NCT01371981 · CITED IN SOURCE DOCUMENTS

Bortezomib and Sorafenib Tosylate in Treating Patients With Newly Diagnosed Acute Myeloid Leukemia

An NCI or FDA source cites this study. A citation does not establish that it applies to an individual diagnosis.

Phase: PHASE3
Status at capture: COMPLETED
Registry last update: 2026-06-02

This randomized phase III trial studies how well bortezomib and sorafenib tosylate work in treating patients with newly diagnosed acute myeloid leukemia. Bortezomib and sorafenib tosylate may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. Giving bortezomib and sorafenib tosylate together with combination chemotherapy may be an effective treatment for acute myeloid leukemia.

Open the original ClinicalTrials.gov record → · Download preserved record

What did the study report?

Outcomes, safety and baseline populations are separate source sections. Quality-of-life measures appear under their original outcome titles.

flow

Participant flow

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baseline

Baseline characteristics

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outcome · POSTED

Event-free Survival (EFS) for Patients Without High Allelic Ratio FLT3/ITD+ Mutations

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outcome · POSTED

EFS for Patients on Arm C, Cohort 1

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outcome · POSTED

EFS for Patients on Arm C, Cohort 2

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outcome · POSTED

EFS for Patients on Arm C, Cohort 3

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outcome · POSTED

Overall Survival (OS) for Patients Without High Allelic Ratio FLT3/ITD+ Mutations

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outcome · POSTED

OS for Patients on Arm C, Cohort 1

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outcome · POSTED

OS for Patients on Arm C, Cohort 2

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outcome · POSTED

OS for Patients on Arm C, Cohort 3

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outcome · POSTED

Relapse Rate for Patients Without High Allelic Ratio FLT3/ITD+ Mutations

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outcome · POSTED

Proportion of Patients Experiencing Grade 3 or Higher Non-hematologic Toxicities and Infections While on Protocol Therapy

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outcome · POSTED

Proportion of High Risk Children Without HR FLT3/ITD+ Converting From Positive MRD at End of Induction I to Negative MRD at the End of Induction II

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outcome · POSTED

Total Scale Score From Parent-reported Pediatric Quality of Life Inventory Module

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outcome · POSTED

Total Scale Score From Parent-reported Cancer Module

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outcome · POSTED

Total Scale Score From Parent-reported Multidimensional Fatigue Scale Module

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outcome · POSTED

Bortezomib Clearance

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outcome · POSTED

Sorafenib Steady State Concentration

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outcome · POSTED

Change in Shortening Fraction

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outcome · POSTED

Change in Ejection Fraction

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outcome · POSTED

Serum Concentrations of GVHD Biomarker

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outcome · NOT POSTED

Course Duration

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outcome · NOT POSTED

Incidence of Treatment-related Mortality

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outcome · NOT POSTED

Length of Hospitalization

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outcome · NOT POSTED

Remission Rate After 1 Course of Therapy

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outcome · NOT POSTED

Remission Rate After 2 Courses of Therapy

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outcome · NOT POSTED

Time to Blood Count Recovery

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adverse events

Adverse events

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more info

Limitations, agreements, and source contact

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Who could take part

eligibility Criteria: Inclusion Criteria: * Patients must be newly diagnosed with de novo acute myelogenous leukemia * Patients with previously untreated primary AML who meet the customary criteria for AML with \>= 20% bone marrow blasts as set out in the 2008 World Health Organization (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/fluorescent in situ hybridization (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) * Patients with any performance status are eligible for enrollment * Prior therapy with hydroxyurea, all-trans retinoic acid (ATRA), corticosteroids (any route), and IT cytarabine given at diagnosis is allowed; hydroxyurea and ATRA must be discontinued prior to initiation of protocol therapy; patients who have previously received any other chemotherapy, radiation therapy or any other antileukemic therapy are not eligible for this protocol 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 * Patients with any of the following oncologic diagnoses are not eligible: * Any concurrent malignancy * Juvenile myelomonocytic leukemia (JMML) * Philadelphia chromosome positive AML * Biphenotypic or bilineal acute leukemia * Acute promyelocytic leukemia * Acute myeloid leukemia arising from myelodysplasia * Therapy-related myeloid neoplasms Note: enrollment may occur pending results of clinically indicated studies to exclude these conditions * Pregnancy and breast feeding * Female patients who are pregnant are ineligible * Lactating females are not eligible unless they have agreed not to breastfeed their infants * Female patients of childbearing potential are not eligible unless a negative pregnancy test result has been obtained * Sexually active patients of reproductive potential are not eligible unless they have agreed to use an effective contraceptive method for the duration of their study participation
healthy Volunteers: false
maximum Age: 29 Years
sex: ALL
std Ages: CHILD
ADULT

