Entinostat and Clofarabine in Treating Patients With Newly Diagnosed, Relapsed, or Refractory Poor-Risk Acute Lymphoblastic Leukemia or Bilineage/Biphenotypic Leukemia

Exclusion Criteria

• •Philadelphia chromosome positive ALL
• •Patients may not have received previous treatment with entinostat or other histone deacetylase (HDAC) inhibitors (including valproic acid) or clofarabine within the previous 6 months
• •Concomitant chemotherapy, radiation therapy, or immunotherapy
• •Hyperleukocytosis with \>= 150,000 blasts/uL (if using hydroxyurea, steroids, maintenance doses of 6-mercaptopurine and/or methotrexate, arsenic, interferon or leukapheresis for blast count control, patient must be off those agents for 24 hours prior to beginning entinostat plus clofarabine)
• •Active disseminated intravascular coagulation (DIC)
• •Active central nervous system (CNS) leukemia; patients with known previous CNS leukemia may continue to receive intrathecal therapy with cytarabine (ara-C), methotrexate, and/or thiotepa plus steroids as prophylaxis against reactivation of active CNS disease
• •Use of investigational cytotoxic agents within 30 days or any anticancer therapy within 14 days before study entry, except for hydroxyurea and steroids, both of which must be discontinued at least 24 hours before study entry; the patient must have recovered from all acute toxicities from any previous therapy; the patient must have recovered from all acute toxicities from any previous therapy
• •Patients must have discontinued all growth factors at least 3 days before study
• •History of severe coronary artery disease, including myocardial infarction within the previous 3 months, arrhythmias other than atrial flutter or fibrillation requiring medication, or uncontrolled congestive heart failure
• •Dyspnea at rest or with minimal exertion
• •Active uncontrolled infection; patients with infection under active treatment and controlled with antibiotics are eligible
• •Patients with active \>= grade 2 graft versus host disease (GVHD)
• •Presence of other life-threatening illness
• •Patients with mental deficits and/or psychiatric history that preclude them from giving informed consent or from following protocol
• •Pregnant or nursing women; breastfeeding should be discontinued if the mother is treated with entinostat
• •Male and female patients who are fertile who do not agree to use an effective barrier method of birth control (i.e., hormonal or barrier method of birth control; abstinence) to avoid pregnancy during the study and for a minimum of 30 days after study treatment
• •Previous history of or current seizure disorder
• •Human immunodeficiency virus (HIV) infected patients who have cluster of differentiation (CD4) cell count =\< 350/mm\^3 or a history of acquired immunodeficiency syndrome (AIDS)-defining conditions