A Phase II Study of Lenalidomide in Previously Untreated, Symptomatic Chronic Lymphocytic Leukemia (CLL).

Introduction: Lenalidomide is an immunomodulatory compound known to downregulate VEGF and TNFa; stimulate production of inhibitory cytokines such as IL-2; and modulate activity of T cells and natural killer cells. These effects form the basis for investigation of lenalidomide in CLL. Promising results from 2 studies in relapsed/refractory CLL have been reported (Chanan-Khan et al J Clin Oncol 2006; Ferrajoli et al ASH 2006). To date, there are no reports using lenalidomide in previously untreated CLL. We present preliminary data on 12 patients (pts) enrolled in an ongoing phase II study of single-agent lenalidomide in previously untreated, symptomatic CLL.

Methods: Eligible pts must have histologically confirmed CLL; no prior therapy (excluding steroids alone for autoimmune cytopenias); and symptomatic disease (any of symptomatic adenopathy/organomegaly, cytopenias, constitutional symptoms, lymphocyte doubling count <12 mos). Starting dose for lenalidomide: 10mg daily with weekly 5mg dose escalations to the target dose of 25mg daily × 21 days every 28 day cycle. Prophylactic allopurinol and ASA are mandated. Steroids are allowed for management of tumor flare symptoms but routine prophylaxis is not used.

Results: In October 2006, accrual was initiated. Two pts were enrolled at the starting dose of 10mg daily. Pt 1 reached the target dose of 25 mg with a lymphocyte reduction from 152 to 25 but at 6 weeks developed acute tumor lysis with renal failure and was removed from study. Pt 2 developed grade 4 neutropenia on cycle 1 day 21 leading to a septic death. The study was halted and the protocol was revised with reduced starting and target doses (2.5mg and 10mg, days 1–21), slower dose escalations (2.5mg cycle 1, 5mg cycle 2, 10mg cycle 3 and thereon), and extension of allopurinol tumor lysis prophylaxis to minimum 3 cycles. Upon study reactivation in March 2007, 10 pts have been accrued. Median age 61(range 33–71), 5 pts with Rai stage III–IV, baseline median Hb 109g/L (range 80–158), platelets 180×10⁹/L (range 43–233), lymphocytes 70×10⁹/L (range 3.4–190), β2microglobulin 214 nmol/L (range 139–498; normal <170). Eight pts have received at least 1 cycle and are evaluable for toxicity. Hematologic toxicity: 5/8 pts developed Gr 3–4 neutropenia, leading to dose reductions in 3 pts and hospitalization for febrile neutropenia in 1 pt. Gr 4 thrombocytopenia developed at the 10mg dose in 1 pt. Nonhematologic toxicity: Gr 1–2 fatigue(5), tumor flare(4), non-desquamating rash(3), and infections(3) are most common. Tumor flare (painful, enlarged nodes often associated with nasal congestion/scalp pruritis) can occur with each dose escalation but is responsive to short course prednisone. No further episodes of tumor lysis have been noted.

Responses: Dramatic lymphocyte reductions at as early as 1 week are seen, with 6 of 8 pts (75%) achieving a partial response (PR), all by end of cycle 2 (using ≤5mg doses). Phosphoproteomic and microarray studies from blood samples at baseline and during treatment will be presented.

Conclusion: Preliminary data from this ongoing phase II study suggests that lenalidomide has significant activity in previously untreated CLL patients. Toxicities such as tumor lysis, tumor flare and myelosuppression are common and mandate a more conservative dosing regimen than previously used in relapsed/refractory CLL or myeloma. Responses seen at low doses (≤5mg daily) are encouraging.