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

• OS [ Time Frame: Up to 11 years ] [ Designated as safety issue: No ]
  The Kaplan-Meier method will be used to estimate OS.
• Remission rate after 1 course of therapy [ Time Frame: 4 weeks ] [ Designated as safety issue: No ]
• Remission rate after 2 courses of therapy [ Time Frame: 8 weeks ] [ Designated as safety issue: No ]
• Proportion of patients dying in each course of therapy [ Time Frame: Up to 11 years ] [ Designated as safety issue: No ]
• Course duration [ Time Frame: Up to 11 years ] [ Designated as safety issue: No ]
• Length of hospitalization [ Time Frame: Up to 11 years ] [ Designated as safety issue: No ]
  Descriptive statistics will be used to summarize length of hospitalization time.
• Time to blood count recovery [ Time Frame: Up to 11 years ] [ Designated as safety issue: No ]
  Cumulative incidence estimates that account for competing events will be used to estimate time to count recovery.
• Relapse rate assessed by bone marrow analysis for leukemic blasts [ Time Frame: Up to 11 years ] [ Designated as safety issue: No ]
  Cumulative incidence estimates that account for competing events will be used to estimate relapse rate.
• Incidence of treatment-related mortality [ Time Frame: Up to 11 years ] [ Designated as safety issue: No ]
  Cumulative incidence estimates that account for competing events will be used to estimate treatment-related mortality.
• Proportion of patients experiencing grade 3 or higher non-hematologic toxicities and infections assessed by Common Terminology Criteria for Adverse Events version 4.0 (CTCAE v4.0) [ Time Frame: Up to 11 years ] [ Designated as safety issue: Yes ]
  The proportion of patients experiencing grade 3 or higher non-hematologic toxicities and infections will be estimated.
• 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 11 years ] [ Designated as safety issue: No ]
  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 confidence interval. In addition, this proportion will be compared with the proportion for high risk children without HR FLT3/ITD+ treated on AAML03P1 and AAML0531.
• Parent-reported questionnaire scores [ Time Frame: At 4 months following start of SCT or intensification II of chemotherapy ] [ Designated as safety issue: No ]
  Questionnaires include the Generic Core Scale, Acute Cancer Module, and Multidimensional Fatigue Module summary and dimension scores of HRQOL and Pediatric Inventory for Parents (PIP). Mean values and their 95% confidence intervals (CI) will be presented.
• Change in parent-reported outcomes over time in recipients of SCT or chemotherapy [ Time Frame: Baseline to up to 11 years ] [ Designated as safety issue: No ]
  Summary measures at each time point as well as the overall trajectory over time in HRQOL and PIP will be described. A mixed linear regression model with repeated measures incorporating covariates as appropriate will be performed.
• Bortezomib pharmacokinetic plasma concentration-time profiles [ Time Frame: Day 8 of induction II ] [ Designated as safety issue: No ]
  Analyzed using descriptive statistics and will be graphically displayed by age group. PK data will be analyzed using methods such as nonlinear mixed effects modeling to estimate bortezomib clearance (Cl) and volume of distribution (Vd) with associated 95% confidence intervals in each age group (2-11 years and 12-16 years of age).
• Systemic exposure of sorafenib tosylate and N-oxide metabolite for each course of induction and intensification (CL, Vd, time to maximum concentration [Tmax]½, area under curve [AUC]) [ Time Frame: Up to 11 years ] [ Designated as safety issue: No ]
  Descriptive statistics will be used to summarize the systemic exposure of sorafenib tosylate and N-oxide metabolite for each course of induction and intensification (CL, Vd, Tmax½, AUC). If sufficient data is available, comparison to steady state pharmacokinetic data from ADVL0413 will be performed using Wilcoxon sign rank test. For plasma inhibitory assay (PIA)-PK correlations, a random effects linear regression model will be used to describe the relationship between PIA and PK levels for each of the trough plasma samples collected for each patient.
• Shortening fraction/ejection fraction percentages and change over time [ Time Frame: Baseline to up to 11 years ] [ Designated as safety issue: No ]
  Analyzed by repeated measures analysis of variance accounting for dexrazoxane exposure and other clinically relevant covariates, including age, gender, body mass index, risk group, and treatment arm.
• Serum concentrations of GVHD biomarkers [ Time Frame: Up to day 28 after SCT ] [ Designated as safety issue: No ]
  Logistic regression modeling will be used to assign individual weights to each individual biomarker and clinical variable to maximize sensitivity and specificity of a mathematical algorithm for the prediction of grade 2-4 GVHD occurring on or before day 56 post-SCT. It will be tested whether algorithms using the day 7, 14, or 28 biomarker panel, or a combination of the biomarker panels at these different time points are most useful for the prediction of GVHD. The different algorithms will be compared on the basis of maximal specificity and sensitivity using the Akaike information criterion.