Treatment arms and interventions

arm Groups

description
See Detailed Description
intervention Names
Drug: Asparaginase
Drug: Cytarabine
Drug: Daunorubicin Hydrochloride
Drug: Etoposide
Other: Laboratory Biomarker Analysis
Drug: Mitoxantrone Hydrochloride
Other: Pharmacological Study
Other: Quality-of-Life Assessment
Other: Questionnaire Administration
label
Arm A
type
EXPERIMENTAL
description
See Detailed Description
intervention Names
Drug: Asparaginase
Drug: Bortezomib
Drug: Cytarabine
Drug: Daunorubicin Hydrochloride
Drug: Etoposide
Other: Laboratory Biomarker Analysis
Drug: Mitoxantrone Hydrochloride
Other: Pharmacological Study
Other: Quality-of-Life Assessment
Other: Questionnaire Administration
label
Arm B
type
EXPERIMENTAL
description
See Detailed Description
intervention Names
Drug: Asparaginase
Drug: Cytarabine
Drug: Daunorubicin Hydrochloride
Drug: Etoposide
Other: Laboratory Biomarker Analysis
Drug: Mitoxantrone Hydrochloride
Other: Pharmacological Study
Other: Quality-of-Life Assessment
Other: Questionnaire Administration
Drug: Sorafenib Tosylate
label
Arm C (Cohort 1)
type
EXPERIMENTAL
description
See Detailed Description.
intervention Names
Drug: Asparaginase
Drug: Cytarabine
Drug: Daunorubicin Hydrochloride
Drug: Etoposide
Other: Laboratory Biomarker Analysis
Drug: Mitoxantrone Hydrochloride
Other: Pharmacological Study
Other: Quality-of-Life Assessment
Other: Questionnaire Administration
Drug: Sorafenib Tosylate
label
Arm C (Cohort 2)
type
EXPERIMENTAL
description
See Detailed Description. Different dose.
intervention Names
Drug: Asparaginase
Drug: Cytarabine
Drug: Daunorubicin Hydrochloride
Drug: Etoposide
Other: Laboratory Biomarker Analysis
Drug: Mitoxantrone Hydrochloride
Other: Pharmacological Study
Other: Quality-of-Life Assessment
Other: Questionnaire Administration
Drug: Sorafenib Tosylate
label
Arm C (Cohort 3)
type
EXPERIMENTAL
description
See Detailed Description. May reassigned to Arm C.
intervention Names
Drug: Cytarabine
Drug: Daunorubicin Hydrochloride
Drug: Etoposide
Other: Laboratory Biomarker Analysis
Other: Pharmacological Study
Other: Quality-of-Life Assessment
Other: Questionnaire Administration
label
Arm D
type
EXPERIMENTAL

