This clinical trial will study ruxolitinib-based treatment of acute graft-versus-host-disease (GVHD) that developed following allogeneic hematopoietic cell transplant. Acute GVHD occurs when donor cells attack the healthy tissue of the body. The most common symptoms are skin rash, jaundice, nausea, vomiting, and/or diarrhea. The standard treatment for GVHD is high dose steroids such as prednisone or methylprednisolone, which suppresses the donor cells, but sometimes there can be either no response or the response does not last. In these cases, the GVHD can become dangerous or even life threatening. High dose steroid treatment can also cause serious complications. Researchers have developed a system, called the Minnesota risk system, to help predict how well the GVHD will respond to steroids based on the symptoms present at the time of diagnosis. The Minnesota risk system classifies patients with newly diagnosed acute GVHD into two groups with highly different responses to standard steroid treatment and long-term outcomes. This protocol maximizes efficiency because all patients with grade II-IV GVHD are eligible for screening and treatment is assigned according to patient risk. Patients with lower risk GVHD, Minnesota standard risk, have high response rates to steroid treatment. In this trial the researchers will test whether ruxolitinib alone is as effective (non-inferior) as steroid-free therapy and safe. Patients will be randomized to two different doses of ruxolitinib to identify the dose which maximizes efficacy while minimizing toxicities such as hematologic and infectious toxicities. Patients with higher risk GVHD, Minnesota high risk, have unacceptable outcomes with systemic corticosteroid treatment alone and the researchers will test whether adding ruxolitinib, a proven effective second line GVHD treatment, can improve outcomes when added to systemic corticosteroids as first line treatment.

Inclusion Criteria:

• Standard risk cohort: Minnesota standard risk GVHD (except patients with grade I [<50% BSA rash])
• High risk cohort: Minnesota high risk GVHD 3 GVHD that developed after DLI for mixed chimerism or poor graft function is allowed
• No prior systemic acute GVHD treatment. Topical or non-absorbed steroids are permitted.
• All donor types, HLA-matches, conditioning regimens, or GVHD prophylaxis strategies are acceptable
• ≥18 years of age
• Standard risk cohort: Hematopoietic engraftment with absolute neutrophil count (ANC) ≥ 1000/μL and platelet count ≥20,000. Use of growth factor supplementation and transfusions to maintain adequate hematologic parameters are allowed.
• High risk cohort: Hematopoietic engraftment with ANC ≥ 500/uL and platelet count ≥20,000. Use of growth factor supplementation and transfusions to maintain adequate hematologic parameters are allowed.

Exclusion Criteria:

• Systemic treatment with ruxolitinib or any other JAK inhibitor within 7 days of study entry
• Prior use of ruxolitinib to treat GVHD at any time
• Relapsed, progressing or persistent malignancy requiring withdrawal of systemic immunosuppression
• Relapse prior to development of GVHD unless subsequently in remission for at least 3 months
• GVHD that developed after DLI for relapse is not allowed without study PI or medical monitor approval
• Uncontrolled infection (i.e., progressive symptoms related to infection despite treatment or persistently positive microbiological cultures despite treatment or any other evidence of severe sepsis)
• Severe organ dysfunction within 3 days of enrollment including requirement for dialysis, mechanical ventilation, continuous BiPAP, or continuous high flow oxygen by nasal cannula, or total bilirubin ≥ 3x upper limit of normal not due to GVHD.
• A clinical presentation resembling de novo chronic GVHD or overlap syndrome developing before or present at the time of enrollment (except for mild oral or ocular GVHD)
• Corticosteroids >10 mg/day methylprednisolone (or other methylprednisolone equivalent, MPE) for any indication within 5 days before the onset of acute GVHD except for adrenal insufficiency or premedication for transfusions/IV meds
• Participation in clinical trials using experimental agents not approved by the FDA for any indication within 14 days of enrollment or five half-lives, whichever is longer provided any prior adverse events have improved to ≤grade 1
• Patients who are pregnant or nursing
• History of allergic reaction to ruxolitinib or any JAK inhibitor

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