This randomized phase III trial studies cytarabine and daunorubicin hydrochloride or idarubicin and cytarabine with or without vorinostat to see how well they work in treating younger patients with previously untreated acute myeloid leukemia. Drugs used in chemotherapy, such as cytarabine, daunorubicin hydrochloride, idarubicin, and vorinostat, work in different ways to stop the growth of cancer cells, either by killing the cells, stopping them from dividing, or by stopping from spreading. Giving more than one drug (combination chemotherapy) and giving the drugs in different doses and in different combinations may kill more cancer cells. It is not yet known which combination chemotherapy is more effective in treating acute myeloid leukemia.

PRIMARY OBJECTIVES:

I. To compare event-free survival (EFS) between patients with acute myeloid leukemia (AML) who receive standard 7+3 (cytarabine and daunorubicin hydrochloride) or idarubicin and high-dose cytarabine (IA) to patients who receive IA + vorinostat. (Chemotherapy) II. To determine whether it is possible to get 60% or more of adults with high-risk AML (by cytogenetics) in first complete remission (CR1) to allogeneic hematopoietic cell transplantation (HCT). (Transplant)

SECONDARY OBJECTIVES:

I. To estimate the frequency and severity of toxicities of the three regimens in this patient population. (Chemotherapy) II. To estimate disease-free survival (DFS) among patients who receive transplant. (Transplant) III. To compare event-free survival (EFS) between patients who receive standard 7 + 3 to patients who receive IA. (Chemotherapy) IV. To estimate the prevalence of the mutations nucleophosmin (nucleolar phosphoprotein B23, numatrin) (NPM1), isocitrate dehydrogenase 1 (NADP+), soluble (IDH1), isocitrate dehydrogenase 2 (NADP+), mitochondrial (IDH2), tet methylcytosine dioxygenase 2 (TET2) and deoxyribonucleic acid (DNA) (cytosine-5-)-methyltransferase 3 alpha (DNMT3A) and the cytogenetic risk distribution of patients on this study and to evaluate the association between these and overall survival (OS), event-free survival (EFS), disease-free survival (DFS), and complete remission rate. (Chemotherapy/Translational Medicine) V. To compare the complete response rate, disease-free survival (DFS), and overall survival (OS) between patients who receive standard 7+3 therapy or IA to patients who receive IA + vorinostat. (Chemotherapy)

TERTIARY OBJECTIVES:

I. Future planned studies will include testing of histone H3 acetylation, induction of gamma H2A histone family, member X (H2AX), analysis of reactive oxygen species (ROS) resistance and DNA methylation profiles. (Chemotherapy/Translational Medicine)

OUTLINE: Patients are randomized to 1 of 3 treatment arms.

INDUCTION/RE-INDUCTION:

ARM I: Patients receive standard dose cytarabine intravenously (IV) continuously on days 1-7 and daunorubicin hydrochloride IV on days 1-3. Patients with residual blasts may receive re-induction treatment beginning on day 15. Patients achieving complete remission (CR) or complete remission with incomplete platelet recover (CRi) may proceed to allogeneic hematopoietic stem cell transplant (HSCT) or to consolidation therapy.

ARM II: Patients receive high dose cytarabine IV continuously on days 1-4 and idarubicin IV over 15 minutes on days 1-3. Patients with residual blasts may receive re-induction treatment beginning on day 28. Patients achieving CR or CRi may proceed to allogeneic HSCT or to consolidation therapy.

ARM III: Patients receive vorinostat orally (PO) thrice daily (TID) on days 1-3, high-dose cytarabine IV continuously on days 4-7, and idarubicin IV over 15 minutes on days 4-6. Patients with residual blasts may receive re-induction treatment beginning on day 28. Patients achieving CR or CRi may proceed to allogeneic HSCT or to consolidation therapy. (Permanently closed to accrual, effective 6/2/2015) Patient previously randomized to Arm III may continue treatment without vorinostat.

CONSOLIDATION:

ARM I: Patients receive cytarabine IV over 3 hours every 12 hours on days 1, 3, and 5.

ARM II: Patients receive cytarabine IV continuously on days 1-3 and idarubicin IV over 15 minutes on days 1-2.

ARM III: Patients receive vorinostat PO TID on days 1-3, cytarabine IV continuously on days 4-6, and idarubicin IV over 15 minutes on days 4-5. (Permanently closed to accrual, effective 6/2/2015) Patient previously randomized to Arm III may continue treatment with or without vorinostat.

In all arms, treatment repeats every 28 days for 4 courses or until transplant in the absence of disease progression or unacceptable toxicity.

TRANSPLANT: Patients may undergo an allogeneic transplant after induction therapy or consolidation therapy.

After completion of study treatment, patients are followed up every 3 months for 1 year, every 6 months for 2 years, and then annually for 2 years.