interventions

arm Group Labels
Arm A
Arm B
Arm C (Cohort 1)
Arm C (Cohort 2)
Arm C (Cohort 3)
description
Given IM
name
Asparaginase
other Names
ASP-1
Asparaginase II
Asparaginase-E.Coli
Colaspase
Elspar
Kidrolase
L-Asnase
L-ASP
L-Asparaginase
L-Asparagine Amidohydrolase
Laspar
Lcf-ASP
type
DRUG
arm Group Labels
Arm B
description
Given IV
name
Bortezomib
other Names
[(1R)-3-Methyl-1-[[(2S)-1-oxo-3-phenyl-2-[(pyrazinylcarbonyl)amino]propyl]amino]butyl]boronic Acid
LDP 341
LDP-341
LDP341
MLN 341
MLN-341
MLN341
PS 341
PS-341
PS341
Velcade
type
DRUG
arm Group Labels
Arm A
Arm B
Arm C (Cohort 1)
Arm C (Cohort 2)
Arm C (Cohort 3)
Arm D
description
Given IT or IV
name
Cytarabine
other Names
.beta.-Cytosine arabinoside
1-.beta.-D-Arabinofuranosyl-4-amino-2(1H)pyrimidinone
1-.beta.-D-Arabinofuranosylcytosine
1-Beta-D-arabinofuranosyl-4-amino-2(1H)pyrimidinone
1-Beta-D-arabinofuranosylcytosine
1.beta.-D-Arabinofuranosylcytosine
2(1H)-Pyrimidinone, 4-Amino-1-beta-D-arabinofuranosyl-
2(1H)-Pyrimidinone, 4-amino-1.beta.-D-arabinofuranosyl-
Alexan
Ara-C
ARA-cell
Arabine
type
DRUG
arm Group Labels
Arm A
Arm B
Arm C (Cohort 1)
Arm C (Cohort 2)
Arm C (Cohort 3)
Arm D
description
Given IV
name
Daunorubicin Hydrochloride
other Names
Cerubidin
Cerubidine
Cloridrato de Daunorubicina
Daunoblastin
Daunoblastina
Daunoblastine
Daunomycin Hydrochloride
Daunomycin, hydrochloride
Daunorubicin.HCl
Daunorubicini Hydrochloridum
FI-6339
Ondena
type
DRUG
arm Group Labels
Arm A
Arm B
Arm C (Cohort 1)
Arm C (Cohort 2)
Arm C (Cohort 3)
Arm D
description
Given IV
name
Etoposide
other Names
Demethyl Epipodophyllotoxin Ethylidine Glucoside
EPEG
Lastet
Toposar
Vepesid
VP 16
VP 16-213
VP 16213
VP-16
VP-16-213
VP-16213
VP16
type
DRUG
arm Group Labels
Arm A
Arm B
Arm C (Cohort 1)
Arm C (Cohort 2)
Arm C (Cohort 3)
Arm D
description
Correlative studies
name
Laboratory Biomarker Analysis
type
OTHER
arm Group Labels
Arm A
Arm B
Arm C (Cohort 1)
Arm C (Cohort 2)
Arm C (Cohort 3)
description
Given IV
name
Mitoxantrone Hydrochloride
other Names
CL 232315
DHAD
DHAQ
Dihydroxyanthracenedione Dihydrochloride
Mitoxantrone Dihydrochloride
Mitoxantroni Hydrochloridum
Mitozantrone Hydrochloride
Mitroxone
Neotalem
Novantrone
Onkotrone
Pralifan
type
DRUG
arm Group Labels
Arm A
Arm B
Arm C (Cohort 1)
Arm C (Cohort 2)
Arm C (Cohort 3)
Arm D
description
Correlative studies
name
Pharmacological Study
type
OTHER
arm Group Labels
Arm A
Arm B
Arm C (Cohort 1)
Arm C (Cohort 2)
Arm C (Cohort 3)
Arm D
description
Ancillary studies
name
Quality-of-Life Assessment
other Names
Quality of Life Assessment
type
OTHER
arm Group Labels
Arm A
Arm B
Arm C (Cohort 1)
Arm C (Cohort 2)
Arm C (Cohort 3)
Arm D
description
Ancillary studies
name
Questionnaire Administration
type
OTHER
arm Group Labels
Arm C (Cohort 1)
Arm C (Cohort 2)
Arm C (Cohort 3)
description
Given PO
name
Sorafenib Tosylate
other Names
BAY 43-9006 Tosylate
BAY 54 9085
BAY 54-9085
BAY 549085
BAY-54-9085
BAY549085
Nexavar
sorafenib
type
DRUG

