Description
PRIMARY OBJECTIVE:
I. To compare event-free survival (EFS) in children with de novo acute myeloid leukemia (AML)
without FLT3 mutations who are randomly assigned to standard induction therapy on Arm A with
daunorubicin, cytarabine (DA) and gemtuzumab ozogamicin (GO) (DA-GO) versus Arm B with
liposome-encapsulated daunorubicin-cytarabine (CPX-351) and GO.
SECONDARY OBJECTIVES:
I. To compare overall survival (OS) and rates of end of Induction 1 (EOI1) minimal residual
disease (MRD) in children with de novo AML without FLT3 mutations who are randomly assigned
to standard induction therapy (Arm A) with DA-GO versus CPX-351 and GO (Arm B).
II. To estimate the EFS and rate of EOI1 MRD in FLT3 internal tandem duplication mutation
positive patients (FLT3/ITD+; as defined by allelic ratio > 0.1) without favorable
cytomolecular characteristics (NPM1 and/or CEBPA) receiving gilteritinib fumarate
(gilteritinib) in combination with DA-GO (Arm AC).
III. To estimate the EFS and rate of EOI1 MRD in patients with non-ITD FLT3 activating
mutations who receive backbone therapy (DA-GO or CPX-351 and GO) with gilteritinib (Arms AD
and BD).
IV. To determine the feasibility of combining gilteritinib and DA-GO or CPX-351 and GO in
patients with FLT3/ITD mutations (Arm AC/Arm BC/Arm AD/Arm BD).
V. To compare EOI1 MRD and EFS in patients with FLT3/ITD AML+ (allelic ratio [AR] > 0.1)
without favorable cytogenetic/molecular characteristics treated with DA-GO-gilteritinib
versus (vs) CPX-GO-gilteritinib (Arm AC vs Arm BC).
VI. To compare the incidence of significant left ventricular systolic dysfunction (LVSD) in
children with de novo AML without FLT3 mutations who are randomly assigned to standard
induction therapy (Arm A) with DA-GO versus CPX-351 and GO (Arm B).
VII. To compare the changes in echocardiography-derived measures of cardiac function,
including left ventricular ejection fraction (EF) and global longitudinal strain (GLS),
throughout AML therapy in patients with low and high risk AML without FLT3 mutations
receiving Arm A vs Arm B.
VIII. Determine if early changes in sensitive echocardiographic measures of cardiac function
(i.e., post-Induction 1 decline in GLS) and elevations in circulating cardiac biomarkers
(i.e., cardiac troponin T and N-terminal pro b-type natriuretic peptide) are associated with
subsequent declines in left ventricular ejection fraction in patients with non-FLT3 mutant
AML receiving therapy on Arms A or B.
IX. To compare longitudinal acute changes in neuropsychological functioning and
neurocognitive late effects between those with central nervous system (CNS) disease and those
without CNS disease and between those treated with hematopoietic stem cell transplant (HSCT)
and those treated with chemotherapy only for patients on Arms A and B.
X. To compare cardiotoxicity measures (EF, GLS, and cardiac biomarkers) in patients receiving
standard induction with dexrazoxane hydrochloride (dexrazoxane) vs. CPX-351 in the context of
gilteritinib therapy and explore whether the differential cardiotoxicity across arms varies
from that observed in non-FLT3 mutant AML without gilteritinib exposure.
EXPLORATORY OBJECTIVES:
I. To estimate the EFS and rate of EOI1 MRD in patients with high allelic ratio (HAR)
FLT3/ITD+ patients, as historically defined by an AR > 0.4, receiving gilteritinib in
combination with DA-GO (Arm AC with AR > 0.4).
II. To estimate the EFS and rate of EOI1 MRD in FLT3/ITD+ patients (as defined by allelic
ratio > 0.1) with NPM1 and/or bZIP CEBPA mutations receiving gilteritinib in combination with
DA-GO (Arm AC).
III. Compare the changes in high sensitivity troponin and natriuretic peptide elevations
throughout AML therapy, as measured at the end of each chemotherapy course, in patients with
low and high risk AML without FLT3 mutations receiving Arm A vs Arm B.
IV. Quantify the association of host factors (age, sex, body mass index [BMI], race),
treatment exposures (cumulative anthracycline dose, anthracycline arm, hematopoietic stem
cell transplant vs. chemotherapy alone), early declines in GLS, and elevations in cardiac
biomarkers (cTnT and NT-proBNP) with subsequent LVSD.
V. Develop a multi-marker risk prediction model incorporating significant host factors,
treatment exposures, and echocardiographic predictors for the development of LVSD within 1
year of completing therapy.
