Lenalidomide has been used as an immunomodulatory agent with good efficacy in the treatment of multiple myeloma. In recent years, it has also been found to have a role in CLL. At the 53rd Annual Meeting of the American Society of Hematology (ASH), there are more studies of lenalidomide for CLL and most of them have good efficacy, which deserve our attention. (1) Lenalidomide monotherapy The CC-5013-CLL-009 trial investigated the efficacy of different starting doses of lenalidomide monotherapy in relapsed refractory CLL, enrolling 60 patients with a median age of 63 (32-78) years, 56.6% of whom had received more than 3 treatments. 68% of the IGHV-unmutated group, 22% of the 11q-, 17% of the 17p-, and 42% of the ZAP70+. 29% of the IGHV-unmutated group were treated with lenalidomide. Twenty-nine patients completed a median of 6 courses of therapy with ORR 37.9%, CR: 3.4%, PR 34.5%, SD 48.3%, and PD 6.9%. The efficacy as monotherapy for relapsed refractory CLL is positive. (2) Lenalidomide in combination with monoclonal antibodies Rituximab, an antibody to CD20, has synergistic effects with lenalidomide without superimposed toxicity, so the combination of lenalidomide and rituximab for relapsed refractory CLL treatment may have a better prospect. scholars from MD Anderson Cancer Center reported the results of their trial. Of the 59 evaluable patients enrolled, all but one had received nucleoside analogs in combination with monoclonal antibodies, and 41% had received more than three treatments. Fludarabine-resistant patients accounted for 20%, IGHV-unmutated group for 73%, 11q- for 27%, and 17p- for 25%, resulting in an ORR of 66%, including 12% CR and 12% nPR, a median PFS of 17.4 months, and an OS of 75% at 36 months. Analysis of the subgroups revealed that fludarabine-resistant patients had a significantly lower response rate than sensitive patients (33% vs. 70%), while There were no significant differences between the other subgroups including cytogenetic subgroups, and in terms of toxicities, grade 3-4 toxicity was mainly hematological and infections. The study concluded that the combination of lenalidomide and rituximab for relapsed refractory CLL can achieve sustained remission and is effective in 17p- patients. The two-drug combination is feasible and safe and warrants further study. Ofatumumab, a fully humanized CD20 antibody, is also effective in relapsed CLL without cross-talk with lenalidomide. At this year’s ASH meeting, Ferrajoli A et al, also from MD Anderson Cancer Center, reported the results of a phase II clinical trial of the combination of the two for relapsed refractory CLL. Thirty-four evaluable patients, median age 62 years (34-82), all previously treated with FCR regimens, 12 (35%) of whom were fludarabine resistant, 22 (65%) in the IGHV-unmutated group, 9 (26%) in the 17p-, 4 (12%) in the 11q-, and 23 (68%) in the ZAP70+ group, were also high-risk refractory patients. The patients were treated for a median of 11 courses, resulting in 22 patients with a treatment response and an ORR of 65%, including 4 CR, 1 CRi and 17 PR. As for toxicities, grade 3-4 toxicities were all hematological, including granulomatous deficiency in 44%, thrombocytopenia in 9% and anemia in 3%. The trial results showed a high response rate and good tolerability of this regimen for relapsed refractory CLL after FCR application, and the treatment response lasted for more than 2 years in some patients. (3) Lenalidomide in combination with Flavopiridol Flavopiridol, a CDK kinase inhibitor, and the immunomodulator lenalidomide are both effective in CLL, and increasing doses of both can lead to tumor lysis syndrome (TLS) and tumor burning reactions. The combination of these two drugs has the potential to reduce toxicity and improve efficacy, as they do not cause T-cell deficiency. Thirty-one patients, median age 60 years (42-74), median of 3 prior regimens, all treated with fludarabine, 40% fludarabine-resistant, 75% Rai stage III-IV, 60% with large masses >5 cm, 60% with 17p-, 11q-37%, and 83% with complex karyotype were enrolled. Of the 23 evaluable patients, 13 (57%) achieved PR, including 7 patients with 17p-, 6 patients with 11q-, 9 patients with complex karyotypes, 5 patients with fludarabine refractory, 6 patients with large masses, and 6 patients with allogeneic transplantation after treatment. Median PFS and OS were 7 and 23 months, respectively. grade 3-4 toxicities included thrombocytopenia (60%), diarrhea (57%), transient transaminase elevation (47%), granulocyte deficiency (47%), hypertriglyceridemia (47%), infection (43%), hypokalemia (37%), anemia (33%), and hypophosphatemia (33%). The study concluded that the combination of lenalidomide and flavopiridol for CLL did not increase the risk of tumor lysis syndrome and tumor burning reaction, was effective in patients with large masses and high-risk cytogenetic types, and could be used for tumor load reduction therapy prior to transplantation. The treatment has a high incidence of grade 3-4 toxicities, but is acceptable considering the pre-treatment profile of this group of patients.