Ruxolitinib Before, During and After Hematopoietic Cell Transplant in Older Patients With Myelofibrosis and Myelodysplastic Syndrome/Myeloproliferative Neoplasm Overlap Syndromes

Inclusion Criteria:

* PART 1 JAK INHIBITOR ADMINISTRATION: Age 18-75 years

  * Patients \> 75 must be considered an HCT candidate, meet all protocol criteria and have comorbidity score =\< 3 and Karnofsky performance status (KPS) \> or = to 90. Patients. \> 75 who do not meet these criteria may be presented at PCC for consensus exception
* PART 1 JAK INHIBITOR ADMINISTRATION: Disease criteria

  * Diagnosis of primary or secondary MF as defined by the 2022 World Health Organization classification system or the International Consensus Classification for Myeloid and Acute Leukemias
  * Diagnosis of an MDS/MPN overlap syndrome as defined by the 2022 World Health Organization
* PART 1 JAK INHIBITOR ADMINISTRATION: Ability to understand and the willingness to sign a written informed consent document
* PART 1 JAK INHIBITOR ADMINISTRATION: Patient must be a potential HCT candidate as assessed by the consenting physician
* PART 1 JAK INHIBITOR ADMINISTRATION: Patient must be agreeable to taking a JAK-inhibitor (ruxolitinib preferred) for at least 8 consecutive weeks immediately prior to conditioning and be willing to take ruxolitinib 5mg BID starting from day -4 prior to and continuing until 12 months post-transplant as tolerated followed by a 6-month taper.
* PART 2 ALLOGENEIC STEM CELL TRANSPLANT: Meeting criteria for Part 1 at time of initiation of JAK-inhibitor, including the ability to understand and willingness to sign a written informed consent. Patients arriving to our institution for HCT and not enrolled in Part 1 may still be enrolled in Part 2 if Part 1 criteria are met. These patients will have Part 1 endpoints transcribed from their medical records
* PART 2 ALLOGENEIC STEM CELL TRANSPLANT: Received a JAK-inhibitor for at least 8 weeks immediately prior to conditioning and be willing to take Rux from day -4 at the 5mg BID dose until 12 months post-transplant as tolerated followed by a 6 month taper
* PART 2 ALLOGENEIC STEM CELL TRANSPLANT: Performance status score

  * Karnofsky ≥ 70 or \> 90 for patients \> 75 years old
* PART 2 ALLOGENEIC STEM CELL TRANSPLANT: HCT-CI Score \< 8; if patient is \> 75 years old HCT-CI \< 3
* PART 2 ALLOGENEIC STEM CELL TRANSPLANT: Calculated creatinine clearance using the Cockcroft-Gault formula or 24-hour urine creatinine clearance must be \> 60 ml/min
* PART 2 ALLOGENEIC STEM CELL TRANSPLANT: Total serum bilirubin must be \< 3mg/dL unless the elevation is thought to be due to Gilbert's disease or hemolysis
* PART 2 ALLOGENEIC STEM CELL TRANSPLANT: Transaminases must be \< 3 x the upper limit of normal
* PART 2 ALLOGENEIC STEM CELL TRANSPLANT: Patients with clinical or laboratory evidence of liver disease will be evaluated for the cause of liver disease, its clinical severity in terms of liver function, and the degree of portal hypertension. Patients with fulminant liver failure, cirrhosis with evidence of portal hypertension or bridging fibrosis, alcoholic hepatitis, hepatic encephalopathy, or correctable hepatic synthetic dysfunction evidenced by prolongation of the prothrombin time, ascites related to portal hypertension, bacterial or fungal abscess, biliary obstruction, chronic viral hepatitis with total serum bilirubin \> 3mg/dL, and symptomatic biliary disease will be excluded
* PART 2 ALLOGENEIC STEM CELL TRANSPLANT: Diffusion capacity of lung for carbon monoxide (DLCO) corrected \> 60% normal. Patient may not be on oxygen
* PART 2 ALLOGENEIC STEM CELL TRANSPLANT: Left ventricular ejection fraction \> 40%
* DONOR: Human leukocyte antigen (HLA)-matched sibling donor
* DONOR: 10 of 10 HLA-matched unrelated donor
* DONOR: 9 of 10 allele or antigen mismatched unrelated donor
* DONOR: Peripheral blood is preferred over bone marrow
* DONOR: Matched unrelated donors may be preferred over siblings if the unrelated donor is \< 30 years and the sibling is \> 60 years. However, sibling donors \< 70 should be preferred over mismatched unrelated donors

Exclusion Criteria:

* PART 1 JAK INHIBITOR ADMINISTRATION: Contraindication to receiving ruxolitinib including patients who have known hypersensitivity to JAK inhibitors and excipients
* PART 1 JAK INHIBITOR ADMINISTRATION: History of prior allogeneic transplant
* PART 1 JAK INHIBITOR ADMINISTRATION: Leukemic transformation (\> 20% blasts)
* PART 1 JAK INHIBITOR ADMINISTRATION: Uncontrolled viral, bacterial, or fungal infection despite being on therapy
* PART 1 JAK INHIBITOR ADMINISTRATION: History of HIV infection
* PART 1 JAK INHIBITOR ADMINISTRATION: History of untreated tuberculosis (TB)
* PART 1 JAK INHIBITOR ADMINISTRATION: Pregnant or breastfeeding
* PART 1 JAK INHIBITOR ADMINISTRATION: Patients with history of myocardial infarction (MI), cerebrovascular accident (CVA) or unprovoked pulmonary embolism (PE)/deep vein thrombosis (DVT) in the past 6 months
* PART 1 JAK INHIBITOR ADMINISTRATION: Secondary malignancy in last 5 years with \> 20% risk of relapse
* PART 2 ALLOGENEIC STEM CELL TRANSPLANT: Contraindication to receiving ruxolitinib including patients who have known hypersensitivity to JAK inhibitors and excipients
* PART 2 ALLOGENEIC STEM CELL TRANSPLANT: History of prior allogeneic transplant
* PART 2 ALLOGENEIC STEM CELL TRANSPLANT: Leukemic transformation (\> 20% blasts)
* PART 2 ALLOGENEIC STEM CELL TRANSPLANT: Uncontrolled viral or bacterial infection at the time of transplant data review and consent conference
* PART 2 ALLOGENEIC STEM CELL TRANSPLANT: Active or recent (prior 6 month) invasive fungal infection without infectious disease (ID) consult and approval
* PART 2 ALLOGENEIC STEM CELL TRANSPLANT: History of HIV infection
* PART 2 ALLOGENEIC STEM CELL TRANSPLANT: History of untreated TB
* PART 2 ALLOGENEIC STEM CELL TRANSPLANT: Requiring supplemental oxygen
* PART 2 ALLOGENEIC STEM CELL TRANSPLANT: Pregnant or breastfeeding
* PART 2 ALLOGENEIC STEM CELL TRANSPLANT: Secondary malignancy in last 5 years with \> 20% risk of relapse
* PART 2 ALLOGENEIC STEM CELL TRANSPLANT: Patients with a history of MI, CVA, or unprovoked PE/DVT in the past 6 months
* PART 2 ALLOGENEIC STEM CELL TRANSPLANT: Patients without an HLA-identical sibling donor, 10 of 10 HLA-matched or 9 of 10 mismatched unrelated donor