Treatment of IgG4-Related Disease With Revlimid and Rituximab

Immunoglobulin G subclass 4 Related Disease (IgG4-RD) is a recently recognized systemic fibroinflammatory condition. Various manifestations of IgG4-RD were previously recognized in individual organ systems, but these entities (including autoimmune pancreatitis, orbital pseudotumor, Reidel's thyroiditis, retroperitoneal fibrosis, idiopathic sialadenitis and dacryoadenitis, etc) are now recognized as manifestations of a common disease process that can affect any organ system. IgG4-RD is characterized by distinctive histologic findings of tissue infiltration by IgG4-positive plasma cells together with storiform fibrosis and obliterative phlebitis. Both clinical and pathologic consensus diagnostic criteria have been defined. Serum IgG4 concentration is a biomarker for IgG4-RD and is elevated in 70% to 90% of patients with active disease.

Inclusion criteria

• Diagnosis of active IgG4-RD based on standard pathologic or clinical criteria (see below) and requiring medical treatment
• Patient is:

• in relapse after prior steroid and/or rituximab (RTX) treatment or while tapering steroid treatment, OR
• has disease that is refractory to steroids, OR
• has contraindications to steroid therapy (including diabetes, mood disorder, obesity)
• Absolute neutrophil count >1500 and platelet count >/= 100,000
• Calculated creatinine clearance (or estimated GFR) greater than or equal to 60ml/min
• In patients without hepatobiliary involvement by IgG4-RD, total bilirubin less than or equal to 1.5 x upper limit of normal (ULN), aspartate aminotransferase (AST) (SGOT) and alanine aminotransferase (ALT) (SGPT) less than or equal to 3 x ULN
• Not pregnant or nursing
• All study participants must be registered into the mandatory Revlimid Risk Evaluation and Mitigation Strategy (REMS™) program, and be willing and able to comply with the requirements of the REMS™ program
• Females of reproductive potential must adhere to the scheduled pregnancy testing as required in the Revlimid REMS™ program
• Able to take aspirin (81 or 325 mg) daily as prophylactic anticoagulation (patients intolerant to acetylsalicylic acid (ASA) may use warfarin or low molecular weight heparin)
• Agrees to use acceptable methods of birth control during and for 12 months after completion of study drug therapy (applies to all men, and women of child bearing potential)
• Females must follow pregnancy testing requirements as outlined in the Revlimid REMS™ program

Exclusion criteria

• Predominant changes of fibrosis (as opposed to active cellular inflammation) within the organs affected by IgG4-RD, such that the likelihood of a disease response to treatment is low
• Presence of active infection that would interfere with therapy on this study, including positive serum hepatitis B surface antigen, HIV or active hepatitis C virus (HCV) infection, untreated syphilis or tuberculosis, clinical history of multiple herpes virus reactivations
• Known immunodeficiency state
• New York Heart Association Classification III or IV heart disease
• Active malignancy requiring therapy
• Receipt of a live vaccine within 4 weeks prior to initiating study drug therapy.
• Allergies: History of severe allergic reactions to human or chimeric monoclonal antibodies, murine protein, or lenalidomide
• Substance abuse: Drug or alcohol abuse that could interfere with participation in the trial according to the protocol
• Known anti-human anti-chimeric antibody formation
• Treatment with infliximab, adalimumab, or etanercept within the past 12 months.
• Currently taking azathioprine, 6-mercaptopurine, methotrexate, mycophenolate mofetil, or other conventional immunomodulators. Patients receiving these drugs must discontinue them prior to enrollment
• Other investigational medication within the previous one month