Acute Myeloid Leukemia
Conditions
Brief summary
This phase II trial studies fluorothymidine F 18 (FLT) positron emission tomography (PET)/computed tomography (CT) in measuring response in patients with previously untreated acute myeloid leukemia. FLT is a radioactive substance that may "light up" where cancer is in the body. FLT is injected into the blood and builds up in cells that are dividing, including cancer cells. Diagnostic procedures, such as PET/CT, may help measure a patient's response to earlier treatment.
Detailed description
PRIMARY OBJECTIVES: I. To evaluate the negative predictive value (NPV) of post-treatment FLT PET/CT imaging for complete remission (CR) in patients receiving induction chemotherapy for acute myeloid leukemia (AML). SECONDARY OBJECTIVES: I. To evaluate the positive predictive value (PPV) of post-treatment FLT PET/CT imaging for complete remission. II. To estimate the sensitivity and specificity of post-treatment FLT PET/CT imaging for detecting complete remission. III. To correlate FLT PET/CT imaging with biologic correlates (minimal residual disease \[MRD\] assessment) IV. To correlate FLT PET/CT imaging with relapse-free survival and overall survival. EXPLORATORY OBJECTIVES: III. To evaluate pre-treatment FLT PET/CT imaging as a predictor of complete remission. IV. To evaluate the change between pre-treatment and post-treatment FLT PET/CT imaging as a predictor of complete remission. OUTLINE: Patients receive anthracycline intravenously (IV) on days 1-3 and cytarabine IV on days 1-7 for up to 2 courses. Patients then undergo FLT PET/CT within 3 days before or after the nadir bone marrow biopsy (between days 10-17 after initiation of first induction cycle and prior to reinduction). Patients may undergo an optional FLT PET/CT prior to induction chemotherapy if it does not interfere with commencement of treatment. Patients also undergo bone marrow biopsy and aspiration and blood sample collection during screening and on the trial. After completion of study, patients are followed up at day 28-35, and then up to 1 year beyond the end of study accrual period.
Interventions
PROCEDUREBiospecimen Collection
Undergo blood sample collection
PROCEDUREBone Marrow Aspiration
Undergo bone marrow biopsy and aspiration
PROCEDUREBone Marrow Biopsy
Undergo bone marrow biopsy and aspiration
DRUGChemotherapy
Given anthracycline IV
PROCEDUREComputed Tomography
Undergo FLT PET/CT
DRUGCytarabine
Given IV
OTHERFluorothymidine F-18
Undergo FLT PET/CT
OTHERLaboratory Biomarker Analysis
Correlative studies
PROCEDUREPositron Emission Tomography
Undergo FLT PET/CT
Sponsors
National Cancer Institute (NCI)
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
DIAGNOSTIC
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Age ≥ 18 years * Patients must have previously untreated AML and be candidates for intensive induction chemotherapy; patients are allowed to have had prior hydroxyurea * Patients must not have acute promyelocytic leukemia (APL) and must not have evidence of t(15;17)(q22;q21) * Patients must have an Eastern Cooperative Oncology Group (ECOG) performance status of 0-3 (restricted to ECOG performance status \[PS\] 0-2 if age \> 70 years) * Patients must have left ventricular ejection fraction (LVEF) \> 45% or within institutional normal limits * Patients must be able to lie still for a 1.5 hour PET scan * Patient must NOT have a history of allergic reaction attributable to compounds of similar chemical or biologic composition to 18F-fluorothymidine * Patient must NOT weigh more than the maximum weight limit for the PET/CT table for the scanner(s) to be used at each center * The patient is participating in the trial at an institution which has agreed to perform the imaging research studies, completed the ECOG-American College of Radiology Imaging Network (ACRIN) defined scanner qualification procedures and received ECOG-ACRIN approval as outlined * Women must not be pregnant or breast-feeding; all females of childbearing potential must have a blood test or urine study within 2 weeks prior to registration to rule out pregnancy; a female of childbearing potential is any woman, regardless of sexual orientation or whether they have undergone tubal ligation, who meets the following criteria: 1) has not undergone a hysterectomy or bilateral oophorectomy; or 2) has not been naturally postmenopausal for at least 24 consecutive months (i.e., has had menses at any time in the preceding 24 consecutive months)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Negative Predictive Value of Post-treatment Fluorothymidine F 18 (FLT) Positron Emission Tomography (PET)/Computed Tomography (CT) Imaging for Complete Remission (CR) in Comparison