Study design

allocation

RANDOMIZED

intervention Model

PARALLEL

masking Info

masking: NONE

primary Purpose

TREATMENT

Enrollment

count: 1645
type: ACTUAL

Registered outcome plans (not posted results)

other Outcomes

description
Descriptive statistics will be used to summarize length of hospitalization time.
measure
Course Duration
time Frame
Up to 6 months
description
Cumulative incidence estimates that account for competing events will be used to estimate treatment-related mortality.
measure
Incidence of Treatment-related Mortality
time Frame
Up to 2 years
description
Descriptive statistics will be used to summarize length of hospitalization time.
measure
Length of Hospitalization
time Frame
Up to 6 months
description
The proportion of patients achieving remission after 1 course of therapy will be estimated along with a corresponding 95% confidence interval.
measure
Remission Rate After 1 Course of Therapy
time Frame
4 weeks
description
The proportion of patients achieving remission after 2 courses of therapy will be estimated along with a corresponding 95% confidence interval.
measure
Remission Rate After 2 Courses of Therapy
time Frame
8 weeks
description
Cumulative incidence estimates that account for competing events will be used to estimate time to count recovery.
measure
Time to Blood Count Recovery
time Frame
Up to 6 months

primary Outcomes

description
The Kaplan-Meier method will be used to estimate 3-year EFS, defined as the time from study entry until induction failure, relapse, secondary malignancy, or death.
measure
Event-free Survival (EFS) for Patients Without High Allelic Ratio FLT3/ITD+ Mutations
time Frame
Up to 3 years
description
The Kaplan-Meier method will be used to estimate 3-year EFS, defined as the time from study entry until induction failure, relapse, secondary malignancy, or death.
measure
EFS for Patients on Arm C, Cohort 1
time Frame
Up to 3 years
description
The Kaplan-Meier method will be used to estimate 3-year EFS, defined as the time from study entry until induction failure, relapse, secondary malignancy, or death.
measure
EFS for Patients on Arm C, Cohort 2
time Frame
Up to 3 years
description
The Kaplan-Meier method will be used to estimate 3-year EFS, defined as the time from study entry until induction failure, relapse, secondary malignancy, or death.
measure
EFS for Patients on Arm C, Cohort 3
time Frame
Up to 3 years

secondary Outcomes

description
The Kaplan-Meier method will be used to estimate 3-year OS, defined as the time from study entry until death.
measure
Overall Survival (OS) for Patients Without High Allelic Ratio FLT3/ITD+ Mutations
time Frame
Up to 3 years
description
The Kaplan-Meier method will be used to estimate 3-year OS, defined as the time from study entry until death.
measure
OS for Patients on Arm C, Cohort 1
time Frame
Up to 3 years
description
The Kaplan-Meier method will be used to estimate 3-year OS, defined as the time from study entry until death.
measure
OS for Patients on Arm C, Cohort 2
time Frame
Up to 3 years
description
The Kaplan-Meier method will be used to estimate 3-year OS, defined as the time from study entry until death.
measure
OS for Patients on Arm C, Cohort 3
time Frame
Up to 3 years
description
Cumulative incidence estimates 3 year relapse rate defined as time from study entry to induction failure or relapse where deaths or secondary malignancies are competing events.
measure
Relapse Rate for Patients Without High Allelic Ratio FLT3/ITD+ Mutations
time Frame
Up to 3 years
description
The proportion of patients experiencing at least one grade 3 or higher non-hematologic toxicity and infection while on protocol therapy will be estimated along with the corresponding 95% confidence interval determined using a binomial exact method. Toxicity will be assessed by Common Terminology Criteria for Adverse Events version 4.0 (CTCAE v4.0).
measure
Proportion of Patients Experiencing Grade 3 or Higher Non-hematologic Toxicities and Infections While on Protocol Therapy
time Frame
Up to 2 years
description
The proportion of high risk children without HR FLT3/ITD+ converting from positive MRD at end of Induction I to negative MRD at the end of Induction II will be estimated as well as the corresponding 95% confidence interval determined using a binomial exact method.
measure
Proportion of High Risk Children Without HR FLT3/ITD+ Converting From Positive MRD at End of Induction I to Negative MRD at the End of Induction II
time Frame
Up to 8 weeks
description
Results represent the total scale scores from the parent report of the PedsQL™ 4.0 Generic Core Scales for timepoint 1 (up to 14 days from start of therapy). Items are reverse-scored and linearly transformed to a 0-100 scale as follows: 0=100, 1=75, 2=50, 3=25, 4=0. Therefore, a higher number is a better outcome. The total score is the sum of all the items divided by the number of items answered on all the scales. "Scores on a scale" is used for a unit of measure.
measure
Total Scale Score From Parent-reported Pediatric Quality of Life Inventory Module
time Frame
Up to 14 days
description
Results represent the total scale scores from the parent report of the PedsQL™ 3.0 Cancer Module for timepoint 1 (up to 14 days from start of therapy). Items are reverse-scored and linearly transformed to a 0-100 scale as follows: 0=100, 1=75, 2=50, 3=25, 4=0. Therefore, a higher number is a better outcome. The total score is the sum of all the items divided by the number of items answered on all the scales. "Scores on a scale" is used for a unit of measure.
measure
Total Scale Score From Parent-reported Cancer Module
time Frame
Up to 14 days
description
Results represent the total scale scores from the parent report of the PedsQL™ Multidimensional Fatigue Scale for timepoint 1 (up to 14 days from start of therapy). Items are reverse-scored and linearly transformed to a 0-100 scale as follows: 0=100, 1=75, 2=50, 3=25, 4=0. Therefore, a higher number is a better outcome. The total score is the sum of all the items divided by the number of items answered on all the scales. "Scores on a scale" is used for a unit of measure.
measure
Total Scale Score From Parent-reported Multidimensional Fatigue Scale Module
time Frame
Up to 14 days
description
Median and range of bortezomib clearance during Induction II.
measure
Bortezomib Clearance
time Frame
Day 8 of Induction II
description
Median and range of sorafenib steady state concentration for Induction I.
measure
Sorafenib Steady State Concentration
time Frame
Up to 30 days

