Bortezomib and Sorafenib Tosylate in Patients With Newly Diagnosed Acute Myeloid Leukemia With or Without Mutations

Inclusion Criteria:

• Patients must be newly diagnosed with de novo acute myelogenous leukemia and must meet 1 of the following criteria:

  • Patients with previously untreated primary AML who meet the customary criteria for AML with ≥ 20% bone marrow blasts as set out in the 2008 WHO Myeloid Neoplasm Classification are eligible
  • Patients with cytopenias and bone marrow blasts who do not meet the customary criteria for the diagnosisof AML (patients with < 20% blasts) are eligible if they have a karyotypic abnormality characteristic ofde novo AML (t(8;21)(q22;q22), inv(16)(p13q22) or t(16;16)(p13;q22) or 11q23 abnormalities), or ifthey have the unequivocal presence of megakaryoblasts, as set out in the 2008 WHO Myeloid NeoplasmClassification
  • Patients with biopsy-proven isolated myeloid sarcoma (myeloblastoma; chloroma, including leukemiacutis) are eligible

• Patients must meet one of the following criteria:

  • Low-risk disease as defined by any of the following:

    • Presence of [inv(16)/t(16;16) or t(8;21)] or presence of NPM orCEBPα mutation, regardless of minimum-residual disease (MRD) status at end of Induction I
    • Standard-risk cytogenetics (neitherfavorable or unfavorable) with negative MRD (< 0.1%) at end of Induction I
    • Patients who do not have MRD data and have non-informative molecular studies (NPM, CEBPα,and cytogenetics) will be classified as having low-risk disease

  • High-risk disease as defined by any of the following:

    • FLT3/ITD+ with high allelic ratio (HR FLT3/ITD+)
    • Unfavorablecytogenetics (monosomy 7, monosomy 5, and del5q)
    • Standard-risk cytogenetics with positive MRD(≥ 0.1%) at end of Induction I
• Patients with juvenile myelomonocytic leukemia (JMML) are not eligible
• Patients with Philadelphia chromosome positive AML, biphenotypic or bilineal acute leukemia,or acute promyelocytic leukemia are not eligible

• High-risk patients may have a donor (bone marrow or cord blood) meeting the following criteria available:

  • Matched family donor (MFD)*

    • HLA, A, B, C, DRB1, identical, or 1 antigen or allele mismatched

      • HLA typing must be performed using molecular high-resolution technique
      • All available first-degree family members (parents and siblings) must be HLA typed
    • Use of syngeneic donors will NOT be permitted in this study

  • Alternative donor

    • HLA, A, B, C, DRB1 identical or 1 antigen- or allele-mismatched unrelated donor
    • HLA A, B, DRB1 4 of 6 antigen-matched unrelated donor cord blood unit with an adequatecell dose (nucleated cell dose > 3.7x10^7/kg or CD34+ cell dose > 2 x 10^5/kg)
    • Mismatched family member donor with at least one haplotype match, or 5 of 6 antigenphenotypic match
• Patients with any performance status are eligible
• Patients with constitutional trisomy 21 are not eligible

• Patients with any of the following are not eligible:

  • Fanconi anemia
  • Shwachman syndrome
  • Any other known bone marrow failure syndrome
  • Another concurrent malignancy
• Not pregnant or nursing
• Negative pregnancy test
• Sexually active patients of reproductive potential are not eligible unless they have agreed to use aneffective contraceptive method for the duration of their study participation

• Prior therapy with hydroxyurea, all-trans retinoic acid (ATRA), corticosteroids (any route), and intrathecal (IT) cytarabinegiven at diagnosis is allowed

  • Hydroxyurea and ATRA must be discontinued prior to initiation of protocoltherapy
• No concurrent peripheral blood stem cell transplantation
• Patients who have previously received any other chemotherapy, radiation therapy, or any otherantileukemic therapy are not eligible for this protocol
• Concomitant administration of strong CYP3A4 inducers and inhibitors (including clinicallyrelevant moderate inhibitors) is prohibited on both sorafenib cohorts