Testing the Addition of an Anti-cancer Drug, Lenalidomide, to the Usual Combination Chemotherapy Treatment ("EPOCH") for Adult T-Cell Leukemia-Lymphoma (ATLL)

Inclusion Criteria:

• Patients must have histologically or cytologically confirmed CD2+, CD3+, or CD4+acute, lymphoma or poor-risk chronic subtypes of ATLL including previously untreatedor previously treated individuals who have received no more than 1 previous cycle ofEPOCH, cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP), orcyclophosphamide, doxorubicin, vincristine, prednisone, and etoposide (CHOPE)

• Patients previously treated with azidothymidine (AZT), interferon (IFN), bexarotene,or mogamulizumab are eligible. Patients with stable disease at high risk of relapsefrom prior non-combination chemotherapy containing treatment are eligible toparticipate

• Documentation of HTLV infection by enzyme-linked immunosorbent assay (ELISA) inindividuals with confirmation of HTLV-1 infection (by immunoblot or polymerase chainreaction [PCR]) or a consistent clinical picture (including two of three of: 1) CD4+leukemia or lymphoma, 2) hypercalcemia, and/or 3) Japanese, Caribbean, or SouthAmerican birthplace) is required for enrollment. Confirmation of HTLV-1 infection isrequired to continue the subject on protocol after the first cycle of therapy.Patients will be enrolled based on reports from local or referral labs (e.g., MayoClinic or LabCorp). Confirmation will be performed by Ratner Lab at WashingtonUniversity, retrospectively, but this is not a Clinical Laboratory ImprovementAmendments (CLIA) assay and is not reimbursed by insurance

• Age ≥ 18 years

• Because no dosing or adverse event (AE) data are currently available on the useof lenalidomide in combination with EPOCH in patients < 18 years of age,children are excluded from this study, but will be eligible for futurepediatric trials

• Eastern Cooperative Oncology Group (ECOG) performance status =< 2 (Karnofsky >= 60%)

• Absolute neutrophil count >= 1,000/mm^3 unless decreased due to bone marrow (BM)involvement with lymphoma

• Platelets >= 100,000/mm^3 unless decreased due to BM involvement with lymphoma

• Total bilirubin =< 1.5 x institutional upper limit of normal (ULN), if potentiallydue to lymphoma, in the dose-expansion cohort, the first cycle may be given withoutlenalidomide and if transaminitis and bilirubinemia improves to meet parameters,participant may be enrolled

• Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2 x institutional ULN, if potentially due to lymphoma, in thedose-expansion cohort, the first cycle may be given without lenalidomide and iftransaminitis and bilirubinemia improve to meet parameters, participant may beenrolled

• Creatinine =< institutional ULN OR glomerular filtration rate (GFR) >= 60mL/min/1.73 m^2 for participants with creatinine levels above institutional normal

• Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviraltherapy with undetectable viral load within 6 months are eligible for this trial

• For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBVviral load must be undetectable on suppressive therapy, if indicated

• Patients with a history of hepatitis C virus (HCV) infection must have been treatedand cured. For patients with HCV infection who are currently on treatment, they areeligible if they have an undetectable HCV viral load

• Patients with treated brain metastases are eligible if follow-up brain imaging aftercentral nervous system (CNS)-directed therapy shows no evidence of progression

• Patients with new or progressive brain metastases (active brain metastases) orleptomeningeal disease are eligible if the treating physician determines thatimmediate CNS specific treatment is not required and is unlikely to be requiredduring the first cycle of therapy

• Patients with a prior or concurrent malignancy whose natural history or treatmentdoes not have the potential to interfere with the safety or efficacy assessment ofthe investigational regimen are eligible for this trial

• Patients with known history or current symptoms of cardiac disease, or history oftreatment with cardiotoxic agents, should have a clinical risk assessment of cardiacfunction using the New York Heart Association Functional Classification. To beeligible for this trial, patients should be class 2B or better

• Patients must have a life expectancy > 12 weeks

• Patients must have no serious active infection requiring therapy at the time ofstudy entry

• Patients must not require the concurrent use of chemotherapy, interferon,zidovudine, arsenic, radiation therapy, or other specific anti-tumor therapy, duringthe course of this study

• The effects of lenalidomide on the developing human fetus are unknown.Immunodulatory derivative (immunomodulatory imide drug [IMiD]) agents as well asother therapeutic agents used in this trial are known to be teratogenic. Females ofchild-bearing potential (FCBP) must have a negative serum or urine pregnancy testwith a sensitivity of at least 25 mIU/mL within 10-14 days prior to, and againwithin 24 hours of starting lenalidomide, and must either commit to continuedabstinence from heterosexual intercourse or begin two acceptable methods of birthcontrol, one highly effective method and one additional effective method at the sametime, at least 28 days before she starts taking lenalidomide. FCBP must also agreeto ongoing pregnancy testing. Men must agree to use a latex condom during sexualcontact with a FCBP even if they have had a successful vasectomy. All patients mustbe counselled at a minimum of every 28 days about pregnancy precautions and risk offetal exposure. Should a woman become pregnant or suspect she is pregnant while sheor her partner are participating in this study, she should inform her treatingphysician immediately. FCBP must use adequate contraception for at least 28 daysafter discontinuation from study. Men treated or enrolled on this protocol must alsoagree to use adequate contraception prior to the study, for the duration of studyparticipation, and for at least 28 days after discontinuation from study

• Ability to understand and the willingness to sign a written informed consentdocument. Participants with impaired decision-making capacity (IDMC) who have alegally-authorized representative (LAR) and/or family member available will also beeligible

Exclusion Criteria:

• Patients that have received prior IMiDs for treatment of ATLL

• Patients who have had chemotherapy or radiotherapy within 4 weeks (6 weeks fornitrosoureas or mitomycin C) prior to entering the study

• Patients who have not recovered to grade 1 or better from AEs due to prioranti-cancer therapy (not including cycle 1 of EPOCH, CHOP, or CHOPE if received offprotocol) within 14 days prior to enrollment, with the exception of alopecia

• Patients who are receiving any other investigational agents or have received themwithin 14 days prior to enrollment

• History of allergic reactions attributed to compounds of similar chemical orbiologic composition to lenalidomide or other agents used in study. Anaphylacticreactions including death have been reported with cyclophosphamide. Possiblecross-sensitivity with other alkylating agents can occur

• Patients unable to take aspirin or prophylactic doses of low molecular weightheparin or direct oral anticoagulants

• Patients with urinary outflow obstruction (contraindication for cyclophosphamide)

• Patients with any form of demyelinating disease should not be given vincristinesulfate injection

• Patients with uncontrolled intercurrent illness

• Patients with psychiatric illness/social situations that would limit compliance withstudy requirements

• Pregnant women are excluded from this study because lenalidomide is an IMiD agentwith the potential for teratogenic or abortifacient effects. Because there is anunknown but potential risk for adverse events in nursing infants secondary totreatment of the mother with lenalidomide, breastfeeding should be discontinued ifthe mother is treated with lenalidomide. These potential risks may also apply toother agents used in this study