Full study description

brief Summary: This randomized phase III trial studies how well bortezomib and sorafenib tosylate work in treating patients with newly diagnosed acute myeloid leukemia. Bortezomib and sorafenib tosylate may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. Giving bortezomib and sorafenib tosylate together with combination chemotherapy may be an effective treatment for acute myeloid leukemia.
detailed Description: PRIMARY OBJECTIVES: I. To compare event-free survival (EFS) and overall survival (OS) in patients with de novo acute myeloid leukemia (AML) without high allelic ratio fms-like tyrosine kinase (FLT3)/internal tandem duplications (ITD)+ mutations who are randomized to standard therapy versus bortezomib/standard combination therapy. II. To determine the feasibility of combining bortezomib with standard chemotherapy in patients with de novo AML. III. To compare the OS and EFS of high-risk patients treated with intensive Induction II with historical controls from AAML03P1 and AAML0531. IV. To determine the feasibility of administering sorafenib (sorafenib tosylate) with standard chemotherapy and in a one year maintenance phase in patients with de novo high allelic ratio FLT3/ITD+ AML. SECONDARY OBJECTIVES: I. To assess the anti-leukemic activity of sorafenib in patients with de novo high allelic ratio FLT3/ITD+ AML. II. To compare the percentage of patients converting from positive minimal residual disease (MRD) to negative MRD after Intensive Induction II with historical controls from AAML03P1 and AAML0531. III. To compare OS, disease-free survival (DFS), cumulative incidence of relapse, and treatment-related mortality from end of Intensification I between patients allocated to best allogenic donor stem cell transplant (SCT) and comparable patients on AAML0531 who did not receive allogenic donor SCT. IV. To compare OS, DFS, cumulative incidence of relapse, treatment-related mortality, and severe toxicity between patients allocated to matched family donor SCT on AAML1031 and AAML0531. V. To assess the health-related quality of life (HRQOL) of patients treated with chemotherapy and stem cell transplant (SCT) for AML. VI. To evaluate bortezomib pharmacokinetics (PK) in patients receiving the combination regimen. VII. To obtain sorafenib and metabolite steady state pharmacokinetics and pharmacokinetic-pharmacodynamic data in subjects with FLT3/ITD receiving sorafenib. VIII. To compare the changes in shortening fraction/ejection fraction over time between patients treated with and without dexrazoxane. IX. To refine the use of minimal-residual disease (MRD) detection with 4-color flow cytometry. X. To evaluate the prognostic significance of molecular MRD and its contribution to risk identification with multidimensional flow cytometry (MDF)-based MRD in patients with translocations amenable to quantitative real time (RT)-polymerase chain reaction (PCR) (e.g., t\[8;21\], inv\[16\], t\[9;11\], Wilms tumor 1 \[WT1\] expression). XI. To determine the leukemic involvement of the hematopoietic early progenitor cell and its role in defining response to therapy. XII. To define the leukemic stem cell population in patients with AML. XIII. To determine the prevalence and prognostic significance of molecular abnormalities of WT1, runt-related transcription factor (RUNX)1, mixed-lineage leukemia (MLL)-partial tandem duplication (PTD), tet methylcytosine dioxygenase 2 (TET2), Cbl proto-oncogene, E3 ubiquitin protein ligase (c-CBL), v-kit Hardy-Zuckerman 4 