• Overall survival [ Designated as safety issue: No ]
• Remission rate after 1 and 2 courses of therapy [ Designated as safety issue: No ]
• Proportion of patients dying in each course of therapy [ Designated as safety issue: Yes ]
• Course duration [ Designated as safety issue: No ]
• Length of hospitalization [ Designated as safety issue: No ]
• Time to blood count recovery [ Designated as safety issue: No ]
• Relapse rate [ Designated as safety issue: No ]
• Treatment-related mortality [ Designated as safety issue: Yes ]
• Frequency of toxicities, including infectious and cardiac complications [ Designated as safety issue: Yes ]

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.

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 1 of 2 treatment arms or offered treatment on a third arm.

INDUCTION I:

ARM A: 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.

ARM B: Patients receive cytarabine IT and ADE chemotherapy as in Induction I, Arm A. Patients also receive bortezomib IV on days 1, 4, and 8.

ARM C (high-risk [HR] FLT3/ITD+ disease): Patients receive cytarabine IT and ADE chemotherapy as in Induction I, Arm A and sorafenib tosylate orally (PO) on days 11-28.

INDUCTION II: Patients without HR FLT3/ITD+ disease begin Induction II administration on day 29.

ARM A (low-risk [LR] patients): Patients receive cytarabine IT and ADE chemotherapy as in Induction I Arm A.

ARM A (HR patients): Patients 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.

ARM B (LR patients): Patients receive cytarabine IT, ADE chemotherapy, and bortezomib as in Induction I Arm B.

ARM B (HR patients): Patients receive cytarabine IT and MA chemotherapy as in Induction II, Arm A (HR patients) and bortezomib IV on days 1, 4, and 8.

ARM C (patients with HR FLT3/ITD+ disease, cohorts 1 and 2): 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 1-28.

Patients who achieve complete remission (CR) proceed to Intensification I (beginning on day 29). Patients with refractory disease are off protocol therapy.

INTENSIFICATION I:

ARM A: 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.

ARM B: Patients receive cytarabine IT and AE chemotherapy in Intensification II, Arm A, and bortezomib IV on days 1, 4, and 8.

ARM C (cohorts 1 and 2): Patients receive cytarabine IT and AE chemotherapy in Intensification II, Arm A, and sorafenib tosylate PO on daily on days 1-28.

Patients who achieve CR proceed to Intensification II or stem cell transplantation (SCT) beginning on day 29. Patients with refractory disease are off protocol therapy.

INTENSIFICATION II:

ARM A (LR): Patients receive cytarabine IT on day 1 and MA chemotherapy as in Induction II, Arm A (HR patients).

ARM B (LR): Patients receive cytarabine IT on day 1, MA chemotherapy as in Induction II, Arm A (HR patients), and bortezomib IV on days 1, 4, and 8.

ARMS A AND B (HR and no donor for SCT): Patients receive high-dose cytarabine IV over 3 hours on days 1, 2, 8, and 9 and asparaginase intramuscularly (IM) on days 2 and 9.

ARM C (HR cohorts 1 and 2): Patients receive cytarabine IT on day 1, MA chemotherapy as in Induction II, Arm A (HR patients), and sorafenib tosylate PO on days 1-28.

STEM CELL TRANPLANTATION (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 in Arm C receive sorafenib tosylate PO starting on day 40-80 after completion of intensification II or SCT for one year.

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.

• Adult Acute Megakaryoblastic Leukemia
• Adult Acute Monoblastic Leukemia
• Adult Acute Monocytic Leukemia
• Adult Acute Myeloid Leukemia With Inv(16)(p13.1q22); CBFB-MYH11
• Adult Acute Myeloid Leukemia With Maturation
• Adult Acute Myeloid Leukemia With Minimal Differentiation
• Adult Acute Myeloid Leukemia With t(16;16)(p13.1;q22); CBFB-MYH11
• Adult Acute Myeloid Leukemia With t(8;21)(q22;q22); RUNX1-RUNX1T1
• Adult Acute Myeloid Leukemia With t(9;11)(p22;q23); MLLT3-MLL
• Adult Acute Myeloid Leukemia Without Maturation
• Adult Acute Myelomonocytic Leukemia
• Adult Erythroleukemia
• Adult Pure Erythroid Leukemia
• Childhood Acute Erythroid Leukemia
• Childhood Acute Megakaryoblastic Leukemia
• Childhood Acute Monoblastic Leukemia
• Childhood Acute Monocytic Leukemia
• Childhood Acute Myeloid Leukemia With Maturation
• Childhood Acute Myeloid Leukemia Without Maturation
• Childhood Acute Myelomonocytic Leukemia
• Untreated Adult Acute Myeloid Leukemia
• Untreated Childhood Myeloid Neoplasm

