AflacLL1901 (CHOA-AML)

Phase 2

Terminated

Conditions: Acute Myeloid Leukemia
AML, Childhood

Interventions: Drug: Cytarabine
Drug: Daunorubicin
Drug: Erwinase
Drug: Etoposide
Drug: Gemtuzumab ozogamicin
Procedure: Stem cell transplantation (SCT)
Drug: Sorafenib

Registration Number: NCT04326439

Lead Sponsor: Emory University

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.

Recruitment & Eligibility

Status: TERMINATED

Sex: All

Target Recruitment: 8

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

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Aflac-AML Regimen for Low Risk AML Patients	Erwinase	Participants in this arm will receive the standard Aflac-AML Regimen with the following chemotherapy: * Induction-1: patients on Induction-I will receive gemtuzumab + ADE therapy based on genotyping. Lasts a total of 28 days. * Induction II - MA * Intensification I - AE * Intensification II - HD ARAC/LASP Patients with low risk status who had low risk markers and were MRD positive at the end of Induction I and continue to be MRD positive after Induction II will come off protocol.
Aflac-AML Regimen for High Risk AML Patients	Stem cell transplantation (SCT)	Participants in this arm will receive standard Aflac-AML Regimen with the following chemotherapy: * Induction-1: patients will receive gemtuzumab in addition to ADE therapy based on genotyping. Induction I lasts a total of 28 days. * Induction 1 for FLT3-ITD patients - ADE (10+3+5) with GO with Sorafenib * Induction II - MA * Induction II for FLT3-ITD patients - MA with Sorafenib * Intensification I - AE * Intensification I for FLT3-ITD patients - AE with sorafenib * Intensification II - HD ARAC/LASP * Intensification II for FLT3-ITD patients - HD ARAC/LASP with sorafenib * Hematopoietic stem cell transplantation (HSCT) If a patient is classified as High risk after Induction I, they may proceed to best allogenic donor SCT following Induction II. These patients may receive a third course of chemotherapy prior to HSCT. In cases where HSCT is not an option, patients can receive 4 cycles of chemotherapy. Only patients with FLT3-ITD mutation will receive sorafenib.
Aflac-AML Regimen for Low Risk AML Patients	Daunorubicin	Participants in this arm will receive the standard Aflac-AML Regimen with the following chemotherapy: * Induction-1: patients on Induction-I will receive gemtuzumab + ADE therapy based on genotyping. Lasts a total of 28 days. * Induction II - MA * Intensification I - AE * Intensification II - HD ARAC/LASP Patients with low risk status who had low risk markers and were MRD positive at the end of Induction I and continue to be MRD positive after Induction II will come off protocol.
Aflac-AML Regimen for Low Risk AML Patients	Cytarabine	Participants in this arm will receive the standard Aflac-AML Regimen with the following chemotherapy: * Induction-1: patients on Induction-I will receive gemtuzumab + ADE therapy based on genotyping. Lasts a total of 28 days. * Induction II - MA * Intensification I - AE * Intensification II - HD ARAC/LASP Patients with low risk status who had low risk markers and were MRD positive at the end of Induction I and continue to be MRD positive after Induction II will come off protocol.
Aflac-AML Regimen for Low Risk AML Patients	Etoposide	Participants in this arm will receive the standard Aflac-AML Regimen with the following chemotherapy: * Induction-1: patients on Induction-I will receive gemtuzumab + ADE therapy based on genotyping. Lasts a total of 28 days. * Induction II - MA * Intensification I - AE * Intensification II - HD ARAC/LASP Patients with low risk status who had low risk markers and were MRD positive at the end of Induction I and continue to be MRD positive after Induction II will come off protocol.
Aflac-AML Regimen for High Risk AML Patients	Cytarabine	Participants in this arm will receive standard Aflac-AML Regimen with the following chemotherapy: * Induction-1: patients will receive gemtuzumab in addition to ADE therapy based on genotyping. Induction I lasts a total of 28 days. * Induction 1 for FLT3-ITD patients - ADE (10+3+5) with GO with Sorafenib * Induction II - MA * Induction II for FLT3-ITD patients - MA with Sorafenib * Intensification I - AE * Intensification I for FLT3-ITD patients - AE with sorafenib * Intensification II - HD ARAC/LASP * Intensification II for FLT3-ITD patients - HD ARAC/LASP with sorafenib * Hematopoietic stem cell transplantation (HSCT) If a patient is classified as High risk after Induction I, they may proceed to best allogenic donor SCT following Induction II. These patients may receive a third course of chemotherapy prior to HSCT. In cases where HSCT is not an option, patients can receive 4 cycles of chemotherapy. Only patients with FLT3-ITD mutation will receive sorafenib.
Aflac-AML Regimen for High Risk AML Patients	Daunorubicin	Participants in this arm will receive standard Aflac-AML Regimen with the following chemotherapy: * Induction-1: patients will receive gemtuzumab in addition to ADE therapy based on genotyping. Induction I lasts a total of 28 days. * Induction 1 for FLT3-ITD patients - ADE (10+3+5) with GO with Sorafenib * Induction II - MA * Induction II for FLT3-ITD patients - MA with Sorafenib * Intensification I - AE * Intensification I for FLT3-ITD patients - AE with sorafenib * Intensification II - HD ARAC/LASP * Intensification II for FLT3-ITD patients - HD ARAC/LASP with sorafenib * Hematopoietic stem cell transplantation (HSCT) If a patient is classified as High risk after Induction I, they may proceed to best allogenic donor SCT following Induction II. These patients may receive a third course of chemotherapy prior to HSCT. In cases where HSCT is not an option, patients can receive 4 cycles of chemotherapy. Only patients with FLT3-ITD mutation will receive sorafenib.