VI. To describe the rates of CNS disease utilizing an updated strategy for diagnosing and
defining CNS disease in pediatric AML.
VII. To describe the rates of CNS relapse (both isolated CNS and combined bone marrow/CNS)
when utilizing this updated strategy as well as changing CNS prophylaxis and treatment to
include triple intrathecal chemotherapy.
VIII. To describe disease-free survival (DFS) and overall survival (OS) in high risk patients
based on multi-dimensional flow cytometry detection of measurable residual disease prior to
hematopoietic stem cell transplant (HSCT).
IX. To describe plasma metabolomics that may impact efficacy, toxicity, and/or
pharmacokinetics of allogeneic HSCT.
X. To estimate the prevalence of non-risk stratifying cytogenetic/molecular variants and
assess their impact on outcome in childhood AML.
OUTLINE: Patients are randomized to either Arm A or B and assigned to Arm C or D based on
FLT3 testing results.
TREATMENT FOR PATIENTS WITHOUT FLT3 MUTATIONS:
ARM A LOW RISK GROUP 1:
INDUCTION 1: Patients receive cytarabine intravenously (IV) over 1-30 minutes every 12 hours
(Q12H) on days 1-10, dexrazoxane IV over 5-15 minutes and daunorubicin IV over 1-15 minutes
on days 1, 3, and 5, and gemtuzumab ozogamicin IV over 2 hours on day 6. Patients with CNS1
receive methotrexate intrathecally (IT), therapeutic hydrocortisone (hydrocortisone) IT, and
cytarabine IT on day 8. Patients with CNS2, CNS3a, and CNS3b receive methotrexate IT,
hydrocortisone IT, and cytarabine IT once weekly (QW) starting on day 8 for 4-6 weeks (may
continue into Induction 2) until the cerebral spinal fluid (CSF) is clear of blasts (CNS1
status). Patients with CNS3c receive methotrexate IT, hydrocortisone IT, and cytarabine IT QW
starting on day 1 for 6 weeks (may continue into Induction 2).
INDUCTION 2: Patients with CNS1 receive methotrexate IT, hydrocortisone IT, and cytarabine IT
on day 0. Patients with CNS2 receive methotrexate IT, hydrocortisone IT, and cytarabine IT QW
starting on day 0 until CNS1 status is reached. Patients also receive cytarabine IV over 1-30
minutes Q12H on days 1-8 and dexrazoxane IV over 5-15 minutes and daunorubicin IV over 1-15
minutes on days 1, 3, and 5.
INTENSIFICATION 1: Patients receive methotrexate IT, hydrocortisone IT, and cytarabine IT on
day 0. Patients also receive high-dose cytarabine IV over 1-3 hours Q12H and etoposide IV
over 90-120 minutes on days 1-5.
INTENSIFICATION 2: Patients receive high-dose cytarabine IV over 3 hours Q12H on days 1, 2,
8, and 9. Patients also receive asparaginase Erwinia chrysanthemi intramuscularly (IM) or IV
over 1-2 hours and asparaginase IM or IV over 30 minutes on days 2 and 9.
ARM B LOW RISK GROUP 1:
INDUCTION 1: Patients receive CPX-351 IV over 90 minutes on days 1, 3, and 5, and gemtuzumab
ozogamicin IV over 2 hours on day 6. Patients with CNS1 receive methotrexate IT,
hydrocortisone IT, and cytarabine IT on day 8. Patients with CNS2, CNS3a, and CNS3b receive
methotrexate IT, hydrocortisone IT, and cytarabine IT QW starting on day 8 for 4-6 weeks (may
continue into Induction 2) until the CSF is clear of blasts (CNS1 status). Patients with
CNS3c receive methotrexate IT, hydrocortisone IT, and cytarabine IT QW starting on day 1 for
6 weeks (may continue into Induction 2).
INDUCTION 2: Patients with CNS1 receive methotrexate IT, hydrocortisone IT, and cytarabine IT
on day 0. Patients with CNS2 receive methotrexate IT, hydrocortisone IT, and cytarabine IT QW
starting on day 0 until CNS1 status is reached. Patients also receive CPX-351 IV over 90
minutes on days 1, 3, and 5.
INTENSIFICATION 1: Patients receive methotrexate IT, hydrocortisone IT, and cytarabine IT on
day 0. Patients also receive high-dose cytarabine IV over 1-3 hours Q12H and etoposide IV
over 90-120 minutes on days 1-5.
INTENSIFICATION 2: Patients receive high-dose cytarabine IV over 3 hours Q12H on days 1, 2,
8, and 9. Patients also receive asparaginase Erwinia chrysanthemi IM or IV over 1-2 hours and
asparaginase IM or IV over 30 minutes on days 2 and 9.