• Drug: Asparaginase
  Given IM
  Other Names:

  • MK-965
  • Re-82-TAD-15
• Drug: Daunorubicin Hydrochloride
  Given IV
  Other Names:

  • DNM
  • DNR
  • DRB
• Drug: Mitoxantrone Hydrochloride
  Given IV
• Drug: Sorafenib Tosylate
  Given PO
  Other Names:

  • BAY 54-9085
  • Nexavar
  • SFN
• Drug: Cytarabine
  Given IT or IV
  Other Names:

  • CHX-3311
  • U-19920
• Drug: Etoposide
  Given IV
  Other Name: Lastet
• Drug: Bortezomib
  Given IV
• Other: Pharmacological Study
  Correlative studies
  Other Name: pharmacological studies
• Other: Laboratory Biomarker Analysis
  Correlative studies
• Other: Questionnaire Administration
  Ancillary studies
• Other: Quality-of-Life Assessment
  Ancillary studies
  Other Name: Quality of Life Assessment

• Experimental: Induction I, Arm A
  Patients receive cytarabine IT on day 1 and ADE chemotherapy comprising cytarabine 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.
  Interventions:

  • Drug: Daunorubicin Hydrochloride
  • Drug: Cytarabine
  • Drug: Etoposide
  • Other: Pharmacological Study
  • Other: Laboratory Biomarker Analysis
  • Other: Questionnaire Administration
  • Other: Quality-of-Life Assessment
• Experimental: Induction I, Arm B
  Patients receive cytarabine IT and ADE chemotherapy as in Induction I, Arm A. Patients also receive bortezomib IV on days 1, 4, and 8.
  Interventions:

  • Drug: Daunorubicin Hydrochloride
  • Drug: Cytarabine
  • Drug: Etoposide
  • Drug: Bortezomib
  • Other: Pharmacological Study
  • Other: Laboratory Biomarker Analysis
  • Other: Questionnaire Administration
  • Other: Quality-of-Life Assessment
• Experimental: Induction I, Arm C
  Patients receive cytarabine IT and ADE chemotherapy as in Induction I, Arm A and sorafenib tosylate PO on days 11-28.
  Interventions:

  • Drug: Daunorubicin Hydrochloride
  • Drug: Sorafenib Tosylate
  • Drug: Cytarabine
  • Drug: Etoposide
  • Other: Pharmacological Study
  • Other: Laboratory Biomarker Analysis
  • Other: Questionnaire Administration
  • Other: Quality-of-Life Assessment
• Experimental: Induction II, Arm A (LR patients)
  Patients receive cytarabine IT and ADE chemotherapy as in Induction I Arm A.
  Interventions:

  • Drug: Daunorubicin Hydrochloride
  • Drug: Cytarabine
  • Drug: Etoposide
  • Other: Laboratory Biomarker Analysis
  • Other: Questionnaire Administration
  • Other: Quality-of-Life Assessment
• Experimental: Induction II, Arm A (HR patients)
  Patients 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.
  Interventions:

  • Drug: Mitoxantrone Hydrochloride
  • Drug: Cytarabine
  • Other: Pharmacological Study
  • Other: Laboratory Biomarker Analysis
  • Other: Questionnaire Administration
  • Other: Quality-of-Life Assessment
• Experimental: Induction II, Arm B (LR patients)
  Patients receive cytarabine IT, ADE chemotherapy, and bortezomib as in Induction I Arm B.
  Interventions:

  • Drug: Daunorubicin Hydrochloride
  • Drug: Cytarabine
  • Drug: Etoposide
  • Drug: Bortezomib
  • Other: Pharmacological Study
  • Other: Laboratory Biomarker Analysis
  • Other: Questionnaire Administration
  • Other: Quality-of-Life Assessment
• Experimental: Induction II, Arm B (HR patients)
  Patients receive MA chemotherapy as in Induction II, Arm A (HR patients) and bortezomib IV on days 1, 4, and 8.
  Interventions:

  • Drug: Daunorubicin Hydrochloride
  • Drug: Mitoxantrone Hydrochloride
  • Drug: Cytarabine
  • Drug: Etoposide
  • Drug: Bortezomib
  • Other: Pharmacological Study
  • Other: Laboratory Biomarker Analysis
  • Other: Questionnaire Administration
  • Other: Quality-of-Life Assessment
• Experimental: Induction II, Arm C

  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 1-28.