Aflac-AML Regimen for Low Risk AML Patients	Gemtuzumab ozogamicin	Participants in this arm will receive the standard Aflac-AML Regimen with the following chemotherapy: * Induction-1: patients on Induction-I will receive gemtuzumab + ADE therapy based on genotyping. Lasts a total of 28 days. * Induction II - MA * Intensification I - AE * Intensification II - HD ARAC/LASP Patients with low risk status who had low risk markers and were MRD positive at the end of Induction I and continue to be MRD positive after Induction II will come off protocol.
Aflac-AML Regimen for High Risk AML Patients	Etoposide	Participants in this arm will receive standard Aflac-AML Regimen with the following chemotherapy: * Induction-1: patients will receive gemtuzumab in addition to ADE therapy based on genotyping. Induction I lasts a total of 28 days. * Induction 1 for FLT3-ITD patients - ADE (10+3+5) with GO with Sorafenib * Induction II - MA * Induction II for FLT3-ITD patients - MA with Sorafenib * Intensification I - AE * Intensification I for FLT3-ITD patients - AE with sorafenib * Intensification II - HD ARAC/LASP * Intensification II for FLT3-ITD patients - HD ARAC/LASP with sorafenib * Hematopoietic stem cell transplantation (HSCT) If a patient is classified as High risk after Induction I, they may proceed to best allogenic donor SCT following Induction II. These patients may receive a third course of chemotherapy prior to HSCT. In cases where HSCT is not an option, patients can receive 4 cycles of chemotherapy. Only patients with FLT3-ITD mutation will receive sorafenib.
Aflac-AML Regimen for High Risk AML Patients	Erwinase	Participants in this arm will receive standard Aflac-AML Regimen with the following chemotherapy: * Induction-1: patients will receive gemtuzumab in addition to ADE therapy based on genotyping. Induction I lasts a total of 28 days. * Induction 1 for FLT3-ITD patients - ADE (10+3+5) with GO with Sorafenib * Induction II - MA * Induction II for FLT3-ITD patients - MA with Sorafenib * Intensification I - AE * Intensification I for FLT3-ITD patients - AE with sorafenib * Intensification II - HD ARAC/LASP * Intensification II for FLT3-ITD patients - HD ARAC/LASP with sorafenib * Hematopoietic stem cell transplantation (HSCT) If a patient is classified as High risk after Induction I, they may proceed to best allogenic donor SCT following Induction II. These patients may receive a third course of chemotherapy prior to HSCT. In cases where HSCT is not an option, patients can receive 4 cycles of chemotherapy. Only patients with FLT3-ITD mutation will receive sorafenib.
Aflac-AML Regimen for High Risk AML Patients	Gemtuzumab ozogamicin	Participants in this arm will receive standard Aflac-AML Regimen with the following chemotherapy: * Induction-1: patients will receive gemtuzumab in addition to ADE therapy based on genotyping. Induction I lasts a total of 28 days. * Induction 1 for FLT3-ITD patients - ADE (10+3+5) with GO with Sorafenib * Induction II - MA * Induction II for FLT3-ITD patients - MA with Sorafenib * Intensification I - AE * Intensification I for FLT3-ITD patients - AE with sorafenib * Intensification II - HD ARAC/LASP * Intensification II for FLT3-ITD patients - HD ARAC/LASP with sorafenib * Hematopoietic stem cell transplantation (HSCT) If a patient is classified as High risk after Induction I, they may proceed to best allogenic donor SCT following Induction II. These patients may receive a third course of chemotherapy prior to HSCT. In cases where HSCT is not an option, patients can receive 4 cycles of chemotherapy. Only patients with FLT3-ITD mutation will receive sorafenib.
Aflac-AML Regimen for High Risk AML Patients	Sorafenib	Participants in this arm will receive standard Aflac-AML Regimen with the following chemotherapy: * Induction-1: patients will receive gemtuzumab in addition to ADE therapy based on genotyping. Induction I lasts a total of 28 days. * Induction 1 for FLT3-ITD patients - ADE (10+3+5) with GO with Sorafenib * Induction II - MA * Induction II for FLT3-ITD patients - MA with Sorafenib * Intensification I - AE * Intensification I for FLT3-ITD patients - AE with sorafenib * Intensification II - HD ARAC/LASP * Intensification II for FLT3-ITD patients - HD ARAC/LASP with sorafenib * Hematopoietic stem cell transplantation (HSCT) If a patient is classified as High risk after Induction I, they may proceed to best allogenic donor SCT following Induction II. These patients may receive a third course of chemotherapy prior to HSCT. In cases where HSCT is not an option, patients can receive 4 cycles of chemotherapy. Only patients with FLT3-ITD mutation will receive sorafenib.

Primary Outcome Measures

Name	Time	Method
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 Outcome Measures

Name	Time	Method
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
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
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)
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