feline sarcoma viral oncogene homolog (KIT), and other novel AML-associated genes in pediatric AML. XIV. Correlate the expression of cluster of differentiation (CD)74 antigen as well as proteasome beta 5-subunit (PSMB5) gene expression and mutation with response to bortezomib. XV. To evaluate the changes in protein expression and unfolded protein response (UPR) in patients with AML. XVI. To determine the expression level of wild-type FLT3, and correlate with outcome and in vitro sensitivity to FLT3 inhibition. XVII. To collect biology specimens at diagnosis, treatment time points, and relapse for future biology studies XVIII. To create a pediatric-specific algorithm to predict the occurrence of grade 2-4 acute graft-versus-host disease (GVHD) prior to its clinical manifestations using a combination of pre-transplant clinical variables and serum GVHD biomarker concentrations in the first weeks after SCT. OUTLINE: This is a dose-escalation study of sorafenib tosylate. Patients are randomized to Arm A or B or offered treatment on 1 of 6 arms. (Arms A and B are closed to new patient enrollment as of 02/04/2016) Arm A: INDUCTION I: Patients receive cytarabine intrathecally (IT) on day 1 and ADE chemotherapy comprising cytarabine intravenously (IV) over 1-30 minutes on days 1-10; daunorubicin hydrochloride IV over 1-15 minutes on days 1, 3, and 5; and etoposide IV over 1-2 hours on days 1-5. INDUCTION II: Patients with low risk (LR) receive cytarabine IT and ADE chemotherapy as in Induction I. Patients with high risk (HR) receive cytarabine IT on day 1 and MA chemotherapy comprising high-dose cytarabine IV over 1-3 hours on days 1-4, and mitoxantrone IV over 15-30 minutes on days 3-6. Patients who achieve complete remission (CR) proceed to Intensification I (beginning on day 37). Patients with refractory disease are off protocol therapy. INTENSIFICATION I: Patients receive cytarabine IT on day 1 and AE chemotherapy comprising high-dose cytarabine IV over 1-3 hours, and etoposide IV over 1-2 hours on days 1-5. Patients who achieve CR proceed to Intensification II or stem cell transplantation (SCT) beginning on day 34. Patients with refractory disease are off protocol therapy. INTENSIFICATION II: Patients with LR receive cytarabine IT on day 1 and MA chemotherapy as in Induction II. Patients with HR and no donor for SCT receive high-dose cytarabine IV over 3 hours on days 1, 2, 8, and 9 and asparaginase intramuscularly (IM) on days 2 and 9. STEM CELL TRANSPLANTATION (SCT) (HR patients with matched family \[MFD\] or unrelated donor): CONDITIONING REGIMEN: Patients receive fludarabine phosphate IV over 30 minutes once daily on days -5 to -2 and busulfan IV over 2 hours 4 times daily on days -5 to -2. TRANSPLANTATION: Patients undergo allogeneic SCT within 36 to 48 hours after the last dose of busulfan. GVHD PROPHYLAXIS: Patients receive tacrolimus IV continuously or PO beginning on day -2 and continuing until day 98 (matched sibling donor) or day 180 (with taper) (other related/unrelated donors or cord blood) and methotrexate IV on days 1, 3, and 6 (matched sibling/cord blood donors) or days 1, 3, 6, and 11 (other related/unrelated donors). Patients with unrelated donors also receive antithymocyte globulin IV over 6-8 hours on days -3 to -1. Arm B: INDUCTION I: Patients receive cytarabine IT and ADE chemotherapy as in Induction I, Arm A. Patients also receive bortezomib IV over 3-5 seconds on days 1, 4, and 8. INDUCTION II: Patients with LR receive cytarabine IT, ADE chemotherapy, and