Inclusion Criteria:

* Age \>= 18 years
* History of MPN as defined by the 2016 World Health Organization criteria, with now pathologically confirmed \>= 5% blasts in the bone marrow or peripheral blood. Prior MPNs could include polycythemia vera, essential thrombocythemia, primary myelofibrosis, secondary myelofibrosis, MPN unclassifiable, MDS/MPN overlap
* Outside diagnostic material is acceptable as long as peripheral blood and/or bone marrow slides are reviewed at the study institution by pathology. Flow cytometric analysis of peripheral blood and/or bone marrow should be performed according to institutional practice guidelines
* Eastern Cooperative Oncology Group (ECOG) performance status 0-2 or Karnofsky \>= 60%
* Serum creatinine clearance \>= 50 ml/min calculated by the Cockcroft-Gault Equation (assessed within 14 days of study day 1)
* Total bilirubin =\< 3 unless due to Gilbert's disease or hemolysis (total bilirubin \> 3 is allowable if thought due to Gilbert's disease, hemolysis, or MPN disease) (assessed within 14 days of study day 1)
* Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) \< 3 x upper limit of normal (ULN) unless thought to be due to MPN disease process (AST/ALT \> 3 is allowable if thought due to MPN disease) (assessed within 14 days of study day 1)
* For patient receiving fedratinib, thiamine level should be above the laboratory lower limit of normal (\>= 70 nmol/L in the University of Washington \[UW\]/Seattle Cancer Care Alliance \[SCCA\] lab). If it is low, it may be repleted but should be rechecked and demonstrated to normalize prior to initiation of therapy
* Patient is considered a potential transplant candidate. The attending/treating physician will determine transplant candidacy at the time of consent
* The use of hydroxyurea prior to study registration is allowed. Patients with symptoms/signs of hyperleukocytosis, white blood count (WBC) \> 100,000/uL, or with concern for other complications of high tumor burden or leukostasis (e.g. hypoxia, disseminated intravascular coagulation) can be treated with leukapheresis or may receive up to 2 doses of cytarabine (up to 500 mg/m\^2 /dose) anytime prior to enrollment
* Capable of providing valid informed consent

Exclusion Criteria:

* Previous treatment with chemotherapy (e.g. hypomethylating agents or cytarabine-based regimens) for MPN with \>= 5% blasts in the blood or marrow. Prior temporary measures to control blood counts is allowed. Prior treatment with hydroxyurea, interferons or JAK inhibitor therapy is allowed
* Active systemic fungal, bacterial, viral, or other infection, unless disease is under treatment with anti-microbials and/or controlled or stable (e.g. if specific, effective therapy is not available/feasible or desired \[e.g. chronic viral hepatitis, human immunodeficiency virus (HIV)\])
* Known hypersensitivity to any study drug
* Females who are pregnant or breastfeeding
* Treatment with any other anti-MDS/leukemia investigational agent within 2 weeks of start of study drugs
* For patients planning to receive fedratinib: concurrent use of strong and moderate CYP3A4 inducers or dual CYP3A4 and CYP2C19 inhibitors that cannot be discontinued
* For patients planned to receive ruxolitinib AND platelets \< 50,000/mm\^2: concurrent use of a strong CYP3A4 inhibitor that cannot be discontinued
* For patients planned to receive pacritinib, corrected QT interval (QTc) > 480 msec (changing of medications/supplementing electrolytes is allowed to determine if this helps QTc reduce to < 480 msec)
* For patients planned to receive pacritinib, concurrent use of medications that are CYP1A2, CYP3A4, P-gp, BCRP, OCT1 substrates that cannot be discontinued