CPX-351 Versus Immediate Stem Cell Transplantation for the Treatment of High-Grade Myeloid Cancers With Measurable Residual Disease

Inclusion Criteria:

* Acute myeloid leukemia (AML) other than acute promyelocytic leukemia (APL), myelodysplastic syndrome with excess blasts-2 (MDS-EB2), or another high-risk myeloid neoplasm (\>= 10% blasts in the blood or marrow), having completed at least one cycle of chemotherapy intended to induce remission
* Subjects must have MRD, defined as the presence of original disease detected by multi-parameter flow cytometry and cytogenetic/molecular assessment within 90 days of chemotherapy intended to induce remission:

  * Abnormal cells identified by multiparameter flow cytometry, present at a frequency of between 0% and 5% of total nucleated cells, judged in the opinion of the hematopathologist to represent continued presence of malignant cells
  * Abnormal karyotype; present in any number of metaphase cells
  * Abnormal fluorescence in-situ hybridization; judged in the opinion of the hematopathologist to represent continued presence of malignant cells
  * The presence of any leukemia associated mutation as detected by DNA sequencing, except mutations in DNMT3A, TET2 (tet methylcytosine dioxygenase 2), or ASXL1. This includes (but is not limited to) the following genes: CBL (CDS), CSF3R (colony stimulation factor 3 receptor; exons 14, 15, 17), EZH2 (exons 15-20), FBXW7 (CDS), FGFR1 (exons 4, 11-17, partial 18), FLT3 (FMS-like tyrosine kinase 3; p.D835H), GATA1 (exons 2-3), GATA2 (exons 3-5), HRAS (exon 1-2), IDH1 (isocitrate dehydrogenase NADP+ 1; p.R132), IDH2 (exon 4), JAK2 (Janus kinase 2; exon 12, 14, 16), KIT (8-18), KMT2A (CDS), KRAS (CDS), MAP2K1 (exons 2, 3, 6), MPL (exon 10), MYD88 (exon 3-5), NOTCH1 (exons 20, 26, 27), NPM1 (exon 12), NRAS (CDS), PDGFRA (exons 12-18), PHF6 (CDS), PTEN (CDS), RB1 (CDS), RUNX1 (exon 4-8), SF3B1 (exon 14-16), SRSF2 (exon 1), STAG2 (CDS), STAT3 (exons 20-21), TP53 (CDS), U2AF1 (exons 2, 6), WT1 (CDS), and ZRSR2 (CDS)
* Allowable prior therapy:

  * For the purposes of this study intensive chemotherapy will include regimens listed below. Additional regimens may be included at the discretion of the study principal investigator (PI)

    * Any regimen including cytarabine at a dose of 100 mg/m\^2/day for at least 7 days and an anthracycline at any dose +/- gemtuzumab ozogamicin (GO)
    * Any regimen including cytarabine at a dose of at least 100 mg/m\^2/day for at least 5 days and a purine analog at any dose (e.g. clofarabine, fludarabine, cladribine) +/- GO
* Ability to understand and voluntarily sign a written informed consent document (ICF)
* Absence of a concomitant illness with a likely survival of \< 1 year
* Medically fit, defined as a treatment related mortality score (TRM) of =\< 13.1 calculated according to Walter et al, Journal of Clinical Oncology (JCO) 2011
* Additionally, subjects should be eligible in the opinion of their treating physician for allogeneic transplantation
* Bilirubin =\< 2.5 x institutional upper limit of normal, unless elevation is thought to be due to Gilberts syndrome or hemolysis (within 14 days of study start \[unless otherwise noted\] to be enrolled in the study)
* Left ventricular ejection fraction \>= 40% assessed by multiple gated acquisition scan (MUGA), echocardiography or other appropriate diagnostic modality within 12 months of enrollment with no clinical evidence of decompensated congestive heart failure
* Creatinine clearance of \>= 30 mL/min as measured by Cockcroft Gault equation (within 14 days of study start \[unless otherwise noted\] to be enrolled in the study)
* Consent of female patients with a negative serum or urine pregnancy test to use a medically acceptable method of contraception throughout the entire study period and for 6 months following the last dose of CPX-351
* Male patients must be willing to refrain from sperm donation for 6 months following the last dose of CPX-351 and must use adequate contraception throughout the entire study period and for 6 months following the last dose of CPX-351
* Patients enrolling in this trial should intend to complete the treatments described and should be eligible in the opinion of the treating physician for allogeneic transplantation
* Patients must have a caregiver capable of providing post-HCT care, who will be present once conditioning therapy begins
* The informed consent document (ICF) must be signed and dated by the subject or by the subject's legally authorized representative if the subject is unable to sign

Exclusion Criteria:

* Allogeneic myeloablative hematopoietic cell transplant within 6 months
* Autologous hematopoietic cell transplant within 6 months
* Known Hypersensitivity to CPX-351

  * Patients may not have known hypersensitivity to CPX-351, daunorubicin, cytarabine, or liposomal products
* Prior treatment with two or more cycles of CPX-351
* Treatment within the last 30 days of other investigational antineoplastic agents
* Evidence of organ dysfunction likely to preclude safe transplantation including the following:

  * Symptomatic coronary artery disease or uncontrolled arrhythmia within the prior 3 months and since most recent anthracycline exposure
  * Myocardial impairment of any cause resulting in heart failure as determined by New York (NY) Heart Association Criteria (class III or IV)
  * Corrected diffusion capacity of the lung for carbon monoxide (DLCOc) \< 40% or forced expiratory volume in 1 second (FEV1) \< 50%
  * Need for supplemental oxygen
* Active systemic fungal, bacterial, viral or other infection, unless under treatment with anti-microbials and/or controlled or stable (e.g. if specific, effective therapy is not available/feasible or desired \[e.g. chronic viral hepatitis, human immunodeficiency virus (HIV)\])
* Female patients who are pregnant, nursing, or lactating
* Patients with an inability to accept blood transfusions
* Inability to give informed consent, or unable to comply with the treatment protocol including appropriate supportive care, follow-up and tests
* Any other condition that would cause a risk to patients if they participate in the trial