  Maintenance: Patients receive sorafenib tosylate PO starting on day 40-80 after completion of intensification II or SCT for one year.

  Interventions:

  • Drug: Daunorubicin Hydrochloride
  • Drug: Sorafenib Tosylate
  • Drug: Cytarabine
  • Drug: Etoposide
  • Other: Pharmacological Study
  • Other: Laboratory Biomarker Analysis
  • Other: Questionnaire Administration
  • Other: Quality-of-Life Assessment
• Experimental: Intensification I, Arm A
  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.
  Interventions:

  • Drug: Cytarabine
  • Drug: Etoposide
  • Other: Pharmacological Study
  • Other: Laboratory Biomarker Analysis
  • Other: Questionnaire Administration
  • Other: Quality-of-Life Assessment
• Experimental: Intensification I, Arm B
  Patients receive cytarabine IT and AE chemotherapy in Intensification II, Arm A, and bortezomib IV on days 1, 4, and 8.
  Interventions:

  • Drug: Cytarabine
  • Drug: Etoposide
  • Drug: Bortezomib
  • Other: Pharmacological Study
  • Other: Laboratory Biomarker Analysis
  • Other: Quality-of-Life Assessment
• Experimental: Intensification I, Arm C
  Patients receive cytarabine IT and AE chemotherapy in Intensification II, Arm A, and sorafenib tosylate PO on daily on days 1-28.
  Interventions:

  • Drug: Daunorubicin Hydrochloride
  • Drug: Sorafenib Tosylate
  • Drug: Cytarabine
  • Drug: Etoposide
  • Other: Pharmacological Study
  • Other: Laboratory Biomarker Analysis
  • Other: Questionnaire Administration
  • Other: Quality-of-Life Assessment
• Experimental: Intensification II, Arm A (LR)
  Patients receive cytarabine IT on day 1 and MA chemotherapy as in Induction II, Arm A (HR patients).
  Interventions:

  • Drug: Daunorubicin Hydrochloride
  • Drug: Cytarabine
  • Drug: Etoposide
  • Other: Pharmacological Study
  • Other: Laboratory Biomarker Analysis
  • Other: Questionnaire Administration
  • Other: Quality-of-Life Assessment
• Experimental: Intensification II, Arm B (LR)
  Patients receive cytarabine IT on day 1, MA chemotherapy as in Induction II, Arm A (HR patients), and bortezomib IV on days 1, 4, and 8.
  Interventions:

  • Drug: Daunorubicin Hydrochloride
  • Drug: Cytarabine
  • Drug: Etoposide
  • Drug: Bortezomib
  • Other: Pharmacological Study
  • Other: Laboratory Biomarker Analysis
  • Other: Questionnaire Administration
  • Other: Quality-of-Life Assessment
• Experimental: Intensification II, Arms A and B
  Patients receive high-dose cytarabine IV over 3 hours on days 1, 2, 8, and 9 and asparaginase IM on days 2 and 9.
  Interventions:

  • Drug: Asparaginase
  • Drug: Cytarabine
  • Other: Pharmacological Study
  • Other: Laboratory Biomarker Analysis
  • Other: Questionnaire Administration
  • Other: Quality-of-Life Assessment
• Experimental: Intensification II, Arm C
  Patients receive cytarabine IT on day 1, MA chemotherapy as in Induction II, Arm A (HR patients), and sorafenib tosylate PO on days 1-28.
  Interventions:

  • Drug: Daunorubicin Hydrochloride
  • Drug: Sorafenib Tosylate
  • Drug: Cytarabine
  • Drug: Etoposide
  • Other: Pharmacological Study
  • Other: Laboratory Biomarker Analysis
  • Other: Questionnaire Administration
  • Other: Quality-of-Life Assessment

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
• All patients and/or their parents or legal guardians must sign a written informed consent
• All institutional, Food and Drug Administration (FDA), and National Cancer Institute (NCI) requirements for human studies must be met

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