ARM A LOW RISK GROUP 2:
INDUCTION 1: Patients receive cytarabine IV over 1-30 minutes Q12H on days 1-10, dexrazoxane
IV over 5-15 minutes and daunorubicin IV over 1-15 minutes on days 1, 3, and 5, and
gemtuzumab ozogamicin IV over 2 hours on day 6. Patients with CNS1 receive methotrexate IT,
hydrocortisone IT, and cytarabine IT on day 8. Patients with CNS2, CNS3a, and CNS3b receive
methotrexate IT, hydrocortisone IT, and cytarabine IT QW starting on day 8 for 4-6 weeks (may
continue into Induction 2) until the CSF is clear of blasts (CNS1 status). Patients with
CNS3c receive methotrexate IT, hydrocortisone IT, and cytarabine IT QW starting on day 1 for
6 weeks (may continue into Induction 2).
INDUCTION 2: Patients with CNS1 receive methotrexate IT, hydrocortisone IT, and cytarabine IT
on day 0. Patients with CNS2 receive methotrexate IT, hydrocortisone IT, and cytarabine IT QW
starting on day 0 until CNS1 status is reached. Patients also receive cytarabine IV over 1-30
minutes Q12H on days 1-8 and dexrazoxane IV over 5-15 minutes and daunorubicin IV over 1-15
minutes on days 1, 3, and 5.
INTENSIFICATION 1: Patients receive methotrexate IT, hydrocortisone IT, and cytarabine IT on
day 0. Patients also receive high-dose cytarabine IV over 1-3 hours Q12H and etoposide IV
over 90-120 minutes on days 1-5.
INTENSIFICATION 2: Patients receive methotrexate IT, hydrocortisone IT, and cytarabine IT on
day 0. Patients also receive high-dose cytarabine IV over 1-3 hours Q12H on days 1-4 and
dexrazoxane IV over 5-15 minutes and mitoxantrone hydrochloride (mitoxantrone) IV over 5-15
minutes on days 3-6.
INTENSIFICATION 3: Patients receive high-dose cytarabine IV over 3 hours Q12H on days 1, 2,
8, and 9. Patients also receive asparaginase Erwinia chrysanthemi IM or IV over 1-2 hours and
asparaginase IM or IV over 30 minutes on days 2 and 9.
ARM B LOW RISK GROUP 2:
INDUCTION 1: Patients receive CPX-351 IV over 90 minutes on days 1, 3, and 5, and gemtuzumab
ozogamicin IV over 2 hours on day 6. Patients with CNS1 receive methotrexate IT,
hydrocortisone IT, and cytarabine IT on day 8. Patients with CNS2, CNS3a, and CNS3b receive
methotrexate IT, hydrocortisone IT, and cytarabine IT QW starting on day 8 for 4-6 weeks (may
continue into Induction 2) until the CSF is clear of blasts (CNS1 status). Patients with
CNS3c receive methotrexate IT, hydrocortisone IT, and cytarabine IT QW starting on day 1 for
6 weeks (may continue into Induction 2).
INDUCTION 2: Patients with CNS1 receive methotrexate IT, hydrocortisone IT, and cytarabine IT
on day 0. Patients with CNS2 receive methotrexate IT, hydrocortisone IT, and cytarabine IT QW
starting on day 0 until CNS1 status is reached. Patients also receive CPX-351 IV over 90
minutes on days 1, 3, and 5.
INTENSIFICATION 1: Patients receive methotrexate IT, hydrocortisone IT, and cytarabine IT on
day 0. Patients also receive high-dose cytarabine IV over 1-3 hours Q12H and etoposide IV
over 90-120 minutes on days 1-5.
INTENSIFICATION 2: Patients receive methotrexate IT, hydrocortisone IT, and cytarabine IT on
day 0. Patients also receive high-dose cytarabine IV over 1-3 hours Q12H on days 1-4 and
dexrazoxane IV over 5-15 minutes and mitoxantrone hydrochloride (mitoxantrone) IV over 5-15
minutes on days 3-6.
INTENSIFICATION 3: Patients receive high-dose cytarabine IV over 3 hours Q12H on days 1, 2,
8, and 9. Patients also receive asparaginase Erwinia chrysanthemi IM or IV over 1-2 hours and
asparaginase IM or IV over 30 minutes on days 2 and 9.
