Acute Myeloid Leukemia, AML, Childhood
Conditions
Keywords
acute myeloid leukemia
Brief summary
The investigators propose to study an Aflac-AML chemotherapy backbone prospectively to validate its use in all pediatric AML and to further evaluate the cardiotoxicity with this approach for low risk AML.
Detailed description
Advances in risk stratification and therapy, have improved the event-free survival (EFS) and overall survival (OS) for pediatric acute myeloid leukemia (AML) to approximately 50% and 65% respectively, with current treatment strategies. Patients with good response to induction and/or those who lack high-risk cytogenetic and molecular features \[classified as low-risk AML (LR-AML)\] have even better outcomes with EFS and OS approaching 70% and 85% respectively; however, treatment-related toxicities remain a major concern. Anthracycline-based therapeutic regimens expose patients to the risk of anthracycline-induced cardiotoxicity. Therefore, strategies that reduce cardiac toxicities using tailored approaches while maintaining and/or improving outcomes are needed for all patients with AML. The Children's Oncology Group (COG) regimens AAML1031 and AAML0531 utilized an anthracycline-intensive backbone for LR-AML with cumulative anthracycline doxorubicin-equivalent doses of up to 492mg/m2. However, high-risk patients treated with chemotherapy alone received an intensified induction chemotherapy (using mitoxantrone-cytarabine) but with overall reduced doses of anthracycline-equivalent (342mg/m2). The investigators piloted an institutional practice to treat all LR-AML patients with four cycle regimen (Aflac-AML) with the goal of reducing cumulative anthracycline exposure, thereby reducing the risk of cardiotoxicity, while providing three high-dose cytarabine courses. In this pilot institutional experience with this approach, they were able to maintain excellent outcomes for this low-risk group with 3-year event-free survival (EFS) and OS of 70.0% ± 0.1% and 85.5% ± 0.08% respectively, from end of course 1. Recent evolution in cytogenetic classification has further delineated risk groups in AML. Gemtuzumab ozogamicin (GO), an antibody-drug conjugate was shown to reduce relapse risk in patients with CC genotype with de-novo AML on COG study AAML0531. The investigators propose to study an Aflac-AML chemotherapy backbone prospectively to validate its use in all pediatric AML and to further evaluate the cardiotoxicity with this approach for low risk AML.
Interventions
PROCEDUREStem cell transplantation (SCT)
Transplantation of multipotent hematopoietic stem cells from bone marrow
DRUGCytarabine
100 mg/m²/dose every 12 hours IV Days 1-10
DRUGDaunorubicin
50 mg/m²/dose IV Days 1, 3, 5
DRUGErwinase
25,000 International Units/m²/dose IM Days 2, 9
DRUGEtoposide
150 mg/m²/dose IV Days 1-5
DRUGGemtuzumab ozogamicin
Administered as a single 3 mg/m2 dose of GO to be given between days 6-10 during Induction I for patients with CC genotype, in addition to ADE therapy.
DRUGSorafenib
200 mg/m2/dose daily, rounded to accommodate tablet size. The maximum dose will be 400 mg. Days 7 through 34.
