Immunomodulatory Drugs (IMiDs) - Thalidomide and Lenalidomide
IMiDs being tested in clinical trials include thalidomide and its more potent derivative lenalidomide (Revlimid). The first generation molecule, thalidomide, has been largely replaced by a second generation molecule, lenalidomide (Revlimid). This lacks the neurotoxic effects of thalidomide. IMiDs drugs can promote killing of tumor cells by T cells and NK cells but also act through anti-angiogenic, anti-inflammatory and anti-proliferative mechanisms.
Lenalidomide is being examined in clinical trials to treat hematological cancers such as multiple myeloma, myelodysplastic syndrome (MDS) and lymphoma. In multiple myeloma, lenalidomide treatment can give result in improved survival. In some MDS patients lenalidomide has been reported to restore effective erythropoiesis (red blood cell production), extend survival and stop progression to acute myeloid leukemia (AML).
Lenalidomide/Thalidomide and Chronic Lymphocytic Leukemia
New therapies have notably improved the outlook of patients with chronic lymphocytic leukemia (CLL). However current therapies are not curative and almost all patients relapse at some point. Lenalidomide has been tested in CLL patients who have not responded to conventional treatment, or who have relapsed. Initial studies have shown promising responses and in a subset of CLL patients, complete responses have been seen.
However other studies have suggested that these drugs can also have serious, life-threatening side-effects including bone marrow toxicity, tumor flare and tumor lysis syndrome. Therefore, the optimal safe dose of lenalidomide in CLL requires further investigation. At present it is difficult to predict responses to lenalidomide from a patient’s biomarkers.
Lenalidomide/Thalidomide and Chronic Myelogenous Leukemia
The signaling molecule NF-kappaB can promote tumor cell survival. The NF-kappaB is known to be highly active in myelodysplastic syndrome (MDS), acute myeloid leukemia (AML), acute lymphocytic leukemia (ALL), chronic myeloid leukemia (CML), chronic lymphocytic leukemia (CLL), lymphoma and multiple myeloma (MM). NF-kappaB might therefore be a useful target for new treatments.
Several drugs effective in the treatment of myeloma, including thalidomide and lenalidomide block NF-kappaB activation. Therefore these drugs could possibly have potential in other leukemias such as AML and CML. Lenalidomide is being tested in the treatment of elderly AML patients in a clinical trial at Stanford University. However, there is at present no studies underway to explore the combination of thalidomide and chronic myelogenous leukemia patients.
Stanford University School of Medicine Website (Clinical Trials Directory) www.med.stanford.edu/clinicaltrials
Transcription Factor NF-kappa B Inhibitors as Single Therapeutic Agents or in Combination with Classical Chemotherapeutic Agents for the Treatment of Hematologic Malignancies by O.Fuchs. Current Molecular Pharmacology, July 2010.
Lenalidomide - a transforming therapeutic agent in myelodysplastic syndromes by A.List. Clinical Lymphoma and Myeloma. 2009, Vol 9, P302-4.
Thalidomide and lenalidomide as new therapeutics for the treatment of chronic lymphocytic leukemia, by F. Awan, A.Johnson, R.Lapalombella, W.Hu M.Lucas, B.Fischer & J.Byrd. Leukemia and Lymphoma 2010, Vol 51, P27-38.