Leflunomide for the Treatment of Relapsed or Refractory CD30+ Lymphoproliferative Disorders

This trial studies how well leflunomide works for the treatment of patients with CD30+ lymphoproliferative disorders that have come back (relapsed) or do not respond to treatment (refractory). Leflunomide may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth.

PRIMARY OBJECTIVE:

I. To evaluate overall response rate of leflunomide treatment.

SECONDARY OBJECTIVES:

I. To assess complete response rate and duration of response of leflunomide treatment.

II. To assess toxicities of leflunomide treatment. III. To assess disease status by the CAILS (composite assessment of index lesion severity).

EXPLORATORY OBJECTIVE:

I. To generate a preliminary ribonucleic acid (RNA) signature associated with response of CD30+ lymphoproliferative disorders (LYPDs) cells to leflunomide.

OUTLINE:

Patients receive leflunomide orally (PO) once daily (QD) on days 1-28. Treatment repeats every 28 days for up to 13 cycles in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 3 months for 12 months.

Eligibility Criteria:
Inclusion Criteria:

* Documented informed consent of the participant and/or legally authorized representative

  * Assent, when appropriate, will be obtained per institutional guidelines
* Patients must have a life expectancy of \> 3 months
* Eastern Cooperative Oncology Group (ECOG) =\< 2
* Patients must have a diagnosis of cutaneous CD30+ LYPD
* Patients must be relapsed or are refractory to at least 1 prior line of therapy
* At least 2 weeks from prior therapy to time of start of treatment. Prior therapy includes steroids (except prednisone or equivalent - up to 10 mg/day is allowed)
* Absolute neutrophil count (ANC) \>= 1000/mm\^3 (within 21 days prior to day 1 of protocol therapy). NOTE: Growth factor is not permitted within 14 days of ANC assessment unless cytopenia is secondary to disease involvement
* Platelets \>= 50,000/mm\^3 (within 21 days prior to day 1 of protocol therapy). NOTE: Platelet transfusions are not permitted within 14 days of platelet assessment unless cytopenia is secondary to disease involvement
* Total bilirubin =\< 1.5 X upper limit of normal (ULN) (unless has Gilbert's disease) (within 21 days prior to day 1 of protocol therapy)
* Aspartate aminotransferase (AST) =\< 2.0 x ULN (within 21 days prior to Day 1 of protocol therapy)
* Alanine aminotransferase (ALT) =\< 2.0 x ULN (within 21 days prior to day 1 of protocol therapy)
* Creatinine clearance of \>= 30 mL/min per 24 hour urine test or the Cockcroft-Gault formula (within 21 days prior to day 1 of protocol therapy)
* Seronegative for human immunodeficiency virus (HIV) antigen (Ag)/antibody (Ab) combo, hepatitis C virus (HCV), active hepatitis B virus (HBV) (surface antigen negative) (within 21 days prior to day 1 of protocol therapy)

  * If positive, hepatitis C RNA quantitation must be performed
* Meets other institutional and federal requirements for infectious disease titer requirements. Note infectious disease testing to be performed within 28 days prior to day 1 of protocol therapy
* Negative for tuberculosis antigen (e.g. T-Spot test)
* Women of childbearing potential (WOCBP): negative urine or serum pregnancy test (within 21 days prior to day 1 of protocol therapy). If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required
* Agreement by females and males of childbearing potential\* to use an effective method of birth control (hormonal or barrier method of birth control or abstinence) or abstain from heterosexual activity for the course of the study through at least three months after the last dose of protocol therapy. The effects of study treatment on a developing fetus have the potential for teratogenic or abortifacient effects. Should a woman become pregnant or suspect that she is pregnant while participating on the trial, she should inform her treating physician immediately

  * Childbearing potential defined as not being surgically sterilized (men and women) or have not been free from menses for \> 2 years (women only)

Exclusion Criteria:

* Current or planned use of other investigational agents, or concurrent biological, chemotherapy, or radiation therapy during the study treatment period
* Current or planned growth factor or transfusion support. If growth factor or transfusion support is provided between screening and start of treatment, the participant will no longer be eligible
* Prior allogeneic transplant
* Acute active infection requiring systemic therapy within 2 weeks prior to enrollment
* Known history of hepatitis B or hepatitis C infection
* Known HIV infection
* History of allergic reactions attributed to compounds of similar chemical or biologic composition to leflunomide or cholestyramine
* Non-hematologic malignancy within the past 3 years aside from the following exceptions:

  * Adequately treated basal cell or squamous cell skin cancer
  * Carcinoma in situ of the cervix
  * Prostate cancer \< Gleason grade 6 with a stable prostate specific antigen (PSA)
  * Successfully treated in situ carcinoma of the breast
* Clinically significant medical disease or condition that, in the investigator's opinion, may interfere with protocol adherence or the patient's ability to give informed consent
* Pregnant women and women who are lactating. Leflunomide has potential for teratogenic or abortifacient effects. Because there is a potential risk for adverse events in nursing infants secondary to treatment of the mother with these agents, breastfeeding should be discontinued if the mother is enrolled on this study
* Any other condition that would, in the investigator's judgment, contraindicate the patient's participation in the clinical study due to safety concerns or compliance with clinical study procedures, e.g., infection/inflammation, intestinal obstruction, unable to swallow medication, social/ psychological issues, etc
* Prospective participants who, in the opinion of the investigator, may not be able to comply with all study procedures (including compliance issues related to feasibility/logistics)