An Open-Label Phase 2 Study of Lenalidomide in Combination with Oral Dexamethasone in the Previously Untreated, Symptomatic Patients with Chronic Lymphocytic Leukemia (CLL).

Abstract Abstract 2895 Introduction: Lenalidomide is an immunomodulatory agent with promising anti-tumor activity in CLL. The use of lenalidomide in this disease, however, can be complicated by tumor lysis syndrome (TLS) and frequent tumor flare (TF). From our experience using low-dose lenalidomide (starting dose 2.5mg, titrating to a target of 10mg daily), TLS can be prevented but TF remains frequent (Chen et al. JCO 2010). In addition, when using low-dose single-agent lenalidomide, few complete responses (CR) are achieved. We therefore proposed the combination of lenalidomide and pulse dexamethasone, aiming to enhance anti-tumor activity through both synergy and mitigation of toxicities such as TF, enabling escalation to higher doses of lenalidomide. Our previous observation of “rebound” peripheral lymphocytosis when using intermittent dosing of lenalidomide led to the current use of continuous daily dosing. We present an interim analysis of the initial 18 of 31 planned pts in this ongoing trial of lenalidomide and dexamethasone as first-line CLL therapy. Methods: Eligible pts were previously untreated with symptomatic CLL (cytopenias, symptomatic adenopathy/organomegaly, constitutional symptoms, lymphocyte doubling count <12 mos). The starting dose for lenalidomide is 5mg daily continuously, with 5mg escalations every 28 days to a maximum of 25 mg, and dexamethasone 12 mg daily orally days 1–7, 14, 21 of each 28 day cycle, both to a maximum of 18 cycles. Supportive measures: allopurinol for TLS prophylaxis, DVT prophylaxis with low dose ASA, sulfatrim for PJP prophyaxis. Results: Demographics: To date, 18 pts have been enrolled: median age 61 yrs (range 40–84), male 13 pts (72%), Rai stage III-IV 13 pts (72%), baseline median Hb 98g/L (range 77–137), absolute lymphocytes 194.5 ×109/L (range 9.3–469.9), ß2M 319 nmol/L (range 253–813; normal <170), bulky nodes 15 pts (83%), organomegaly 9 pts (50%), del17p/del11q on FISH 3 pts (17%), ZAP70+ 12 pts (67%) and unmutated IgVH in 9 of 17 pts tested (53%). Seventeen pts have received at least 1 cycle and are evaluable for toxicity and response. The median number of cycles received is 8 (range 1–18). Hematologic toxicity: 9 pts (53%) have developed Gr 3–4 neutropenia during at least 1 cycle; 4 pts (24%) febrile neutropenia; 6 pts (35%) have required GCSF support. Only 2 pts (12%) have developed Gr 3–4 thrombocytopenia, without bleeding. Nonhematologic toxicity: Non-desquamating rash (65%), fatigue (59%), diarrhea (53%), cough (53%), insomnia (47%), and constipation (47%), are common (most grade 1–2). Grade 3–4 toxicities include: atrial fibrillation with pulmonary embolism (1 pt), fatigue (2 pts), insomnia (1 pt), skin rash (1 pt), diarrhea (1 pt), muscle weakness (1 pt), infection (1 pt). Infections are frequent (all grades in 50% of pts, grade 3 in 6%), primarily affecting upper airway/lungs. One pt developed H1N1 influenzae, complicated by aspergillus pneumonia and multiorgan failure. In contrast to the high rate of TF from our previous single-agent lenalidomide trial (88%), TF is considerably less common in the current trial (5 pts; 29%). No TLS has been noted. Dose modifications/study withdrawals: The maximum 25mg dose has been achieved in 4 pts, with a median tolerated daily dose of 15 mg (range 2.5–25 mg). Grade 3–4 neutropenia is the most common cause of dose interruptions/reductions. Responses: All 17 pts have achieved stable disease (SD) or better with overall responses 59%: 9 PR (53%), 7 SD (41%), 1 CR (6%). Responses were reached at a median of 4 months (range 1.8–9.6). No patients have progressed to date. Correlatives: Recent studies have identified cereblon (CRBN) as a direct target of lenalidomide with expression required for anti-tumor activity. CRBN protein was detected by Western blot analysis in CD19-selected cells derived from screening blood samples of all 17 pts evaluated to date and correlation with response is ongoing. Conclusion: Preliminary results from this phase 2 study suggests that lenalidomide plus dexamethasone has significant activity in previously untreated CLL, is generally well-tolerated, and dramatically reduces the incidence of TF symptoms. This may facilitate dose escalation beyond the 10mg daily dose used in our previous single agent study and lead to higher quality responses. Rebound lymphocytosis has not been noted with continuous dosing. Response data are encouraging but whether this combination can achieve durable CR is forthcoming. Disclosures: Chen: Celgene: Honoraria, Research Funding; Lundbeck: Consultancy; GlaxoSmithKline: Research Funding; Janssen: Consultancy, Research Funding. Off Label Use: Lenalidomide is not approved for use in chronic lymphocytic leukemia. Johnston:Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Trudel:Celgene: Honoraria, Research Funding, Speakers Bureau.

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