Testing the Addition of an Anti-cancer Drug, Lenalidomide, to the Usual Combination Chemotherapy Treatment ("EPOCH") for Adult T-Cell Leukemia-Lymphoma (ATL)
Testing the Addition of an Anti-cancer Drug, Lenalidomide, to the Usual Combination Chemotherapy Treatment ("EPOCH") for Adult T-Cell Leukemia-Lymphoma (ATL)
This phase I trial studies the side effects and best dose of lenalidomide when given together
 with usual combination chemotherapy (etoposide, prednisone, vincristine sulfate [Oncovin],
 cyclophosphamide, and doxorubicin hydrochloride [hydroxydaunorubicin hydrochloride], or
 "EPOCH") in treating adult T-cell leukemia-lymphoma. Lenalidomide may help shrink or slow the
 growth of adult T-cell leukemia-lymphoma. Drugs used in chemotherapy, such as etoposide,
 vincristine, cyclophosphamide, and doxorubicin, work in different ways to stop the growth of
 cancer cells, either by killing the cells, by stopping them from dividing, or by stopping
 them from spreading. Anti-inflammatory drugs such as prednisone lower the body's immune
 response and are used with other drugs in the treatment of some types of cancer. Giving
 lenalidomide and the usual combination chemotherapy may work better in treating adult T-cell
 leukemia-lymphoma compared to the usual combination chemotherapy alone.
PRIMARY OBJECTIVE:

 I. To determine the safest and most tolerable dose and schedule of lenalidomide to combine
 with etoposide, prednisone, vincristine sulfate (Oncovin), cyclophosphamide, and doxorubicin
 hydrochloride (hydroxydaunorubicin hydrochloride) (EPOCH) chemotherapy in adult T-cell
 leukemia-lymphoma (ATL/ATLL).

 SECONDARY OBJECTIVES:

 I. To observe and record anti-tumor activity. II. To determine if lenalidomide and EPOCH
 activity results in significant improvement in remission rates and duration of remissions as
 compared to historical controls.

 III. To determine if lenalidomide and EPOCH activity correlates with T-cell receptor (TCR)
 pathway gene mutational spectrum.

 IV. To determine effects of lenalidomide and EPOCH on human T-cell leukemia virus type 1
 (HTLV-1) proviral deoxyribonucleic acid (DNA) and ribonucleic acid (RNA) loads.

 V. To determine effects of lenalidomide and EPOCH on HTLV-1 clonality.

 OUTLINE: This is a dose-escalation study of lenalidomide.

 INDUCTION THERAPY: Patients receive lenalidomide orally (PO) once daily (QD) on days 1-14 of
 21 day cycles or days 1-21 or 1-28 of 28 day cycles. Patients also receive doxorubicin
 hydrochloride intravenously (IV) continuously on days 1-4, vincristine sulfate IV
 continuously on days 1-4, etoposide IV continuously on days 1-4, prednisone PO on days 1-5,
 and cyclophosphamide IV over 1-4 hours on day 5. Treatment repeats every 21 or 28 days for up
 to 4 cycles in the absence of disease progression or unacceptable toxicity.

 MAINTENANCE THERAPY: Patients with complete response (CR), partial response (PR), or stable
 disease (SD) may receive up to 2 additional cycles of lenalidomide, doxorubicin
 hydrochloride, vincristine sulfate, etoposide, prednisone, and cyclophosphamide at the
 discretion of the investigator and/or up to an additional 2 years of lenalidomide in the
 absence of disease progression or unacceptable toxicity.

 After completion of study treatment, patients are followed up for 2 years.
Inclusion Criteria:

 -  Patients must have histologically or cytologically confirmed CD2+, CD3+, or CD4+
 acute, lymphoma or poor-risk chronic subtypes of ATLL including previously untreated
 or previously treated individuals who have received no more than 1 previous cycle of
 combination chemotherapy. If the patient has a cycle of EPOCH prior to entering on the
 study, doses of EPOCH during the first cycle with lenalidomide should be altered as
 described for cycle 2 EPOCH modifications below

 -  For patients who receive a cycle of EPOCH prior to enrollment on the protocol,
 cycle 2 (the first cycle on protocol) dose of EPOCH is altered according to
 toxicities in cycle 1

