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

OUTLINE: Patients receive decitabine intravenously (IV) once daily (QD) over 1 hour on days 1-10, and either ruxolitinib orally (PO) twice daily (BID), fedratinib PO daily, or pacritinib PO BID on days 1-28. Treatment repeats every 28 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up for up to 5 years.

Arms

Experimental: Treatment (decitabine, ruxolitinib, fedratinib, pacritinib)

Patients receive decitabine IV QD over 1 hour on days 1-10, and either ruxolitinib PO BID, fedratinib PO daily, or pacritinib PO BID on days 1-28. Treatment repeats every 28 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity.

Interventions

Drug: - Decitabine

Given IV

Drug: - Ruxolitinib

Given PO

Drug: - Fedratinib

Given PO

Other: - Questionnaire Administration

Ancillary studies

Drug: - Pacritinib

Given PO