This phase II trial studies efficacy of extracorporeal photopheresis and low dose aldesleukin (interleukin-2) in treating patients with chronic graft-versus-host disease (cGVHD) that does not respond to upfront treatment with steroids. In graft-vs-host disease, patients have a small quantity of a white blood cell called T regulatory cells or T-reg cells that helps to control the immune system. Extracorporeal photopheresis is a procedure where patient's blood is removed and treated with ultraviolet light and drugs that become active when exposed to light. The treated blood is then returned to the patient and may be effective in increasing T-reg cells in patients with cGVHD. Aldesleukin increases the activity and growth of white blood cells, and it has shown to enhance T-reg cells in patients with cGVHD and may be effective improving GVHD symptoms.

PRIMARY OBJECTIVES:

I. To evaluate the anti-cGVHD activity of extracorporeal photopheresis (ECP) when combined with low dose IL-2 (interleukin 2) (aldesleukin), in patients with steroid refractory cGVHD, as assessed by overall cGVHD response rate (complete response [CR]+partial response [PR]+stable disease [SD]).

SECONDARY OBJECTIVES:

I. Characterize and evaluate toxicities, including type, frequency, severity, attribution, time course and duration.

II. Estimate overall and failure-free survival, non-relapse mortality (NRM) and relapse, through 1 year after initiation of treatment.

III. Characterize chronic GVHD Symptom Scale scores -self-report (with assistance from register nurses [RNs] and medical doctors [MDs]).

IV. Assess the immunologic effects of low-dose daily subcutaneous (SC) IL-2 + ECP.

V. Correlate clinical endpoints of response with ECP performance parameters.

OUTLINE:

Patients receive aldesleukin subcutaneously (SC) daily for 12 weeks. Patients also undergo ECP twice weekly on weeks 1-4 and then receive 2 ECP treatments every 2 weeks on weeks 5-12. Patients responding to upfront therapy with aldesleukin and ECP have the option to continue combination therapy per the discretion of the treating physician until clinical benefit is maintained or toxicities develop.

After completion of study treatment, patients are followed up periodically.

Inclusion Criteria:

• Recipients of allogeneic stem cell transplantation with myeloablative or non-myeloablative conditioning regimens; alternative donor transplants (umbilical cord blood and haploidentical) are allowed
• Patients with chronic GVHD requiring systemic therapy are eligible
• Participants must have steroid-refractory cGVHD, which is defined as having persistent signs and symptoms of cGVHD despite the use of prednisone at 0.20 mg/kg/day (or 0.5 mg/kg every other day) for at least 4 weeks (or equivalent dosing of alternate corticosteroids) without complete resolution of signs and symptoms
• Karnofsky performance status of 70-100 %
• Estimated life expectancy greater than 3 months
• Women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control or abstinence) prior to study entry and for six months following duration of study participation; should a woman become pregnant or suspect that she is pregnant while participating on the trial, she should inform her treating physician immediately
• Stable dose of corticosteroids for 2 weeks prior to enrollment, i.e. the patient's steroid dose (mg/kg) will remain unchanged (eg 0.5 mg/kg) in the 2 weeks preceding enrollment; allowances will be made for up or down titrating the dose based on changes in body weight
• Total bilirubin < 2.0 mg/dl-exception permitted in patients with Gilbert's syndrome
• Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2 x upper limit of normal (ULN), unless hepatic dysfunction is a manifestation of presumed cGVHD
• Abnormal liver function tests (LFTs) in the context of active cGVHD involving other organ systems may also be permitted if the treating physician documents the LFTs as being consistent with hepatic cGVHD and a liver biopsy will not be mandated in this situation
• Serum creatinine within normal institutional limits or creatinine clearance > 60 mL/min/1.73 m^2 for participants with creatinine levels above institutional normal
• Absolute neutrophil count (ANC) > 1000/mm^3
• Platelets > 50,000/mm^3
• All subjects must have the ability to understand and the willingness to sign a written informed consent
• Patients with steroid refractory cGVHD typically have received salvage with multiple lines of therapy; hence in this trial there will be no restriction in terms of prior lines of therapy received; prior ECP exposure is allowed, however prior IL-2 use is excluded

Exclusion Criteria:

• Patients should not have any uncontrolled illness including ongoing or active infection; patients with an ongoing prednisone requirement of > 1 mg/kg/day (or equivalent) will be excluded
• History of thrombotic microangiopathy, hemolytic-uremic syndrome or thrombotic thrombocytopenic purpura
• Exposure to any new immunosuppressive medication in the 4 weeks prior to enrollment
• Donor lymphocyte infusion within 100 days prior to enrollment
• Active malignant relapse
• Uncontrolled cardiac angina or symptomatic congestive heart failure (New York Heart Association [NYHA] class III or IV)
• Human immunodeficiency virus (HIV)-positive individuals on combination antiretroviral therapy are ineligible
• Patients may not be receiving any other investigational agents, or concurrent parenteral biological, chemotherapy, or radiation therapy. Oral chemotherapeutic agents or biologics-for example ruxolitinib therapy (either past or current exposure)-is allowed
• History of allergic reactions attributed to compounds of similar chemical or biologic composition to IL-2
• Patients must not have received prior chemotherapy (pentostatin) within 4 weeks before study enrollment, and those who have not recovered from the adverse events due to agents administered more than 4 weeks earlier are excluded
• Pregnant women are excluded from this study; breastfeeding should be discontinued if the mother is treated with IL-2
• Patients with other active malignancies are ineligible for this study, other than superficial localized skin cancer (basal or squamous cell carcinoma)
• Subjects, who in the opinion of the investigator may not be able to comply with IL-2 or ECP treatment requirements or the safety monitoring requirements of the study, will be excluded from participation