ARM A HIGH RISK GROUP:
INDUCTION 1: Patients receive cytarabine IV over 1-30 minutes Q12H on days 1-10, dexrazoxane
IV over 5-15 minutes and daunorubicin IV over 1-15 minutes on days 1, 3, and 5, and
gemtuzumab ozogamicin IV over 2 hours on day 6. Patients with CNS1 receive methotrexate IT,
hydrocortisone IT, and cytarabine IT on day 8. Patients with CNS2, CNS3a, and CNS3b receive
methotrexate IT, hydrocortisone IT, and cytarabine IT QW starting on day 8 for 4-6 weeks (may
continue into Induction 2) until the CSF is clear of blasts (CNS1 status). Patients with
CNS3c receive methotrexate IT, hydrocortisone IT, and cytarabine IT QW starting on day 1 for
6 weeks (may continue into Induction 2).
INDUCTION 2: Patients with CNS1 receive methotrexate IT, hydrocortisone IT, and cytarabine IT
on day 0. Patients with CNS2 receive methotrexate IT, hydrocortisone IT, and cytarabine IT QW
starting on day 0 until CNS1 status is reached. Patients also receive cytarabine IV over 1-30
minutes Q12H on days 1-8 and dexrazoxane IV over 5-15 minutes and daunorubicin IV over 1-15
minutes on days 1, 3, and 5.
INTENSIFICATION 1: Patients receive methotrexate IT, hydrocortisone IT, and cytarabine IT on
day 0. Patients also receive high-dose cytarabine IV over 1-3 hours Q12H and etoposide IV
over 90-120 minutes on days 1-5.
HSCT: After completion of Intensification 1 and investigator assigned conditioning regimen,
patients undergo allogeneic HSCT.
ARM B HIGH RISK GROUP:
INDUCTION 1: Patients receive CPX-351 IV over 90 minutes on days 1, 3, and 5, and gemtuzumab
ozogamicin IV over 2 hours on day 6. Patients with CNS1 receive methotrexate IT,
hydrocortisone IT, and cytarabine IT on day 8. Patients with CNS2, CNS3a, and CNS3b receive
methotrexate IT, hydrocortisone IT, and cytarabine IT QW starting on day 8 for 4-6 weeks (may
continue into Induction 2) until the CSF is clear of blasts (CNS1 status). Patients with
CNS3c receive methotrexate IT, hydrocortisone IT, and cytarabine IT QW starting on day 1 for
6 weeks (may continue into Induction 2).
INDUCTION 2: Patients with CNS1 receive methotrexate IT, hydrocortisone IT, and cytarabine IT
on day 0. Patients with CNS2 receive methotrexate IT, hydrocortisone IT, and cytarabine IT QW
starting on day 0 until CNS1 status is reached. Patients also receive CPX-351 IV over 90
minutes on days 1, 3, and 5.
INTENSIFICATION 1: Patients receive methotrexate IT, hydrocortisone IT, and cytarabine IT on
day 0. Patients also receive high-dose cytarabine IV over 1-3 hours Q12H and etoposide IV
over 90-120 minutes on days 1-5.
HSCT: After completion of Intensification 1 and investigator assigned conditioning regimen,
patients undergo allogeneic HSCT.
TREATMENT FOR PATIENTS WITH FLT3/ITD MUTATIONS (ITD AR > 0.1):
ARM AC LOW RISK GROUP 2:
CONTINUED INDUCTION 1 (WITH GILTERITINIB): Patients receive cytarabine IV over 1-30 minutes
Q12H on days 1-10, dexrazoxane IV over 5-15 minutes and daunorubicin IV over 1-15 minutes on
days 1, 3, and 5, gemtuzumab ozogamicin IV over 2 hours on day 6, and gilteritinib orally
(PO) once daily (QD) on days 11-31. Patients with CNS1 receive methotrexate IT,
hydrocortisone IT, and cytarabine IT on day 8. Patients with CNS2, CNS3a, and CNS3b receive
methotrexate IT, hydrocortisone IT, and cytarabine IT QW starting on day 8 for 4-6 weeks (may
continue into Induction 2) until the CSF is clear of blasts (CNS1 status). Patients with
CNS3c receive methotrexate IT, hydrocortisone IT, and cytarabine IT QW starting on day 1 for
6 weeks (may continue into Induction 2).
INDUCTION 2 (WITH GILTERITINIB): Patients with CNS1 receive methotrexate IT, hydrocortisone
IT, and cytarabine IT on day 0. Patients with CNS2 receive methotrexate IT, hydrocortisone
IT, and cytarabine IT QW starting on day 0 until CNS1 status is reached. Patients also
receive cytarabine IV over 1-30 minutes Q12H on days 1-8, dexrazoxane IV over 5-15 minutes
and daunorubicin IV over 1-15 minutes on days 1, 3, and 5, and gilteritinib PO QD on days
11-38.
