Vorinostat, Azacitidine, and Gemtuzumab Ozogamicin in Treating Older Patients With Relapsed or Refractory Acute Myeloid Leukemia

Inclusion Criteria:

• Prior morphological diagnosis of AML other then acute promyelocytic leukemia according to the 2001 World Health Organization (WHO) diagnostic criteria; patients with biphenotypic AML are eligible
• Requiring first salvage chemotherapy for persistent or relapsing disease, as defined by standard criteria, after at least one course of conventional chemotherapy, e.g. with "7+3"
• A bone marrow biopsy is not routinely required, but should be obtained if the aspirate is dilute, hypocellular, or inaspirable; outside bone marrow examinations performed within the stipulated time period are acceptable as long as the slides are reviewed at the study institution
• Flow cytometric analysis of the bone marrow aspirate should be performed according to institutional practice guidelines
• Duration of CR1 < 12 months (or primary resistant disease)
• Patients with prior autologous or allogeneic hematopoietic cell transplantation (HCT) are eligible if relapse occurs 6-12 months post-transplant
• Eastern Cooperative Oncology Group (ECOG)/WHO/Zubrod performance status of 0-3, assessed within 14 days prior to registration
• Must be off any active therapy for AML with the exception of hydroxyurea for at least 14 days prior to study registration, and all grade 3 and 4 non-hematological toxicities must have resolved
• Willingness to discontinue taking any medications that are generally accepted to have a risk causing Torsades de Pointes during the study
• Bilirubin =< 1.5 x Institutional Upper Limit of Normal (IULN) unless elevation is thought to be due to hepatic infiltration by AML, Gilbert's syndrome, or hemolysis (assessed within 7 days prior to registration
• Serum glutamic oxaloacetic transaminase (SGOT) (aspartate aminotransferase [AST]) and serum glutamic pyruvate transaminase (SPGT) (alanine aminotransferase [ALT]) =< 1.5 x IULN unless elevation is thought to be due to hepatic infiltration by AML (assessed within 7 days prior to registration)
• Serum creatinine =< 1.5 x IULN (assessed within 7 days prior to registration)
• No clinical or radiographical evidence of heart failure
• White blood cell count (WBC) < 25,000/uL, assessed within 3 days prior to registration; patients with WBC >= 25,000/uL must undergo cytoreduction with hydroxyurea prior to enrollment and will not be treated if the WBC remains >= 25,000/ uL despite hydroxyurea treatment
• Patients with symptoms/signs of hyperleukocytosis or WBC > 100,000/uL can be treated with leukapheresis prior to enrollment
• Collection of bone marrow and peripheral blood specimens for correlative studies prior to study treatment is highly recommended; submission of peripheral blood only is acceptable as long as the peripheral blast count is > 5,000/uL and blast count > 50% of total WBC
• Women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation; should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately
• Ability to understand and the willingness to sign a written informed consent document; the consent can be obtained from a legally authorized representative if the patient is unable to provide informed consent

Exclusion Criteria:

• Patients in remission or with second or later relapse

• Diagnosis of another malignancy, unless the patient was diagnosed at least 2 years earlier and has been disease-free for at least 6 months following the completion of curative intent therapy with the following exceptions:

  • Patients with treated non-melanoma skin cancer, in situ carcinoma, or cervical intraepithelial neoplasia, regardless of the disease-free duration, are eligible for this study if definitive treatment for the condition has been completed
  • Patients with organ-confined prostate cancer with no evidence of recurrent or progressive disease based on prostate-specific antigen (PSA) values are also eligible for this study if hormonal therapy has been initiated or a radical prostatectomy has been performed
• Refractory/relapsing blast crisis of chronic myelogenous leukemia (CML)
• Prior anti-AML treatment with GO, histone deacetylase (HDAC) inhibitor (including the use of valproic acid for control of seizure activity or other purposes), or demethylating agent
• Known hypersensitivity to GO, vorinostat, azacitidine, or mannitol
• Clinical evidence suggestive of central nervous system (CNS) involvement with leukemia unless a lumbar puncture confirms the absence of leukemic blasts in the cerebrospinal fluid (CSF)
• Human immunodeficiency virus (HIV)-positive patients are excluded if their cluster of differentiation (CD)4 count is below 200 cells/uL or if they have active acquired immune deficiency syndrome (AIDS)-related complications, as these patients are at increased risk of lethal infections when treated with marrow-suppressive therapy
• Pregnancy; women of child-bearing potential must undergo pregnancy test within 7 days prior to registration; breastfeeding should be discontinued if the mother is treated with vorinostat, azacitidine, and GO
• Uncontrolled systemic fungal, bacterial, viral, or other infection (defined as exhibiting ongoing signs/symptoms related to the infection and without improvement, despite appropriate antibiotics or other treatment)
• Patients may not be receiving any other investigational agents