bortezomib as in Induction I. Patients with HR receive cytarabine IT and MA chemotherapy as in Induction II, Arm A (HR patients) and bortezomib IV on days 1, 4, and 8. INTENSIFICATION I: Patients receive cytarabine IT and AE chemotherapy in Arm A, Intensification II, and bortezomib IV on days 1, 4, and 8. Patients who achieve CR proceed to Intensification II or stem cell transplantation (SCT) beginning on day 34. Patients with refractory disease are off protocol therapy. INTENSIFICATION II: Patients with LR receive cytarabine IT on day 1, MA chemotherapy as in Arm A, Induction II (HR patients), and bortezomib IV on days 1, 4, and 8. Patients with HR and no donor for SCT receive high-dose cytarabine IV over 3 hours on days 1, 2, 8, and 9 and asparaginase intramuscularly (IM) on days 2 and 9. STEM CELL TRANSPLANTATION (SCT) (HR patients with matched family \[MFD\] or unrelated donor): CONDITIONING REGIMEN: Patients receive fludarabine phosphate IV over 30 minutes once daily on days -5 to -2 and busulfan IV over 2 hours 4 times daily on days -5 to -2. TRANSPLANTATION: Patients undergo allogeneic SCT within 36 to 48 hours after the last dose of busulfan. GVHD PROPHYLAXIS: Patients receive tacrolimus IV continuously or PO beginning on day -2 and continuing until day 98 (matched sibling donor) or day 180 (with taper) (other related/unrelated donors or cord blood) and methotrexate IV on days 1, 3, and 6 (matched sibling/cord blood donors) or days 1, 3, 6, and 11 (other related/unrelated donors). Patients with unrelated donors also receive antithymocyte globulin IV over 6-8 hours on days -3 to -1. ARM C (COHORT 1): INDUCTION II: Patients receive cytarabine IT on day 1, cytarabine IV over 1-30 minutes on days 1-8, daunorubicin hydrochloride IV over 1-15 minutes on days 1, 3, and 5, etoposide IV over 1-2 hours on days 1-5, and sorafenib tosylate PO on days 9-36. INTENSIFICATION I: Patients receive cytarabine IT and AE chemotherapy in Arm A, Intensification II, and sorafenib tosylate PO on daily on days 6-28. INTENSIFICATION II: Patients receive cytarabine IT on day 1, MA chemotherapy as in Arm A, Induction II (HR patients), and sorafenib tosylate PO on days 7-34. STEM CELL TRANSPLANTATION (SCT) (HR patients with matched family \[MFD\] or unrelated donor): CONDITIONING REGIMEN: Patients receive fludarabine phosphate IV over 30 minutes once daily on days -5 to -2 and busulfan IV over 2 hours 4 times daily on days -5 to -2. TRANSPLANTATION: Patients undergo allogeneic SCT within 36 to 48 hours after the last dose of busulfan. GVHD PROPHYLAXIS: Patients receive tacrolimus IV continuously or PO beginning on day -2 and continuing until day 98 (matched sibling donor) or day 180 (with taper) (other related/unrelated donors or cord blood) and methotrexate IV on days 1, 3, and 6 (matched sibling/cord blood donors) or days 1, 3, 6, and 11 (other related/unrelated donors). Patients with unrelated donors also receive antithymocyte globulin IV over 6-8 hours on days -3 to -1. MAINTENANCE: Patients receive sorafenib tosylate PO starting on day 40-100 after completion of intensification II or SCT for one year. ARM C (COHORT 2): INDUCTION I: Patients receive cytarabine IT and ADE chemotherapy as in Arm A, Induction I and sorafenib tosylate PO at the time of known HR FLT3/ITD+ (including in Induction I and concurrently with chemotherapy). INDUCTION II: Patients receive cytarabine IT on day 1, cytarabine IV over 1-30 minutes on days 1-8, daunorubicin hydrochloride IV over 1-15 minutes on days 1, 