INTENSIFICATION 1 (WITH GILTERITINIB): Patients receive methotrexate IT, hydrocortisone IT,
and cytarabine IT on day 0. Patients also receive high-dose cytarabine IV over 1-3 hours Q12H
and etoposide IV over 90-120 minutes on days 1-5, and gilteritinib PO QD on days 6-33.
INTENSIFICATION 2 (WITH GILTERITINIB): Patients receive methotrexate IT, hydrocortisone IT,
and cytarabine IT on day 0. Patients also receive high-dose cytarabine IV over 1-3 hours Q12H
on days 1-4, dexrazoxane IV over 5-15 minutes and mitoxantrone IV over 5-15 minutes on days
3-6, and gilteritinib PO QD on days 7-34.
INTENSIFICATION 3 (WITH GILTERITINIB): Patients receive high-dose cytarabine IV over 3 hours
Q12H on days 1, 2, 8, and 9, asparaginase Erwinia chrysanthemi IM or IV over 1-2 hours and
asparaginase IM or IV over 30 minutes on days 2 and 9, and gilteritinib PO QD on days 10-37.
POST-CHEMOTHERAPY GILTERITINIB MAINTENANCE: Patients receive gilteritinib PO QD on days
1-365.
ARM BC LOW RISK GROUP 2:
CONTINUED INDUCTION 1 (WITH GILTERITINIB): Patients receive CPX-351 IV over 90 minutes on
days 1, 3, and 5, gemtuzumab ozogamicin IV over 2 hours on day 6, and gilteritinib PO QD on
days 11-31. Patients with CNS1 receive methotrexate IT, hydrocortisone IT, and cytarabine IT
on day 8. Patients with CNS2, CNS3a, and CNS3b receive methotrexate IT, hydrocortisone IT,
and cytarabine IT QW starting on day 8 for 4-6 weeks (may continue into Induction 2) until
the CSF is clear of blasts (CNS1 status). Patients with CNS3c receive methotrexate IT,
hydrocortisone IT, and cytarabine IT QW starting on day 1 for 6 weeks (may continue into
Induction 2).
INDUCTION 2 (WITH GILTERITINIB): Patients with CNS1 receive methotrexate IT, hydrocortisone
IT, and cytarabine IT on day 0. Patients with CNS2 receive methotrexate IT, hydrocortisone
IT, and cytarabine IT QW starting on day 0 until CNS1 status is reached. Patients also
receive CPX-351 IV over 90 minutes on days 1, 3, and 5 and gilteritinib PO QD on days 11-38.
INTENSIFICATION 1 (WITH GILTERITINIB): Patients receive methotrexate IT, hydrocortisone IT,
and cytarabine IT on day 0. Patients also receive high-dose cytarabine IV over 1-3 hours Q12H
and etoposide IV over 90-120 minutes on days 1-5, and gilteritinib PO QD on days 6-33.
INTENSIFICATION 2 (WITH GILTERITINIB): Patients receive methotrexate IT, hydrocortisone IT,
and cytarabine IT on day 0. Patients also receive high-dose cytarabine IV over 1-3 hours Q12H
on days 1-4, dexrazoxane IV over 5-15 minutes and mitoxantrone IV over 5-15 minutes on days
3-6, and gilteritinib PO QD on days 7-34.
INTENSIFICATION 3 (WITH GILTERITINIB): Patients receive high-dose cytarabine IV over 3 hours
Q12H on days 1, 2, 8, and 9, asparaginase Erwinia chrysanthemi IM or IV over 1-2 hours and
asparaginase IM or IV over 30 minutes on days 2 and 9, and gilteritinib PO QD on days 10-37.
POST-CHEMOTHERAPY GILTERITINIB MAINTENANCE: Patients receive gilteritinib PO QD on days
1-365.
ARM AC HIGH RISK GROUP:
CONTINUED INDUCTION 1 (WITH GILTERITINIB): Patients receive cytarabine IV over 1-30 minutes
Q12H on days 1-10, dexrazoxane IV over 5-15 minutes and daunorubicin IV over 1-15 minutes on
days 1, 3, and 5, gemtuzumab ozogamicin IV over 2 hours on day 6, and gilteritinib orally
(PO) once daily (QD) on days 11-31. Patients with CNS1 receive methotrexate IT,
hydrocortisone IT, and cytarabine IT on day 8. Patients with CNS2, CNS3a, and CNS3b receive
methotrexate IT, hydrocortisone IT, and cytarabine IT QW starting on day 8 for 4-6 weeks (may
continue into Induction 2) until the CSF is clear of blasts (CNS1 status). Patients with
CNS3c receive methotrexate IT, hydrocortisone IT, and cytarabine IT QW starting on day 1 for
6 weeks (may continue into Induction 2).
