In this study we plan to assess the safety and tolerability of the combination of dexamethasone, and lenalidomide (D+L) in patients with relapsed or refractory CLL, a subgroup with limited treatment options. Lenalidomide offers an alternative way of treating CLL. In a Phase 1 safety and pharmacokinetics study (study 1398/180) in healthy male volunteers, it was demonstrated that lenalidomide administered at a dose of 100 mg twice a day for 6 days had an acceptable safety profile with grade 1-2 rash and pruritus being the primary adverse events associated with the administration of the compound. In myeloma and MDS, lenalidomide has been studied mostly at two doses: 25 mg/day and 10 mg/day. In CLL significant toxicity was observed with these two dose levels, including tumour lysis syndrome and tumour flare.47,48 We therefore plan to start therapy with lenalidomide at a relatively low dose of 5mg/day, days 1-28, with cycle 1 and escalate to the maximum dose of 10mg/day with cycles 2-12. We have elected to administer lenalidomide continuously as opposed to pulsing over 14-21 days of each cycle to reduce the risk of tumour flare reaction (TFR), when this agent is reintroduced with each cycle. Finally, lenalidomide will be administered in combination with Dexamethasone, at a dose of 20mg/day for 4 days in each 28 day cycle as this allows convenient oral administration. We and others have demonstrated that Dexamethasone level is effective in CLL patients who are refractory or have relapsed following primary Fludarabine therapy. The combination of D+L will likely reduce toxicity, especially TFR, whilst improving overall efficacy without promoting the emergence of chemoresistant clones in which tumour suppressor genes have been inactivated.