With Blast Counts From Bone Marrow Biopsy (BMBX) | Up to day 35 | Three imaging parameters (standardized uptake value \[SUV\]mean, SUVmax, heterogeneity of FLT uptake \[SUVhetero\]) will be measured from an FLT PET/CT scan and SUVmax will be the primary endpoint. Higher values of SUVmax assume to indicate a non-response the therapy and a cut point of 7 (SUVmax \>7) will be used as the threshold indicating a negative scan. The binomial proportion of negative predictive value (NPV) and the corresponding exact confidence intervals will be calculated. In addition, the calculated NPV will be tested against the null hypothesis to see if it's significantly larger than 0.64 (NPV of day-14 BMBX in CR prediction). CR:Complete remission CRi: Complete remission with incomplete platelet recovery LFS: Leukemia-free state Non-responders defined as Not (CR,CRi,or LFS) Negative predictive value (NPV) of the post-treatment FLT PET/CT scan is Probability ((not CR,CRi,or LFS) │ SUVmax \>7 ) |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Positive Predictive Value (PPV) of Post-treatment FLT PET/CT Imaging for Complete Remission | Up to day 35 | The binomial proportion of PPV and the corresponding exact confidence intervals will be calculated. In addition, the calculated PPV will be tested to see if it's significantly larger than 0.79 (PPV of day-14 BMBX in CR prediction). |
| Sensitivity of Post-treatment FLT PET/CT for Detecting Complete Remission (a Clinical Response of CR, CRi, or LFS ) | Up to day 35 | The binomial proportions and the corresponding exact confidence intervals will be calculated for sensitivity estimation where FLT Test : Negative: SUV \>7; Positive: SUV\<=7 Clinical Response: Negative: not (CR, CRi, or LFS); Positive (Responders): CR, CRi, or LFS |
| Specificity of Post-treatment FLT PET/CT for Detecting Complete Remission | Up to day 35 | The binomial proportions and the corresponding exact confidence intervals will be calculated for specificity estimation. Test response: Negative: SUV \>7; Positive: SUV\<=7 Clinical Response = Complete remissions: Negative (Non-Responders): not (CR, CRi, or LFS); Positive (Responders): CR, CRi, or LFS |
| FLT PET/CT Imaging Parameters With Biologic Correlates (Minimal Residual Disease Assessment) | Up to day 35 | FLT PET/CT imaging features will be compared with biologic correlates (minimal residual disease \[MRD\] assessment). |
| FLT PET/CT Imaging to Predict Relapse-free Survival | Up to day 35 and up to 4 years for RFS | compare the Recurrence-Free Survival (RFS) between positive and negative post-treatment FLT PET/CT scans, where an SUVmax less than or equal to 7 (i.e., low FLT uptake) was considered a positive result, and an SUVmax greater than 7 (i.e., high FLT uptake) was a negative result. Participants were followed for survival outcomes until study closure when the last participant has been followed for 1 year after study enrollment. The relapse endpoint included both reappearance of blasts in the blood; and presence of more than 5% blasts not attributable to another cause Time-to-relapse was measured from the date of the remission bone marrow biopsy to the date of first recurrence or death, whichever came first. RFS was only evaluable for participants with a clinical response of CR, CRi, or LFS at the remission bone marrow biopsy. |
| FLT PET/CT Imaging to Predict Overall Survival | Up to day 35 and up to 4 years for RFS | compare the Overall Survival (OS) between positive and negative post-treatment FLT PET/CT scans, where an SUVmax\<= 7 (i.e., low FLT uptake) was considered a positive result, and an SUVmax \> 7 (i.e., high FLT uptake) was a negative result. Participants were followed for survival outcomes until study closure when the last participant has been followed for 1 year after study enrollment. |
Countries
United States
Contacts
PRINCIPAL_INVESTIGATORRobert Jeraj
ECOG-ACRIN Cancer Research Group
Participant flow
Recruitment details
The study was activated on December 9, 2015 and finished accrual on October 16, 2018 after enrolling 87 participants from 9 institutions
Participants by arm
| Arm | Count |
|---|---|
| Diagnostic (Anthracycline, Cytarabine, FLT PET/CT) Patients receive anthracycline IV on days 1-3 and cytarabine IV on days 1-7 for up to 2 courses. Patients then undergo FLT PET/CT within 3 days before or after the nadir bone marrow biopsy (between days 10-17 after initiation of first induction cycle and prior to reinduction). Patients may undergo an optional FLT PET/CT prior to induction chemotherapy if it does not interfere with commencement of treatment. Patients also undergo bone marrow biopsy and aspiration and blood sample collection during screening and on the trial.