INDUCTION 2 (WITH GILTERITINIB): Patients with CNS1 receive methotrexate IT, hydrocortisone
IT, and cytarabine IT on day 0. Patients with CNS2 receive methotrexate IT, hydrocortisone
IT, and cytarabine IT QW starting on day 0 until CNS1 status is reached. Patients also
receive cytarabine IV over 1-30 minutes Q12H on days 1-8, dexrazoxane IV over 5-15 minutes
and daunorubicin IV over 1-15 minutes on days 1, 3, and 5, and gilteritinib PO QD on days
11-38.
INTENSIFICATION 1 (WITH GILTERITINIB): Patients receive methotrexate IT, hydrocortisone IT,
and cytarabine IT on day 0. Patients also receive high-dose cytarabine IV over 1-3 hours Q12H
and etoposide IV over 90-120 minutes on days 1-5, and gilteritinib PO QD on days 6-33.
HSCT: After completion of Intensification 1 and investigator assigned conditioning regimen,
patients undergo allogeneic HSCT.
POST-HSCT GILTERITINIB MAINTENANCE: Beginning 30-120 days after completion of HSCT, patients
receive gilteritinib PO QD on days 1-365.
ARM BC HIGH RISK GROUP:
CONTINUED INDUCTION 1 (WITH GILTERITINIB): Patients receive CPX-351 IV over 90 minutes on
days 1, 3, and 5, gemtuzumab ozogamicin IV over 2 hours on day 6, and gilteritinib PO QD on
days 11-31. Patients with CNS1 receive methotrexate IT, hydrocortisone IT, and cytarabine IT
on day 8. Patients with CNS2, CNS3a, and CNS3b receive methotrexate IT, hydrocortisone IT,
and cytarabine IT QW starting on day 8 for 4-6 weeks (may continue into Induction 2) until
the CSF is clear of blasts (CNS1 status). Patients with CNS3c receive methotrexate IT,
hydrocortisone IT, and cytarabine IT QW starting on day 1 for 6 weeks (may continue into
Induction 2).
INDUCTION 2 (WITH GILTERITINIB): Patients with CNS1 receive methotrexate IT, hydrocortisone
IT, and cytarabine IT on day 0. Patients with CNS2 receive methotrexate IT, hydrocortisone
IT, and cytarabine IT QW starting on day 0 until CNS1 status is reached. Patients also
receive CPX-351 IV over 90 minutes on days 1, 3, and 5 and gilteritinib PO QD on days 11-38.
INTENSIFICATION 1 (WITH GILTERITINIB): Patients receive methotrexate IT, hydrocortisone IT,
and cytarabine IT on day 0. Patients also receive high-dose cytarabine IV over 1-3 hours Q12H
and etoposide IV over 90-120 minutes on days 1-5, and gilteritinib PO QD on days 6-33.
HSCT: After completion of Intensification 1 and investigator assigned conditioning regimen,
patients undergo allogeneic HSCT.
POST-HSCT GILTERITINIB MAINTENANCE: Beginning 30-120 days after completion of HSCT, patients
receive gilteritinib PO QD on days 1-365.
TREATMENT FOR NON-ITD FLT3 ACTIVATING MUTATIONS:
ARM AD LOW RISK GROUP 2:
CONTINUED INDUCTION 1 (WITH GILTERITINIB): Patients receive cytarabine IV over 1-30 minutes
Q12H on days 1-10, dexrazoxane IV over 5-15 minutes and daunorubicin IV over 1-15 minutes on
days 1, 3, and 5, gemtuzumab ozogamicin IV over 2 hours on day 6, and gilteritinib orally
(PO) once daily (QD) on days 11-31. Patients with CNS1 receive methotrexate IT,
hydrocortisone IT, and cytarabine IT on day 8. Patients with CNS2, CNS3a, and CNS3b receive
methotrexate IT, hydrocortisone IT, and cytarabine IT QW starting on day 8 for 4-6 weeks (may
continue into Induction 2) until the CSF is clear of blasts (CNS1 status). Patients with
CNS3c receive methotrexate IT, hydrocortisone IT, and cytarabine IT QW starting on day 1 for
6 weeks (may continue into Induction 2).
