Lenalidomide Induces Complete and Partial Responses in Patients with Relapsed and Treatment-Refractory Chronic Lymphocytic Leukemia (CLL).
Authors: Ferrajoli Alessandra , O’Brien Susan M. , Faderl Stefan H. , Wierda William G. , Davis Dietrich , Lee Bang-Ning , Reuben James M. , Schlette Ellen J. , Kantarjian Hagop M. , Keating Michael J. 
Published: October 2019

Abstract
Lenalidomide is an immunomodulatory drug indicated as treatment for 5q-MDS and previously treated MM. Several of its properties, i.e. inhibition of TNF-α and VEGF, modulation of T-cell activity and impact on the microenvironment suggest that lenalidomide may play a role in the treatment of CLL. A pilot study by Chanan-Khan et al. has shown clinical activity in this disease (Blood 106: 447a). To further investigate the activity of lenalidomide in CLL, we conducted a phase II study. Patients (pts) were eligible if they had received at least one purine analog-based regimen. All pts received lenalidomide at 10 mg daily for 28 days followed by titration upward by 5 mg increments every 28 days to a maximum dose of 25 mg daily. De-escalation to 5 mg daily was allowed. The planned 35 pts have been enrolled. Twenty-two pts have received treatment for at least 3 months and are therefore evaluable for response. The median daily dose of lenalidomide at three months was 10 mg. The median age was 64 yrs (range 49–82), the median number of prior treatments was 4 (1–15), and the median β2M was 4.1 mg/dL (1.6–10.1). Twelve pts (55%) had Rai stage III or IV disease. Eight pts (36%) were refractory to fludarabine and 7 pts (32%) to alkylating agents. Responses according to NCI-WG criteria assessed after 3 months of treatment showed that 7 pts (32%) achieved a response [1 CR (5%), 1 nodular PR (5%), 5 PR (23%)]. Nine pts (41%) attained stable disease or clinical improvement and are continuing on treatment, and 6 pts (27%) progressed, including one early death that occurred on day 22 secondary to mucormycosis. A tumor flare reaction was observed in 6 pts (27%), fatigue was reported in 59% (G3 in 5%), nausea in 45%, pruritus in 31% and diarrhea in 22% (G 3 in 5%). Myelosuppression occurred in 55% of the pts (32% ≥G3 neutropenia and/or thrombocytopenia). Infectious complications were observed in 6 pts: 2 cases of neutropenic fever and 4 episodes of pneumonia. To decipher lenalidomide’s mechanism of action we measured plasma levels of tumor necrosis factor (TNF)-α, soluble TNF receptor 1 (TNF-R1), interferon (IFN)-γ, VEGF, bFGF, interleukin (IL)-1β, -2, -6, -8, -10, -12, IL-1 receptor antagonist (IL-1RA), and soluble IL-2 receptor (IL-2R) in 19 pts pre-treatment, on day 28, and after 3 months of therapy. We found a significant reduction in plasma VEGF level on day 28 in 4 pts that achieved a response [mean reduction of 55.6 (± 15.3) pg/mL, p = 0.036] and on day 90 in 4 pts with stable disease or clinical improvement [mean reduction of 50.9 (± 3.3) pg/mL, p = 0.003]. There were no changes in the levels of the other cytokines, including TNF-α. Further correlative studies include measurement of marrow vascularity, number of circulating T regulatory cells and CLL apoptotic rate. In conclusion, we found that lenalidomide is active in heavily pre-treated pts with relapsed CLL. Myelosuppression has been the most significant toxicity. Results of ongoing correlative studies will be presented.