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Clofarabine and Cytarabine or Standard Induction Therapy and Chemotherapy with or without Natural Killer Cell Transplant in Treating Younger Patients with Newly Diagnosed Acute Myeloid Leukemia

Trial Status: Complete

The overall goal of this study is to see if the remission rate can be increased. This research study also plans to compare the response rate after one course of chemotherapy in participants treated with the standard 3-drug chemotherapy combination (cytarabine, daunorubicin [daunorubicin hydrochloride], etoposide) versus those treated with a new 2 drug combination (clofarabine and cytarabine); to find out if a new therapy called natural killer (NK) cell transplantation will be effective treatment for participants with standard risk acute myeloid leukemia (AML); to learn more about the biology and genetics of AML by performing research studies on blood and bone marrow samples; to learn more about how drugs used in the treatment of AML work in the body of participants with AML, how the drugs affect the body, and how participants’ genetics may predict who will have more side effects from treatment and who will or will not respond to the leukemia treatment; and to find out if major infections in participants treated on this study can be prevented by giving planned antibiotics and antifungal drugs after chemotherapy when the blood counts are very low.

Inclusion Criteria

  • Patients must have one of the following three characteristics: * Acute myeloid leukemia fulfilling the criteria of the World Health Organization (WHO) classification * < 20% marrow myeloblasts and evidence of a clonal de novo AML genetic abnormality [e.g., t(8;21), inv(16), t(9;11)] * Myeloid sarcoma (also referred to as extramedullary myeloid tumor, granulocytic sarcoma, or chloroma), with or without evidence of a leukemic process in the bone marrow or peripheral blood, with confirmation of myeloid differentiation * Patients with secondary AML following treatment of primary malignancy are eligible
  • No prior therapy for this malignancy except for one dose of intrathecal therapy and the use of hydroxyurea or low-dose cytarabine (100-200 mg/m^2 per day for one week or less) for hyperleukocytosis
  • Written informed consent according to institutional guidelines
  • Female patients of childbearing potential must have a negative pregnancy test within 2 weeks prior to enrollment
  • Male and female participants must use an effective contraceptive method during the study and for a minimum of 6 months after study treatment
  • CRITERIA FOR RANDOMIZATION * Participants must meet the following criteria to qualify for HD-ADE versus Clo/AraC randomization; participants who do not meet these criteria may still be enrolled, but will be treated on HD-ADE arm and will NOT be randomized
  • Normal creatinine for age
  • Serum bilirubin =< 1.5 x upper limit of normal (ULN)
  • Aspartate aminotransferase (AST/serum glutamic oxaloacetic transaminase [SGOT]) and alanine aminotransferase (ALT/serum glutamate pyruvate transaminase [SGPT]) =< 2.5 x ULN
  • Alkaline phosphatase =< 2.5 x ULN

Exclusion Criteria

  • Down syndrome
  • Acute promyelocytic leukemia (APL)
  • Juvenile myelomonocytic leukemia (JMML)
  • Fanconi anemia (FA)
  • Kostmann syndrome
  • Shwachman syndrome
  • Other bone marrow failure syndromes
  • Use of concomitant chemotherapy, radiation therapy, or immunotherapy other than as specified in the protocol
  • Use of investigational agents within 30 days or any anticancer therapy for this malignancy within 2 weeks before study entry with the exception of IT therapy, hydroxyurea, or low-dose cytarabine as stated above; the patient must have recovered from all acute toxicities from any previous therapy
  • Systemic fungal, bacterial, viral, or other infection not controlled (defined as exhibiting ongoing signs/symptoms related to the infection and without improvement, despite appropriate antibiotics or other treatment)
  • Pregnant or lactating patients
  • Any significant concurrent disease, illness, or psychiatric disorder that would compromise patient safety or compliance, interfere with consent, study participation, follow up, or interpretation of study results


Palo Alto
Lucile Packard Children's Hospital Stanford University
Contact: Gary Van Houten Dahl
Phone: 650-723-5535
San Diego
Rady Children's Hospital - San Diego
Contact: Deborah E. Schiff
Phone: 858-966-5934


University of Chicago Comprehensive Cancer Center
Contact: Jennifer Lynn McNeer
Phone: 773-702-6808


Dana-Farber Cancer Institute
Contact: Barbara Alsen Degar
Phone: 866-790-4500


Children's Hospital of Michigan
Contact: Jeffrey Warren Taub
Phone: 313-745-5515


Saint Jude Children's Research Hospital
Contact: Jeffrey E. Rubnitz
Phone: 901-595-2308


Fort Worth
Cook Children's Medical Center
Contact: Kenneth Matthew Heym
Phone: 682-885-2103


National University Hospital Singapore
Contact: Allen Eng Juh Yeoh
Phone: 65 6772 4406


I. To compare the immunologic complete response rate after one course of therapy in patients who receive cytarabine + daunorubicin + etoposide (ADE) with that in patients who receive clofarabine + cytarabine (Clo/AraC).


