This phase II trial studies how well ruxolitinib phosphate works in treating patients with diffuse large B-cell or peripheral T-cell non-Hodgkin lymphoma that has returned (relapsed) or that does not respond to treatment (refractory) after donor stem cell transplant. Ruxolitinib phosphate may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth.

PRIMARY OBJECTIVES:

I. Assess the overall response rate (ORR) of subjects with relapsed diffuse large B-cell lymphoma (DLBCL) and peripheral T-cell lymphoma (PTCL) who are relapsed or refractory to front-line treatment and ineligible for stem cell transplantation or have recurrent disease after stem cell transplantation to oral ruxolitinib (ruxolitinib phosphate).

SECONDARY OBJECTIVES:

I. Evaluate safety of oral ruxolitinib in subjects with DLBCL and PTCL. II. Determine progression-free survival (PFS), duration of response, and overall response (OS) in subjects with DLBCL and PTCL.

TERTIARY OBJECTIVES:

I. Explore the relationship between responses to oral ruxolitinib and alterations in gene expression profiling (GEP) signatures as well as biomarker immunophenotypic changes related to JAK2/STAT3, NF-kB, PI3K/AKT, and mTOR pathways.

II. Evaluate potential effect of oral ruxolitinib exposure on JAK2/STAT3 pathway inhibition in serial tumor samples.

OUTLINE:

Patients receive ruxolitinib phosphate orally (PO) twice daily (BID) on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 3 months for 1 year and then every 6 months thereafter.

Inclusion Criteria:

• Subjects must have histologically documented relapsed or refractory disease, with a diagnosis of one of the following lymphoid malignancies: diffuse large B-cell lymphoma, peripheral T-cell lymphoma (any subtype); subjects must have received at least one prior systemic chemotherapy and must have either received an autologous stem cell transplant, refused or been deemed ineligible for an autologous stem cell transplant
• Subjects must be willing and able to have a fresh tumor biopsy prior to start of study treatment for research evaluations and cohort categorizing; Note: if insufficient fresh tissue is obtained to provide sub-classification for cohorts, then tissue material from a previous relapse biopsy and/or original diagnostic block may be requested to meet this criterion
• Subjects must have measurable lesions (at least one target lesion measuring 2 cm in diameter) by computerized tomography (CT) scan, and/or measurable lymphoma cutaneous lesions of any size
• Eastern Cooperative Oncology Group (ECOG) performance status 0-2
• Absolute neutrophil count (ANC) >= 1,000/mm^3
• Platelet count >= 75,000/mm^3
• Hemoglobin >= 8.0 g/dL
• Serum creatinine =< 2.0 g/dL or calculated creatinine clearance >= 60 mL/min (Cockcroft-Gault method)
• Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 2.5 x institutional upper limit of normal (ULN) or =< 5 x ULN if liver involved by lymphoma
• Bilirubin < 2.0 x ULN unless subject has Gilbert's disease, low-grade hemolysis, or liver involvement with lymphoma
• At least 2 weeks since prior chemotherapy, biological therapy, radiation therapy, major surgery, other investigational, or anti-cancer therapy that is considered disease-directed and recovered from prior toxicities to grade 0-1 at least 2 weeks prior to investigational therapy
• Females will be either postmenopausal for at least 1 year or surgically sterile for at least 3 months; OR females of child-bearing potential must have a negative pregnancy test at screening and agree to take appropriate precautions to avoid pregnancy from screening until 3 months after their last dose of study medication
• Males must agree to take appropriate precautions to avoid fathering a child from screening until 3 months after their last dose of study medication
• Able to comprehend and willing to sign an informed consent form (ICF)

Exclusion Criteria:

• History of or active central nervous system (CNS) malignancy
• Allogeneic stem cell transplant within the last 6 months, or active-graft-versus-host disease following allogeneic transplant, or subjects currently on immunosuppressive therapy following allogeneic transplant
• Uncontrolled intercurrent illness including, but not limited to, ongoing active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situation that would limit compliance with study requirements as judged by treating physician; subjects receiving antibiotics that are under control may be included in the study
• Pregnant or breastfeeding women
• Clinically symptomatic and uncontrolled cardiovascular disease
• History of myocardial infarction, severe/unstable angina, or symptomatic congestive heart failure, within the 6 months prior to study drug administration
• Current or recent history (< 21 days prior to start of treatment) of a clinically significant bacterial, viral, fungal, parasitic or mycobacterial infection
• History of other malignancy, with the exception of squamous cell carcinoma of the skin, basal cell carcinoma of the skin, cervical intraepithelial neoplasia, or other malignancies that have been in remission for at least 3 years
• Presence of a malabsorption syndrome possibly affecting drug absorption (e.g., Crohn's disease or chronic pancreatitis)
• Any prior or concomitant use of another JAK inhibitor
• Known active hepatitis B or C, or human immunodeficiency virus (HIV) infection
• Subjects who, in the opinion of the investigator, are unable or unlikely to comply with the dosing schedule and study evaluations