INDUCTION 2 (WITH GILTERITINIB): Patients with CNS1 receive methotrexate IT, hydrocortisone
IT, and cytarabine IT on day 0. Patients with CNS2 receive methotrexate IT, hydrocortisone
IT, and cytarabine IT QW starting on day 0 until CNS1 status is reached. Patients also
receive cytarabine IV over 1-30 minutes Q12H on days 1-8, dexrazoxane IV over 5-15 minutes
and daunorubicin IV over 1-15 minutes on days 1, 3, and 5, and gilteritinib PO QD on days
11-38.
INTENSIFICATION 1 (WITH GILTERITINIB): Patients receive methotrexate IT, hydrocortisone IT,
and cytarabine IT on day 0. Patients also receive high-dose cytarabine IV over 1-3 hours Q12H
and etoposide IV over 90-120 minutes on days 1-5, and gilteritinib PO QD on days 6-33.
INTENSIFICATION 2 (WITH GILTERITINIB): Patients receive methotrexate IT, hydrocortisone IT,
and cytarabine IT on day 0. Patients also receive high-dose cytarabine IV over 1-3 hours Q12H
on days 1-4, dexrazoxane IV over 5-15 minutes and mitoxantrone IV over 5-15 minutes on days
3-6, and gilteritinib PO QD on days 7-34.
INTENSIFICATION 3 (WITH GILTERITINIB): Patients receive high-dose cytarabine IV over 3 hours
Q12H on days 1, 2, 8, and 9, asparaginase Erwinia chrysanthemi IM or IV over 1-2 hours and
asparaginase IM or IV over 30 minutes on days 2 and 9, and gilteritinib PO QD on days 10-37.
POST-CHEMOTHERAPY GILTERITINIB MAINTENANCE: Patients receive gilteritinib PO QD on days
1-365.
ARM BD LOW RISK GROUP 2:
CONTINUED INDUCTION 1 (WITH GILTERITINIB): Patients receive CPX-351 IV over 90 minutes on
days 1, 3, and 5, gemtuzumab ozogamicin IV over 2 hours on day 6, and gilteritinib PO QD on
days 11-31. Patients with CNS1 receive methotrexate IT, hydrocortisone IT, and cytarabine IT
on day 8. Patients with CNS2, CNS3a, and CNS3b receive methotrexate IT, hydrocortisone IT,
and cytarabine IT QW starting on day 8 for 4-6 weeks (may continue into Induction 2) until
the CSF is clear of blasts (CNS1 status). Patients with CNS3c receive methotrexate IT,
hydrocortisone IT, and cytarabine IT QW starting on day 1 for 6 weeks (may continue into
Induction 2).
INDUCTION 2 (WITH GILTERITINIB): Patients with CNS1 receive methotrexate IT, hydrocortisone
IT, and cytarabine IT on day 0. Patients with CNS2 receive methotrexate IT, hydrocortisone
IT, and cytarabine IT QW starting on day 0 until CNS1 status is reached. Patients also
receive CPX-351 IV over 90 minutes on days 1, 3, and 5 and gilteritinib PO QD on days 11-38.
INTENSIFICATION 1 (WITH GILTERITINIB): Patients receive methotrexate IT, hydrocortisone IT,
and cytarabine IT on day 0. Patients also receive high-dose cytarabine IV over 1-3 hours Q12H
and etoposide IV over 90-120 minutes on days 1-5, and gilteritinib PO QD on days 6-33.
INTENSIFICATION 2 (WITH GILTERITINIB): Patients receive methotrexate IT, hydrocortisone IT,
and cytarabine IT on day 0. Patients also receive high-dose cytarabine IV over 1-3 hours Q12H
on days 1-4, dexrazoxane IV over 5-15 minutes and mitoxantrone IV over 5-15 minutes on days
3-6, and gilteritinib PO QD on days 7-34.
INTENSIFICATION 3 (WITH GILTERITINIB): Patients receive high-dose cytarabine IV over 3 hours
Q12H on days 1, 2, 8, and 9, asparaginase Erwinia chrysanthemi IM or IV over 1-2 hours and
asparaginase IM or IV over 30 minutes on days 2 and 9, and gilteritinib PO QD on days 10-37.
POST-CHEMOTHERAPY GILTERITINIB MAINTENANCE: Patients receive gilteritinib PO QD on days
1-365.
ARM AD HIGH RISK GROUP:
CONTINUED INDUCTION 1 (WITH GILTERITINIB): Patients receive cytarabine IV over 1-30 minutes
Q12H on days 1-10, dexrazoxane IV over 5-15 minutes and daunorubicin IV over 1-15 minutes on
days 1, 3, and 5, gemtuzumab ozogamicin IV over 2 hours on day 6, and gilteritinib orally
(PO) once daily (QD) on days 11-31. Patients with CNS1 receive methotrexate IT,
hydrocortisone IT, and cytarabine IT on day 8. Patients with CNS2, CNS3a, and CNS3b receive
methotrexate IT, hydrocortisone IT, and cytarabine IT QW starting on day 8 for 4-6 weeks (may
continue into Induction 2) until the CSF is clear of blasts (CNS1 status). Patients with
CNS3c receive methotrexate IT, hydrocortisone IT, and cytarabine IT QW starting on day 1 for
6 weeks (may continue into Induction 2).