Sponsors
Emory University
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
No minimum to 21 Years
Healthy volunteers
No
Inclusion criteria
* Age: Patients must be less than 21 years of age at the time of study enrollment * Diagnosis: Patients must be newly diagnosed with AML * Patients with previously untreated primary AML who meet the customary criteria for AML with ≥ 20% bone marrow blasts as set out in the 2016 WHO Myeloid Neoplasm Classification are eligible. * Attempts to obtain bone marrow either by aspirate or biopsy must be made unless clinically prohibitive. In cases where it is clinically prohibitive, peripheral blood with an excess of 20% blasts and in which adequate flow cytometric and cytogenetics/FISH testing is feasible can be substituted for the marrow exam at diagnosis. * Patients with \<20% bone marrow blasts are eligible if they have: * A karyotypic abnormality characteristic of de novo AML (t(8;21)(q22;q22), inv(16)(p13q22) or t(16;16)(p13;q22) or 11q23 abnormalities, * the unequivocal presence of megakaryoblasts, or * Biopsy proven isolated myeloid sarcoma (myeloblastoma; chloroma, including leukemia cutis) * Performance Level: Patients with acceptable organ function and any performance status are eligible for enrollment
Exclusion criteria
* Patients with any of the following constitutional conditions are not eligible: * Fanconi anemia * Shwachman syndrome * Any other known bone marrow failure syndrome * Patients with constitutional trisomy 21 or with constitutional mosaicism of trisomy 21 Note: Enrollment may occur, pending results of clinically indicated studies to exclude these conditions. * Other Excluded Conditions: * Any concurrent malignancy * Juvenile myelomonocytic leukemia (JMML) * Philadelphia chromosome positive AML * Biphenotypic or bilineal acute leukemia * Acute promyelocytic leukemia (APL) * Acute myeloid leukemia arising from myelodysplasia * Therapy-related myeloid neoplasms
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Event-free Survival (EFS) in Low Risk Patients and High Risk Patients | Up to 2 years post-intervention | Event-free survival defined as the time from on study to death, failure to achieve remission or relapse in newly diagnosed patients with pediatric acute myeloid leukemia in the Low risk stratification group and High risk stratification group |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Minimal Residual Disease (MRD) Negative Status | Post-induction I, an average of 28 days | Number of patients that are in remission (MRD negative) after course 1 in participants receiving GO and those that did not receive GO. |
| Disease-free Survival (DFS) for Patients Who Are MRD Negative | Up to 2 years post-intervention | Disease-free survival for patients who are MRD negative but lack high or low risk molecular and cytogenetic features, defined as time from end of first course of therapy to death or relapse |
| Overall Survival (OS) | Up to 2 years post-intervention | Time from study entry and from end of first course of therapy for newly diagnosed patients with pediatric acute myeloid leukemia |
| Proportion of Patients Who Develop Infection and/or Febrile Neutropenia During Each Treatment Course | At the end of each cycle (each cycle average is 28 days) | Number of participants that developed infection and/or febrile neutropenia at the end of each treatment cycle. |
| Duration of Hospital Admission in Patients That Developed Infection and Febrile Neutropenia at the End of Each Treatment Cycle | At the end of each cycle (each cycle average is 28 days) | Duration of hospital admission in patients that developed infection and febrile neutropenia at the end of each treatment cycle |
| Cardiotoxicity in Patients With de Novo AML That Receive the Four-cycle Aflac-AML Regimen With the Inclusion of Dexrazoxane | At completion of Cycle 4 (each cycle average is 28 days) | Number of patients that develop cardiac ejection fraction \<50% (CTCAE V5.0 grade 2 or greater dysfunction) either during therapy (early cardiotoxicity) or after completion of therapy (late cardiotoxicity) |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Aflac-AML Low Risk Patients Patients were classified as low risk following Induction I. All were MRD negative without low or high risk genetic and prognostic factors.
* Induction I: AraC/Daunorubicin/Etoposide (10+3+5) +/- GO based on CC genotype
* Induction II: Mitoxantrone/AraC
* Intensification I: AraC/Etoposide
* Intensification II: HD AraC/Asparaginase | 5 |
| Aflac-AML High Risk Patients Patients were classified as high risk following Induction I. All were MRD negative with high risk genetic and prognostic factors.