Biospecimen Collection: Undergo blood sample collection
Bone Marrow Aspiration: Undergo bone marrow biopsy and aspiration
Bone Marrow Biopsy: Undergo bone marrow biopsy and aspiration
Chemotherapy: Given anthracycline IV
Computed Tomography: Undergo FLT PET/CT
Cytarabine: Given IV
Fluorothymidine F-18: Undergo FLT PET/CT
Laboratory Biomarker Analysis: Correlative studies
Positron Emission Tomography: Undergo FLT PET/CT | 87 |
| Total | 87 |
Baseline characteristics
| Characteristic | Diagnostic (Anthracycline, Cytarabine, FLT PET/CT) |
|---|---|
| Age, Continuous | 59 years |
| Ethnicity (NIH/OMB) Hispanic or Latino | 4 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 80 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 3 Participants |
| Leukemia classification AML with myelodysplasia-related changes | 25 Participants |
| Leukemia classification Other AML | 62 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 4 Participants |
| Race (NIH/OMB) More than one race | 1 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 1 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 4 Participants |
| Race (NIH/OMB) White | 77 Participants |
| Sex: Female, Male Female | 40 Participants |
| Sex: Female, Male Male | 47 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 30 / 87 |
| other Total, other adverse events | 4 / 87 |
| serious Total, serious adverse events | 24 / 87 |
Outcome results
Primary
Negative Predictive Value of Post-treatment Fluorothymidine F 18 (FLT) Positron Emission Tomography (PET)/Computed Tomography (CT) Imaging for Complete Remission (CR) in Comparison With Blast Counts From Bone Marrow Biopsy (BMBX)
Three imaging parameters (standardized uptake value \[SUV\]mean, SUVmax, heterogeneity of FLT uptake \[SUVhetero\]) will be measured from an FLT PET/CT scan and SUVmax will be the primary endpoint. Higher values of SUVmax assume to indicate a non-response the therapy and a cut point of 7 (SUVmax \>7) will be used as the threshold indicating a negative scan. The binomial proportion of negative predictive value (NPV) and the corresponding exact confidence intervals will be calculated. In addition, the calculated NPV will be tested against the null hypothesis to see if it's significantly larger than 0.64 (NPV of day-14 BMBX in CR prediction). CR:Complete remission CRi: Complete remission with incomplete platelet recovery LFS: Leukemia-free state Non-responders defined as Not (CR,CRi,or LFS) Negative predictive value (NPV) of the post-treatment FLT PET/CT scan is Probability ((not CR,CRi,or LFS) │ SUVmax \>7 )
Time frame: Up to day 35
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Diagnostic (Anthracycline, Cytarabine, FLT PET/CT) Negative | Negative Predictive Value of Post-treatment Fluorothymidine F 18 (FLT) Positron Emission Tomography (PET)/Computed Tomography (CT) Imaging for Complete Remission (CR) in Comparison With Blast Counts From Bone Marrow Biopsy (BMBX) | 0.20 Proportion of Negative scans |
p-value: >0.99binomial exact test
Secondary
FLT PET/CT Imaging Parameters With Biologic Correlates (Minimal Residual Disease Assessment)
FLT PET/CT imaging features will be compared with biologic correlates (minimal residual disease \[MRD\] assessment).
Time frame: Up to day 35
Secondary
FLT PET/CT Imaging to Predict Overall Survival
compare the Overall Survival (OS) between positive and negative post-treatment FLT PET/CT scans, where an SUVmax\<= 7 (i.e., low FLT uptake) was considered a positive result, and an SUVmax \> 7 (i.e., high FLT uptake) was a negative result. Participants were followed for survival outcomes until study closure when the last participant has been followed for 1 year after study enrollment.