3, and 5, etoposide IV over 1-2 hours on days 1-5, and sorafenib tosylate PO on days 9-36. INTENSIFICATION I: Patients receive cytarabine IT and AE chemotherapy in Arm A, Intensification II, and sorafenib tosylate PO on daily on days 6-28. INTENSIFICATION II: Patients receive cytarabine IT on day 1, MA chemotherapy as in Arm A, Induction II (HR patients), and sorafenib tosylate PO on days 7-34. STEM CELL TRANSPLANTATION (SCT) (HR patients with matched family \[MFD\] or unrelated donor): CONDITIONING REGIMEN: Patients receive fludarabine phosphate IV over 30 minutes once daily on days -5 to -2 and busulfan IV over 2 hours 4 times daily on days -5 to -2. TRANSPLANTATION: Patients undergo allogeneic SCT within 36 to 48 hours after the last dose of busulfan. GVHD PROPHYLAXIS: Patients receive tacrolimus IV continuously or PO beginning on day -2 and continuing until day 98 (matched sibling donor) or day 180 (with taper) (other related/unrelated donors or cord blood) and methotrexate IV on days 1, 3, and 6 (matched sibling/cord blood donors) or days 1, 3, 6, and 11 (other related/unrelated donors). Patients with unrelated donors also receive antithymocyte globulin IV over 6-8 hours on days -3 to -1. MAINTENANCE: Patients receive sorafenib tosylate PO starting on day 40-100 after completion of intensification II or SCT for one year. ARM C (COHORT 3): INDUCTION I: Patients receive cytarabine IT and ADE chemotherapy as in Arm A, Induction I and sorafenib tosylate PO on days 11-28. INDUCTION II: Patients receive cytarabine IT on day 1, cytarabine IV over 1-30 minutes on days 1-8, daunorubicin hydrochloride IV over 1-15 minutes on days 1, 3, and 5, etoposide IV over 1-2 hours on days 1-5, and sorafenib tosylate PO on days 9-36. INTENSIFICATION I: Patients receive cytarabine IT and AE chemotherapy in Arm A, Intensification II, and sorafenib tosylate PO on daily on days 6-28. INTENSIFICATION II: Patients receive cytarabine IT on day 1, MA chemotherapy as in Arm A, Induction II (HR patients), and sorafenib tosylate PO on days 7-34. STEM CELL TRANSPLANTATION (SCT) (HR patients with matched family \[MFD\] or unrelated donor): CONDITIONING REGIMEN: Patients receive fludarabine phosphate IV over 30 minutes once daily on days -5 to -2 and busulfan IV over 2 hours 4 times daily on days -5 to -2. TRANSPLANTATION: Patients undergo allogeneic SCT within 36 to 48 hours after the last dose of busulfan. GVHD PROPHYLAXIS: Patients receive tacrolimus IV continuously or PO beginning on day -2 and continuing until day 98 (matched sibling donor) or day 180 (with taper) (other related/unrelated donors or cord blood) and methotrexate IV on days 1, 3, and 6 (matched sibling/cord blood donors) or days 1, 3, 6, and 11 (other related/unrelated donors). Patients with unrelated donors also receive antithymocyte globulin IV over 6-8 hours on days -3 to -1. MAINTENANCE: Patients receive sorafenib tosylate PO starting on day 40-100 after completion of intensification II or SCT for one year. ARM D: INDUCTION I: Patients with unknown FLT3/ITD status prior to study enrollment receive cytarabine IT and ADE chemotherapy as in Arm A, Induction I. If patients are determined to be HR FLT3/ITD+ no later than the end of Induction I they will be eligible to participate in Arm C. After completion of study therapy, patients are followed up monthly for 6 months, every 2 months for 6 months, every 4 months for 1 year, every 6 months for 1 year, and then yearly thereafter.

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