Induction I: AraC/Daunorubicin/Etoposide (10+3+5) +/- GO based on CC genotype\^ Induction II: Mitoxantrone/AraC\^ Intensification:\* AraC/Etoposide\^ OR HD AraC/Asparaginase\^ Allogenic HSCT
* \^If has FLT3-ITD mutation, Sorafenib is added
* \* Depending on timing patients may proceed to HSCT following Induction II or receive Intensification. If HSCT is not an option, patients can receive 4 cycles of chemotherapy | 3 |
| Total | 8 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Proceeded to HSCT after Induction 2 | 0 | 2 |
| Overall Study | Refractory CNS Leukemia after 6 doses IT cytarabine | 1 | 0 |
| Overall Study | Relapse after Induction 2 | 0 | 1 |
| Overall Study | Withdrawal by Subject | 1 | 0 |
Baseline characteristics
| Characteristic | Aflac-AML Low Risk Patients | Total | Aflac-AML High Risk Patients |
|---|---|---|---|
| Age, Continuous | 1.8 years STANDARD_DEVIATION 0.8 | 2.7 years STANDARD_DEVIATION 2.7 | 4.1 years STANDARD_DEVIATION 4.4 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants | 2 Participants | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 4 Participants | 6 Participants | 2 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 2 Participants | 2 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 1 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 2 Participants | 5 Participants | 3 Participants |
| Region of Enrollment United States | 5 participants | 8 participants | 3 participants |
| Sex: Female, Male Female | 1 Participants | 2 Participants | 1 Participants |
| Sex: Female, Male Male | 4 Participants | 6 Participants | 2 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 8 | 0 / 5 | 0 / 3 | 0 / 3 | 0 / 3 |
| other Total, other adverse events | 8 / 8 | 5 / 5 | 3 / 3 | 3 / 3 | 3 / 3 |
| serious Total, serious adverse events | 0 / 8 | 0 / 5 | 0 / 3 | 0 / 3 | 0 / 3 |
Outcome results
Primary
Event-free Survival (EFS) in Low Risk Patients and High Risk Patients
Event-free survival defined as the time from on study to death, failure to achieve remission or relapse in newly diagnosed patients with pediatric acute myeloid leukemia in the Low risk stratification group and High risk stratification group
Time frame: Up to 2 years post-intervention
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Aflac-AML Low Risk Patients | Event-free Survival (EFS) in Low Risk Patients and High Risk Patients | 1.20 years |
| Aflac-AML High Risk Patients | Event-free Survival (EFS) in Low Risk Patients and High Risk Patients | 0.76 years |
Secondary
Cardiotoxicity in Patients With de Novo AML That Receive the Four-cycle Aflac-AML Regimen With the Inclusion of Dexrazoxane
Number of patients that develop cardiac ejection fraction \<50% (CTCAE V5.0 grade 2 or greater dysfunction) either during therapy (early cardiotoxicity) or after completion of therapy (late cardiotoxicity)
Time frame: At completion of Cycle 4 (each cycle average is 28 days)
Population: The definition of late cardiotoxicity is after completion of therapy. All 3 of the high risk patients came off protocol early and did not complete therapy. For the low risk patients, 2 did not complete therapy. Among the 3 that did complete therapy, 1 patient has been lost to follow-up since completion of therapy with no cardiac data available.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Aflac-AML Low Risk Patients | Cardiotoxicity in Patients With de Novo AML That Receive the Four-cycle Aflac-AML Regimen With the Inclusion of Dexrazoxane | Early cardiotoxicity | 0 Participants |
| Aflac-AML Low Risk Patients | Cardiotoxicity in Patients With de Novo AML That Receive the Four-cycle Aflac-AML Regimen With the Inclusion of Dexrazoxane | Late cardiotoxicity | 0 Participants |
| Aflac-AML High Risk Patients | Cardiotoxicity in Patients With de Novo AML That Receive the Four-cycle Aflac-AML Regimen With the Inclusion of Dexrazoxane | Early cardiotoxicity | 0 Participants |
| Aflac-AML High Risk Patients | Cardiotoxicity in Patients With de Novo AML That Receive the Four-cycle Aflac-AML Regimen With the Inclusion of Dexrazoxane | Late cardiotoxicity | 0 Participants |
Secondary
Disease-free Survival (DFS) for Patients Who Are MRD Negative
Disease-free survival for patients who are MRD negative but lack high or low risk molecular and cytogenetic features, defined as time from end of first course of therapy to death or relapse
Time frame: Up to 2 years post-intervention
Population: All patients were MRD negative at the end of Induction I. No patients were assigned low risk due to low risk molecular and cytogenetic features. All high risk patients had high risk molecular and cytogenetic features.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Aflac-AML Low Risk Patients | Disease-free Survival (DFS) for Patients Who Are MRD Negative | 1.08 years |
Secondary