INDUCTION 2 (WITH GILTERITINIB): Patients with CNS1 receive methotrexate IT, hydrocortisone
IT, and cytarabine IT on day 0. Patients with CNS2 receive methotrexate IT, hydrocortisone
IT, and cytarabine IT QW starting on day 0 until CNS1 status is reached. Patients also
receive cytarabine IV over 1-30 minutes Q12H on days 1-8, dexrazoxane IV over 5-15 minutes
and daunorubicin IV over 1-15 minutes on days 1, 3, and 5, and gilteritinib PO QD on days
11-38.
INTENSIFICATION 1 (WITH GILTERITINIB): Patients receive methotrexate IT, hydrocortisone IT,
and cytarabine IT on day 0. Patients also receive high-dose cytarabine IV over 1-3 hours Q12H
and etoposide IV over 90-120 minutes on days 1-5, and gilteritinib PO QD on days 6-33.
HSCT: After completion of Intensification 1 and investigator assigned conditioning regimen,
patients undergo allogeneic HSCT.
POST-HSCT GILTERITINIB MAINTENANCE: Beginning 30-120 days after completion of HSCT, patients
receive gilteritinib PO QD on days 1-365.
ARM BD HIGH RISK GROUP:
CONTINUED INDUCTION 1 (WITH GILTERITINIB): Patients receive CPX-351 IV over 90 minutes on
days 1, 3, and 5, gemtuzumab ozogamicin IV over 2 hours on day 6, and gilteritinib PO QD on
days 11-31. Patients with CNS1 receive methotrexate IT, hydrocortisone IT, and cytarabine IT
on day 8. Patients with CNS2, CNS3a, and CNS3b receive methotrexate IT, hydrocortisone IT,
and cytarabine IT QW starting on day 8 for 4-6 weeks (may continue into Induction 2) until
the CSF is clear of blasts (CNS1 status). Patients with CNS3c receive methotrexate IT,
hydrocortisone IT, and cytarabine IT QW starting on day 1 for 6 weeks (may continue into
Induction 2).
INDUCTION 2 (WITH GILTERITINIB): Patients with CNS1 receive methotrexate IT, hydrocortisone
IT, and cytarabine IT on day 0. Patients with CNS2 receive methotrexate IT, hydrocortisone
IT, and cytarabine IT QW starting on day 0 until CNS1 status is reached. Patients also
receive CPX-351 IV over 90 minutes on days 1, 3, and 5 and gilteritinib PO QD on days 11-38.
INTENSIFICATION 1 (WITH GILTERITINIB): Patients receive methotrexate IT, hydrocortisone IT,
and cytarabine IT on day 0. Patients also receive high-dose cytarabine IV over 1-3 hours Q12H
and etoposide IV over 90-120 minutes on days 1-5, and gilteritinib PO QD on days 6-33.
HSCT: After completion of Intensification 1 and investigator assigned conditioning regimen,
patients undergo allogeneic HSCT.
POST-HSCT GILTERITINIB MAINTENANCE: Beginning 30-120 days after completion of HSCT, patients
receive gilteritinib PO QD on days 1-365.
NOTE: During Induction 2 or Intensification 2, patients in Arms A and B with left ventricular
systolic dysfunction receive a replacement course of high-dose cytarabine IV over 3 hours on
days 1, 2, 8, and 9, and asparaginase Erwinia chrysanthemi IM or IV over 1-2 hours and
asparaginase IM or IV over 30 minutes on days 2 and 9. Patients in Arms AC, BC, AD, and BD
receive treatment as in Arms A and B and also receive gilteritinib PO QD on days 10-37
(Induction 2) or days 10-37 (Intensification 2).
All treatment continues in the absence of disease progression or unacceptable toxicity.
OPTIONAL NEUROCOGNITIVE STUDY:
Patients may complete the Cogstate assessment battery at the end of Induction 1, at the end
of therapy, and at 9 and 60 months post-enrollment.
After completion of study treatment, patients are followed up monthly for 6 months and then
every other month for 6 months (year 1), every 4 months during year 2, every 6 months during
year 3, then yearly for years 4-10. Patients who undergo HSCT are also followed up at 30,
100, and 180 days, 9 months, and 1 year post-HSCT.