IMMUNOMODULATORY DERIVATIVES OF THALIDOMIDE (IMiDs)
Thalidomide is a sedative drug that was withdrawn from themarket in the 1960s because of its disastrous teratogenic effects when used during pregnancy. Nevertheless, it has significant immunomodulatory actions and is currently in active use or in clinical trials for over 40 different illnesses. Thalidomide inhibits angiogenesis and has anti-inflammatory and immunomodulatory effects. It inhibits tumor necrosis factor-alpha (TNF-α), reduces phagocytosis by neutrophils, increases production of IL-10, alters adhesion molecule expression, and enhances cell-mediated immu-nity via interactions with T cells. The complex actions of thalido-mide continue to be studied as its clinical use evolves. Owing to thalidomide’s serious toxicity profile, considerable effort has been expended in the development of analogs. Immunomodulatory derivatives of thalidomide are termed IMiDs. Some IMiDs are much more potent than thalidomide in regulating cytokines and affecting T-cell proliferation.
Thalidomide is currently used in the treatment of multiple myeloma at initial diagnosis and for relapsed-refractory disease. Patients generally show signs of response within 2–3 months of starting the drug, with response rates from 20% to 70%. When combined with dexamethasone, the response rates in myeloma are 90% or more in some studies. Many patients have durable responses—up to 12–18 months in refractory disease and even longer in some patients treated at diagnosis. The success of thali-domide in myeloma has led to numerous clinical trials in other diseases such as myelodysplastic syndrome, acute myelogenous leukemia, and graft-versus-host disease, as well as in solid tumors like colon cancer, renal cell carcinoma, melanoma, and prostatecancer, with variable results to date. Thalidomide has been used for many years in the treatment of some manifestations of leprosy and has been reintroduced in the USA for erythema nodosum leprosum; it is also useful in management of the skin manifesta-tions of lupus erythematosus.
The adverse effect profile of thalidomide is extensive. The most important toxicity is teratogenesis. Because of this effect, thalido-mide prescription and use are closely regulated by the manufac-turer. Other adverse effects of thalidomide include peripheral neuropathy, constipation, rash, fatigue, hypothyroidism, and increased risk of deep vein thrombosis. Thrombosis is sufficiently frequent, particularly in the hematologic malignancy population, that most patients are placed on some type of anticoagulant when thalidomide treatment is initiated. Lenalidomide is an IMiD that in animal and in vitro studies has been shown to be similar to thalidomide in action, but with less toxicity, especially teratoge-nicity. Lenalidomide was approved by the Food and Drug Administration (FDA) in late 2005 as a consequence of trials that showed its effectiveness in the treatment of the myelodysplastic syndrome with the chromosome 5q31 deletion. Clinical trials using lenalidomide to treat newly diagnosed as well as relapsed or refractory multiple myeloma showed similar efficacy, leading to FDA approval for myeloma as well. Its side effect profile is similar to that of thalidomide, although with less teratogenic effect and fewer thromboembolic events. Pomalidomide (CC4047) is another oral IMiD that is being investigated for the treatment of multiple myeloma and myelodysplasia. The only IMiD currently used as an immunosuppressive medication (ie, in transplant recipients) is thalidomide.