Inclusion Criteria:
* Patients must have histologically or cytologically confirmed LCH, ECD or HS. Confirmation of outside pathology at BWH will be performed but is not mandatory prior to study enrollment (see section 3).
* Detectable disease by at least one of the following modalities: CT, PET, bone scan, or MRI.
* Patients with LCH must require systemic therapy according to the Histiocyte Society LCH Evaluation and Treatment Guidelines (HS 2009)
\-- Or
* Patients with HS requiring systemic treatment as defined by disease that cannot be surgically resected and/or encompassed in a single radiation field.
* Age 18 years or older.
* ECOG performance status ≤2 (Karnofsky ≥60%, see Appendix A)
* Participants must have normal organ and marrow function as defined below:
* absolute neutrophil count ≥1,000/mcL
* platelets ≥100,000/mcL
* total bilirubin within 1.5 times normal institutional limits
* AST(SGOT)/ALT(SGPT) ≤3 × institutional upper limit of normal
* creatinine within 2 times normal institutional limits
\--- OR
* creatinine clearance ≥30 mL/min/1.73 m2. Note, dose adjustments are required for CrCl ≥30 mL/min but ≤60 ml/min.
* Able to take aspirin 81 mg daily as prophylactic anticoagulation if not on warfarin, low molecular weight heparin or oral factor Xa inhibitor. Patients intolerant to ASA may use warfarin or low molecular weight heparin at doses designed to treat deep venous thrombosis.
* All study participants must be registered into the mandatory Revlimid REMS® program, and be willing and able to comply with the requirements of the REMS® program.
* Women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation.
* Ability to understand and the willingness to sign a written informed consent document.
Exclusion Criteria:
* Prior chemotherapy or radiation within 2 weeks (6 weeks for nitrosoureas or mitomycin C) prior to entering the study or those who have not recovered from adverse events due to agents administered more than 2 weeks earlier.
* Participants who are receiving any other investigational agents.
* Prior treatment with lenalidomide. Patients previously treated with thalidomide who discontinued treatment for reasons aside from an adverse reaction to thalidomide are permitted.
* History of another invasive malignancy unless treated with curative intent 5 years or more prior to study entry. Patients with localized carcinoma of the cervix, non-melanoma skin cancer, or early stage prostate cancer requiring observation only are eligible regardless of timing of diagnosis.
* Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements.
* Pregnant women are excluded from this study because lenalidomide has known teratogenic 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.
* Known active hepatitis B (HBV) or hepatitis C (HCV) infection. Patients who are positive only for HBV surface antibody as a result of prior vaccination are eligible. Patients with a positive HBV core antibody but undetectable HBV viral load are eligible.
* HIV-positive participants on combination antiretroviral therapy are ineligible because of the potential for pharmacokinetic interactions with lenalidomide. In addition, these participants are at increased risk of lethal infections when treated with marrow-suppressive therapy. Appropriate studies will be undertaken in participants receiving combination antiretroviral therapy when indicated.
* Concomitant corticosteroids unless patient has been on a stable dose of prednisone (or equivalent) of ≤10 mg daily for at least 2 weeks prior to first dose of study drug.
* Inability to swallow pills.