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

 -  Documentation of HTLV infection by enzyme-linked immunosorbent assay (ELISA) in
 individuals with confirmation of HTLV-1 infection (by immunoblot or polymerase chain
 reaction [PCR]) or a consistent clinical picture (including two of three of: 1) CD4+
 leukemia or lymphoma, 2) hypercalcemia, and/or 3) Japanese, Caribbean, or South
 American birthplace) is required for enrollment. Confirmation of HTLV-1 infection is
 required 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., Mayo
 Clinic or LabCorp). Confirmation will be performed by Ratner Lab at Washington
 University, retrospectively, but this is not a Clinical Laboratory Improvement
 Amendments (CLIA) assay and is not reimbursed by insurance

 -  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 >= 75,000/mm^3 unless decreased due to BM involvement with lymphoma

 -  Total bilirubin =< 1.5 x institutional upper limit of normal (ULN), if potentially due
 to lymphoma, in the dose-expansion cohort, the first cycle may be given without
 lenalidomide 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 the dose-expansion
 cohort, the first cycle may be given without lenalidomide and if transaminitis and
 bilirubinemia improve to meet parameters, participant may be enrolled

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

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

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

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

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

 -  Patients with new or progressive brain metastases (active brain metastases) or
 leptomeningeal disease are eligible if the treating physician determines that
 immediate CNS specific treatment is not required and is unlikely to be required during
 the first cycle of therapy

 -  Patients with a prior or concurrent malignancy whose natural history or treatment does
 not have the potential to interfere with the safety or efficacy assessment of the
 investigational regimen are eligible for this trial

 -  Patients with known history or current symptoms of cardiac disease, or history of
 treatment with cardiotoxic agents, should have a clinical risk assessment of cardiac
 function using the New York Heart Association Functional Classification. To be
 eligible 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 of study
 entry

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

 -  The effects of lenalidomide on the developing human fetus are unknown. Immunodulatory
 derivative (immunomodulatory imide drug [IMiD]) agents as well as other therapeutic
 agents used in this trial are known to be teratogenic. Females of child-bearing
 potential (FCBP) must have a negative serum or urine pregnancy test with a sensitivity
 of at least 25 mIU/mL within 10-14 days prior to, and again within 24 hours of
 starting lenalidomide, and must either commit to continued abstinence from
 heterosexual intercourse or begin two acceptable methods of birth control, one highly
 effective method and one additional effective method at the same time, at least 28
 days before she starts taking lenalidomide. FCBP must also agree to ongoing pregnancy
 testing. Men must agree to use a latex condom during sexual contact with a FCBP even
 if they have had a successful vasectomy. All patients must be counselled at a minimum
 of every 28 days about pregnancy precautions and risk of fetal exposure. Should a
 woman become pregnant or suspect she is pregnant while she or her partner are
 participating in this study, she should inform her treating physician immediately.
 FCBP must use adequate contraception for at least 28 days after discontinuation from
 study. Men treated or enrolled on this protocol must also agree to use adequate
 contraception prior to the study, for the duration of study participation, and for at
 least 28 days after discontinuation from study

 -  Ability to understand and the willingness to sign a written informed consent document.
 Participants with impaired decision-making capacity (IDMC) who have a
 legally-authorized representative (LAR) and/or family member available will also be
 eligible

 Exclusion Criteria:

 -  Patients that have received prior IMiDs for treatment of ATLL

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

 -  Patients who have not recovered from adverse events (AEs) due to prior anti-cancer
 therapy (i.e., have residual toxicities > grade 1) within 14 days prior to enrollment,
 with the exception of alopecia

 -  Patients who are receiving any other investigational agents or have received them
 within 14 days prior to enrollment

 -  History of allergic reactions attributed to compounds of similar chemical or biologic
 composition to lenalidomide or other agents used in study. Anaphylactic reactions
 including death have been reported with cyclophosphamide. Possible cross-sensitivity
 with other alkylating agents can occur

 -  Patients unable to take aspirin or prophylactic doses of low molecular weight heparin
 or direct oral anticoagulants will not be eligible for maintenance treatment with
 lenalidomide, but may enroll and receive induction therapy with lenalidomide plus
 EPOCH

 -  Patients with urinary outflow obstruction (contraindication for cyclophosphamide)

 -  Patients with any form of demyelinating disease should not be given vincristine
 sulfate injection

 -  Patients with uncontrolled intercurrent illness

 -  Patients with psychiatric illness/social situations that would limit compliance with
 study requirements

 -  Pregnant women are excluded from this study because lenalidomide is an IMiD agent with
 the potential for teratogenic or abortifacient effects. Because there is an unknown
 but potential risk for adverse events in nursing infants secondary to treatment of the
 mother with lenalidomide, breastfeeding should be discontinued if the mother is
 treated with lenalidomide. These potential risks may also apply to other agents used
 in this study