I. To estimate the event-free survival (EFS) of standard risk (SR) patients who receive chemotherapy alone and the EFS of SR patients who receive chemotherapy followed by natural killer (NK) cell transplantation.


I. To genotype natural killer (NK) cell receptors and measure their expressions at diagnosis and after induction therapy, and to explore the associations of these features with treatment outcome.

II. To assess the prognostic value of levels of minimal residual disease in peripheral blood at day 8 of induction I.

III. To validate new markers and methods for minimal residual disease (MRD) detection.

IV. To identify new prognostic factors by applying new technologies to study patient material

V. To identify pharmacogenetic, pharmacokinetic and pharmacodynamic predictors for treatment-related outcomes in the context of the systemic therapy used in the protocol.

VI. To describe the impact of antibiotic and antifungal prophylaxis on invasive bacterial and fungal infections, febrile neutropenia, hospitalization, and antibiotic resistance.

VII. To explore the feasibility and toxicity of administering vorinostat in combination with chemotherapy in selected high-risk patients.

OUTLINE: This is a randomized, phase III study of induction therapy and a phase II study of NK cell transplantation.

INDUCTION I: Patients are randomized to 1 of 2 treatment arms.

ARM I (high-dose [HD]-ADE): Patients receive cytarabine intravenously (IV) over 3 hours twice daily (BID) on days 1, 3, and 5; daunorubicin hydrochloride IV over 6 hours once daily (QD) on days 2, 4, and 6; and etoposide IV over 4 hours QD on days 2-6.

ARM II (CLO/ARAC): Patients receive clofarabine IV over 2 hours QD on days 1-5 followed by cytarabine IV over 2 hours QD on days 1-5.

In both arms, treatment repeats every 21 days for up to 2 courses.

INDUCTION II (low-dose [LD]-ADE): Patients receive cytarabine IV over 30 minutes BID on days 1-8; daunorubicin hydrochloride IV over 6 hours QD on days 2, 4, and 6; and etoposide IV over 4 hours QD on days 1-5. Patients with FMS-related tyrosine kinase 3 internal tandem duplication (FLT3-ITD) also receive sorafenib tosylate orally (PO) BID beginning one day after completion of Induction II and continuing for 21 days. Other high-risk (HR) patients also receive vorinostat PO QD, BID, or thrice daily (TID) on days -2 to 0 and days 1-6.

CONSOLIDATION I: Patients not undergoing stem cell transplant (SCT) receive mitoxantrone hydrochloride IV over 1 hour QD on days 3-5 and cytarabine IV over 2 hours BID on days 1-4. Patients with low levels of MRD may proceed directly to SCT; patients with a killer immunoglobulin-like receptor (KIR)-mismatched family member may proceed to NK cell transplantation; and patients with higher levels of MRD may receive additional consolidation chemotherapy before SCT.

CONSOLIDATION II: Patients receive cytarabine IV over 3 hours BID on days 1, 2, 8, and 9 and asparaginase intramuscularly (IM) or IV over 1 hour over 3 hours on days 2 and 9.

NK CELL TRANSPLANTATION: Patients receive cyclophosphamide IV over 1 hour on day -7; fludarabine phosphate IV over 30 minutes on days -6 to -2; aldesleukin subcutaneously (SC) on days -1, 1, 3, 5, 7, and 9. Patients undergo NK cell infusion on day 0. Patients then proceed to SCT.

CENTRAL NERVOUS SYSTEM (CNS) THERAPY: All patients undergo intrathecal (IT) chemotherapy comprising methotrexate, hydrocortisone, and cytarabine at the time of diagnosis.

Treatment continues in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up periodically for 5 years.

Trial Phase Phase II/III

Trial Type Treatment

Lead Organization
Saint Jude Children's Research Hospital

Principal Investigator
Jeffrey E. Rubnitz

  • Primary ID AML08
  • Secondary IDs NCI-2011-03659
  • ID NCT00703820