Duration of Hospital Admission in Patients That Developed Infection and Febrile Neutropenia at the End of Each Treatment Cycle
Duration of hospital admission in patients that developed infection and febrile neutropenia at the end of each treatment cycle
Time frame: At the end of each cycle (each cycle average is 28 days)
Population: All 3 of the high risk patients came off protocol early and did not complete therapy. For the low risk patients, 2 did not complete therapy. Among the 3 that did complete therapy, 1 patient has been lost to follow-up since completion of therapy with no cardiac data available.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Aflac-AML Low Risk Patients | Duration of Hospital Admission in Patients That Developed Infection and Febrile Neutropenia at the End of Each Treatment Cycle | Cycle 4 - Induction 4 | 27.5 days | Standard Deviation 0.7 |
| Aflac-AML Low Risk Patients | Duration of Hospital Admission in Patients That Developed Infection and Febrile Neutropenia at the End of Each Treatment Cycle | Cycle 1 - Induction 1 | 33 days | Standard Deviation 5.1 |
| Aflac-AML Low Risk Patients | Duration of Hospital Admission in Patients That Developed Infection and Febrile Neutropenia at the End of Each Treatment Cycle | Cycle 2 - Induction 2 | 29.3 days | Standard Deviation 1.5 |
| Aflac-AML Low Risk Patients | Duration of Hospital Admission in Patients That Developed Infection and Febrile Neutropenia at the End of Each Treatment Cycle | Cycle 3 - Induction 3 | 29 days | Standard Deviation 5.7 |
| Aflac-AML High Risk Patients | Duration of Hospital Admission in Patients That Developed Infection and Febrile Neutropenia at the End of Each Treatment Cycle | Cycle 1 - Induction 1 | 30 days | Standard Deviation 5.7 |
| Aflac-AML High Risk Patients | Duration of Hospital Admission in Patients That Developed Infection and Febrile Neutropenia at the End of Each Treatment Cycle | Cycle 2 - Induction 2 | 30.0 days | Standard Deviation 1.4 |
Secondary
Minimal Residual Disease (MRD) Negative Status
Number of patients that are in remission (MRD negative) after course 1 in participants receiving GO and those that did not receive GO.
Time frame: Post-induction I, an average of 28 days
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Aflac-AML Low Risk Patients | Minimal Residual Disease (MRD) Negative Status | 5 Participants |
| Aflac-AML High Risk Patients | Minimal Residual Disease (MRD) Negative Status | 3 Participants |
Secondary
Overall Survival (OS)
Time from study entry and from end of first course of therapy for newly diagnosed patients with pediatric acute myeloid leukemia
Time frame: Up to 2 years post-intervention
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Aflac-AML Low Risk Patients | Overall Survival (OS) | 1.97 years |
| Aflac-AML High Risk Patients | Overall Survival (OS) | 1.98 years |
Secondary
Proportion of Patients Who Develop Infection and/or Febrile Neutropenia During Each Treatment Course
Number of participants that developed infection and/or febrile neutropenia at the end of each treatment cycle.
Time frame: At the end of each cycle (each cycle average is 28 days)
Population: All 3 of the high risk patients came off protocol early and did not complete therapy. For the low risk patients, 2 did not complete therapy. Among the 3 that did complete therapy, 1 patient has been lost to follow-up since completion of therapy with no cardiac data available.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Aflac-AML Low Risk Patients | Proportion of Patients Who Develop Infection and/or Febrile Neutropenia During Each Treatment Course | Cycle 1 - Induction 1 | 5 Participants |
| Aflac-AML Low Risk Patients | Proportion of Patients Who Develop Infection and/or Febrile Neutropenia During Each Treatment Course | Cycle 2 - Induction 2 | 3 Participants |
| Aflac-AML Low Risk Patients | Proportion of Patients Who Develop Infection and/or Febrile Neutropenia During Each Treatment Course | Cycle 3 - Induction 3 | 2 Participants |
| Aflac-AML Low Risk Patients | Proportion of Patients Who Develop Infection and/or Febrile Neutropenia During Each Treatment Course | Cycle 4 - Induction 4 | 2 Participants |
| Aflac-AML High Risk Patients | Proportion of Patients Who Develop Infection and/or Febrile Neutropenia During Each Treatment Course | Cycle 4 - Induction 4 | 0 Participants |
| Aflac-AML High Risk Patients | Proportion of Patients Who Develop Infection and/or Febrile Neutropenia During Each Treatment Course | Cycle 1 - Induction 1 | 2 Participants |
| Aflac-AML High Risk Patients | Proportion of Patients Who Develop Infection and/or Febrile Neutropenia During Each Treatment Course | Cycle 3 - Induction 3 | 0 Participants |
| Aflac-AML High Risk Patients | Proportion of Patients Who Develop Infection and/or Febrile Neutropenia During Each Treatment Course | Cycle 2 - Induction 2 | 2 Participants |