Inclusion Criteria:

• STEP 1 - INDUCTION/RE-INDUCTION

• Patients must have morphologically confirmed newly diagnosed acute myelogenous leukemia (AML) with blood or bone marrow disease; patients with only extramedullary disease in the absence of bone marrow or blood involvement are not eligible; note: this protocol uses World Health Organization (WHO) diagnostic criteria for AML; patients with acute promyelocytic leukemia (APL, French-American-British [FAB], M3) or blastic transformation of chronic myelogenous leukemia (CML) are not eligible; patients with known core binding factor (CBF) or fms-like tyrosine kinase 3 (FLT3) related leukemias are eligible for this study, but should preferentially be placed on National Cancer Institute (NCI)-sponsored protocols specific for these subtypes, if available

• Patients must have diagnostic/pre-treatment specimens obtained within 28 days prior to registration submitted for cytogenetic (and fluorescent in situ hybridization [FISH] if possible) analysis to determine risk status; high risk classification will be defined as del(5q)/-5, del(7q)/-7, abn3q26 [inv(3)/t(3;3)], 11q23 rearrangement [except t(9;11)], 17p-, t(6;9), t(9;22), complex (at least 3 unrelated abnormalities [abn]), and monosomal karyotype (either loss of two different chromosomes or loss of one chromosome along with a structural chromosome abnormality other than add, ring and mar); karyograms and cytogenetics/FISH analysis reports must be submitted for discipline review

• Patients must be chemo-naïve, i.e., not have received any prior induction chemotherapy for AML or myelodysplastic syndrome (MDS); temporary prior measures such as apheresis or hydroxyurea are allowed; prior anthracycline therapy is allowed, but must not exceed a dose of 200 mg/m^2 daunorubicin or equivalent; prior all-trans retinoic acid (ATRA) for suspected APL is allowed; prior methotrexate for central nervous system (CNS) involvement is allowed; patients with prior history of MDS must not have received azacitidine, decitabine, lenalidomide or vorinostat

• Patients must have peripheral blood and bone marrow aspirate specimens obtained within 28 days prior to registration submitted for translational medicine; with patient consent, residuals will be banked for future research

• Patients must have Zubrod performance status =< 3

• Patients must have either echocardiogram (ECHO) or multi gated acquisition scan (MUGA) with ejection fraction >= 45% within 28 days prior to registration

• Patients must not have prolonged corrected QT (QTc) interval (> 500 msec) determined by electrocardiogram (EKG) within 28 days prior to registration

• Patients must not have cardiac disease defined as: New York Heart Association (NYHA) > class II; patients must not have unstable angina (angina symptoms at rest) or new onset angina (began within the last 3 months) or myocardial infarction within the past 6 months

• Patients must not have any coexisting medical condition that is likely to interfere with study procedures or results, and must be reasonable candidates for intensive chemotherapy, in the opinion of their treating physicians

• Patients who are known to be human immunodeficiency virus (HIV) positive (+) are eligible providing they meet all of the following additional criteria within 28 days prior to registration:

  • Cluster of differentiation (CD) 4 cells >= 500/mm^3
  • Viral load < 50 copies of HIV messenger ribonucleic acid (mRNA)/mm^3 if on combination antiretroviral therapy (cART) or < 25,000 copies of HIV mRNA if not on cART
  • No zidovudine or stavudine as part of cART; patients who are HIV+ and do not meet all of these criteria are not eligible for this study

• Patients with known hepatitis B or hepatitis C infection may be eligible providing they have viral load < 800,000 IU/mL within 28 days prior to registration

• Patients must be able to take oral medications

• Patients must have a history and physical examination obtained within 28 days prior to registration

• Patients must not be pregnant or nursing; women/men of reproductive potential must have agreed to use an effective contraceptive method; a woman is considered to be of "reproductive potential" if she has had menses at any time in the preceding 12 consecutive months; in addition to routine contraceptive methods, "effective contraception" also includes heterosexual celibacy and surgery intended to prevent pregnancy (or with a side-effect of pregnancy prevention) defined as a hysterectomy, bilateral oophorectomy or bilateral tubal ligation; however, if at any point a previously celibate patient chooses to become heterosexually active during the time period for use of contraceptive measures outlined in the protocol, he/she is responsible for beginning contraceptive measures

• Prior malignancy is allowed providing it does not require concurrent therapy; exception: active hormonal therapy is allowed

• Patients must not be receiving valproic acid

• All patients must be informed of the investigational nature of this study; patients or a legally authorized representative must sign and give written informed consent in accordance with institutional and federal guidelines

• As part of the Oncology Patient Enrollment Network (OPEN) registration process the treating institution's identity is provided in order to ensure that the current (within 365 days) date of institutional review board approval for this study has been entered in the system

• STEP 2 - CONSOLIDATION

• Patients may be registered for consolidation provided that they were eligible for the initial induction/re-induction registration and satisfy the following additional criteria:

  • Patients must have achieved morphologic remission (complete remission [CR] or complete remission with incomplete blood count recover [CRi]) after completion of induction or re-induction therapy; patient must remain in remission until beginning consolidation and this must be documented by bone marrow and peripheral blood examination within 28 days prior to registration to Step 2
  • All non-hematologic treatment related toxicities that are deemed clinically significant by the treating physician must have resolved to =< grade 2
  • Patients must not have received allogeneic stem cell transplant