Time frame: Up to day 35 and up to 4 years for RFS
Population: All participants who received an FLT PET/CT scan were included in the OS analysis,
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Diagnostic (Anthracycline, Cytarabine, FLT PET/CT) Negative | FLT PET/CT Imaging to Predict Overall Survival | Survivors | 37 Participants |
| Diagnostic (Anthracycline, Cytarabine, FLT PET/CT) Negative | FLT PET/CT Imaging to Predict Overall Survival | Non-survivors | 14 Participants |
| FLT PET/CT Negative | FLT PET/CT Imaging to Predict Overall Survival | Survivors | 10 Participants |
| FLT PET/CT Negative | FLT PET/CT Imaging to Predict Overall Survival | Non-survivors | 10 Participants |
Comparison: Kaplan-Meier curves were constructed for the positive and negative scan groups, and the null hypothesis that the survival distributions of the two groups were equal was tested using the log-rank test.p-value: 0.08log-rank test
Secondary
FLT PET/CT Imaging to Predict Relapse-free Survival
compare the Recurrence-Free Survival (RFS) between positive and negative post-treatment FLT PET/CT scans, where an SUVmax less than or equal to 7 (i.e., low FLT uptake) was considered a positive result, and an SUVmax greater than 7 (i.e., high FLT uptake) was a negative result. Participants were followed for survival outcomes until study closure when the last participant has been followed for 1 year after study enrollment. The relapse endpoint included both reappearance of blasts in the blood; and presence of more than 5% blasts not attributable to another cause Time-to-relapse was measured from the date of the remission bone marrow biopsy to the date of first recurrence or death, whichever came first. RFS was only evaluable for participants with a clinical response of CR, CRi, or LFS at the remission bone marrow biopsy.
Time frame: Up to day 35 and up to 4 years for RFS
Population: Only participants with a clinical response of CR, CRi, or LFS at the remission bone marrow biopsy (ie., where RFS is evaluable)
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Diagnostic (Anthracycline, Cytarabine, FLT PET/CT) Negative | FLT PET/CT Imaging to Predict Relapse-free Survival | Recurrence | 25 Participants |
| Diagnostic (Anthracycline, Cytarabine, FLT PET/CT) Negative | FLT PET/CT Imaging to Predict Relapse-free Survival | Disease-free | 16 Participants |
| FLT PET/CT Negative | FLT PET/CT Imaging to Predict Relapse-free Survival | Recurrence | 6 Participants |
| FLT PET/CT Negative | FLT PET/CT Imaging to Predict Relapse-free Survival | Disease-free | 6 Participants |
Comparison: Kaplan-Meier curves were constructed for the positive and negative scan groups, and the null hypothesis that the survival distributions of the two groups were equal was tested using the log-rank test.p-value: 0.68log-rank test
Secondary
Positive Predictive Value (PPV) of Post-treatment FLT PET/CT Imaging for Complete Remission
The binomial proportion of PPV and the corresponding exact confidence intervals will be calculated. In addition, the calculated PPV will be tested to see if it's significantly larger than 0.79 (PPV of day-14 BMBX in CR prediction).
Time frame: Up to day 35
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Diagnostic (Anthracycline, Cytarabine, FLT PET/CT) Negative | Positive Predictive Value (PPV) of Post-treatment FLT PET/CT Imaging for Complete Remission | 0.89 Proportion of Positive Scans |
p-value: 0.06binomial exact test
Secondary
Sensitivity of Post-treatment FLT PET/CT for Detecting Complete Remission (a Clinical Response of CR, CRi, or LFS )
The binomial proportions and the corresponding exact confidence intervals will be calculated for sensitivity estimation where FLT Test : Negative: SUV \>7; Positive: SUV\<=7 Clinical Response: Negative: not (CR, CRi, or LFS); Positive (Responders): CR, CRi, or LFS
Time frame: Up to day 35
Population: Responders: Patients with a Positive clinical response: CR, CRi, or LFS.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Diagnostic (Anthracycline, Cytarabine, FLT PET/CT) Negative | Sensitivity of Post-treatment FLT PET/CT for Detecting Complete Remission (a Clinical Response of CR, CRi, or LFS ) | 0.77 Proportion of Responders |
Secondary
Specificity of Post-treatment FLT PET/CT for Detecting Complete Remission
The binomial proportions and the corresponding exact confidence intervals will be calculated for specificity estimation. Test response: Negative: SUV \>7; Positive: SUV\<=7 Clinical Response = Complete remissions: Negative (Non-Responders): not (CR, CRi, or LFS); Positive (Responders): CR, CRi, or LFS
Time frame: Up to day 35
Population: Non-Responders: No Clinical Response for any of CR, CRi, or LFS.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Diagnostic (Anthracycline, Cytarabine, FLT PET/CT) Negative | Specificity of Post-treatment FLT PET/CT for Detecting Complete Remission | 0.38 Proportion of Non-Responders |