Deletion 7 or 7q Positive | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Deletion 7 or 7q Uninterpretable results | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 1 Participants | 6 Participants | 4 Participants | 7 Participants | 18 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Immunophenotype at LSC0 CD34- | 0 Participants | 0 Participants | 1 Participants | 5 Participants | 6 Participants |
| Immunophenotype at LSC0 CD34+CD38-ALDH(high) | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 1 Participants |
| Immunophenotype at LSC0 CD34+CD38-ALDH(int) | 1 Participants | 6 Participants | 3 Participants | 1 Participants | 11 Participants |
| inv(16 or t(16;16) Negative | 1 Participants | 4 Participants | 4 Participants | 7 Participants | 16 Participants |
| inv(16 or t(16;16) Positive | 0 Participants | 2 Participants | 0 Participants | 0 Participants | 2 Participants |
| inv(16 or t(16;16) Uninterpretable results | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| inv(3) or t(3;3) Negative | 1 Participants | 5 Participants | 4 Participants | 7 Participants | 17 Participants |
| inv(3) or t(3;3) Positive | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| inv(3) or t(3;3) Uninterpretable results | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| KNMT2A Negative | 1 Participants | 6 Participants | 4 Participants | 7 Participants | 18 Participants |
| KNMT2A Positive | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| KNMT2A Uninterpretable results | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| LSC0 Status (prior to induction) Leukemia Stem Cells Detected | 1 Participants | 6 Participants | 3 Participants | 1 Participants | 11 Participants |
| LSC0 Status (prior to induction) Leukemia Stem Cells Not Detected | 0 Participants | 0 Participants | 1 Participants | 6 Participants | 7 Participants |
| LSC1 Status (post induction, at enrollment) Indeterminate/Unknown Results | 1 Participants | 0 Participants | 1 Participants | 2 Participants | 4 Participants |
| LSC1 Status (post induction, at enrollment) Leukemia Stem Cells Detected | 0 Participants | 0 Participants | 1 Participants | 1 Participants | 2 Participants |
| LSC1 Status (post induction, at enrollment) Leukemia Stem Cells Not Detected | 0 Participants | 6 Participants | 2 Participants | 4 Participants | 12 Participants |
| Plus 21 Negative | 1 Participants | 5 Participants | 4 Participants | 7 Participants | 17 Participants |
| Plus 21 Positive | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Plus 21 Uninterpretable results | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Plus 8 Negative | 1 Participants | 6 Participants | 4 Participants | 7 Participants | 18 Participants |
| Plus 8 Positive | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Plus 8 Uninterpretable results | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 2 Participants | 3 Participants | 2 Participants | 7 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) White | 1 Participants | 4 Participants | 1 Participants | 4 Participants | 10 Participants |
| Region of Enrollment United States | 1 participants | 6 participants | 4 participants | 7 participants | 18 participants |
| Sex: Female, Male Female | 0 Participants | 2 Participants | 2 Participants | 4 Participants | 8 Participants |
| Sex: Female, Male Male | 1 Participants | 4 Participants | 2 Participants | 3 Participants | 10 Participants |
| t(6;9) Negative | 1 Participants | 5 Participants | 4 Participants | 7 Participants | 17 Participants |
| t(6;9) Positive | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| t(6;9) Uninterpretable results | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| t(8;21) Negative | 1 Participants | 4 Participants | 4 Participants | 6 Participants | 15 Participants |
| t(8;21) Positive | 0 Participants | 2 Participants | 0 Participants | 1 Participants | 3 Participants |
| t(8;21) Uninterpretable results | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| t(9;11) Negative | 1 Participants | 5 Participants | 4 Participants | 7 Participants | 17 Participants |
| t(9;11) Positive | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| t(9;11) Uninterpretable results | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| t(9;22) Negative | 1 Participants | 5 Participants | 4 Participants | 7 Participants | 17 Participants |
| t(9;22) Positive | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| t(9;22) Uninterpretable results | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 1 | 1 / 6 | 0 / 4 | 4 / 7 |
| other Total, other adverse events | 0 / 1 | 0 / 6 | 0 / 4 | 0 / 7 |
| serious Total, serious adverse events | 0 / 1 | 0 / 6 | 0 / 4 | 0 / 7 |
Outcome results
Primary
2 Year Relapse Free Survival (RFS)
Comparison of 2 year RFS in patient with detectable LSCs in the marrow at the end of consolidation to the 2 year RFS of patients without detectable LSCs. IWG Criteria (Cheson 2003) was utilized to classify relapse, with relapse defined as ≥ 5% blasts in the marrow or peripheral blood, extramedullary disease, or disease presence determined by a physician upon clinical assessment.
Time frame: 2 years
Population: The primary efficacy analyses will be conducted on the subset of subjects who were included in the evaluable cohort (HCT or chemo treatment arm) and who also had a successful/interpretable end of consolidation eLSC assay. This excludes subjects in OC1 and 2, as they did not achieve CR to induction or did not have the immunophenotype of interest.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| eLSC- (Evaluable Cohort) | 2 Year Relapse Free Survival (RFS) | NA Participants |