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

Introduction: Although lenalidomide, as an immunomodulatory agent, has anti-tumor activity in CLL, its use in this disease is complicated by tumor lysis (TLS) and tumor flare (TF), especially when used frontline. From our experience using low-dose lenalidomide (10mg daily), TLS can be prevented but TF remains frequent and few CRs are achieved (Chen et al. 2010). The current trial tests the combination of lenalidomide and dexamethasone, aiming to enhance anti-tumor activity through synergy and mitigation of toxicities such as TF, enabling escalation to higher doses of lenalidomide. We hypothesized that higher doses of lenalidomide with dexamethasone, given over a finite 18 cycles, may achieve deeper and more durable responses, without requiring long term continuous treatment. Final analysis of 31 patients is presented.

Methods: Eligible patients had treatment-naïve, symptomatic CLL. The starting dose for lenalidomide was 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 ASA, sulfatrim for pneumocystis prophylaxis.

Results:

Demographics: 31 pts were enrolled: median age 59 yrs (range 40-84), male 21 pts (68%), Rai stage III-IV 18 pts (58%), median peripheral lymphocytes 185 x10⁹/L (range 9.3-509), β2M 4.1 mg/L (range 1.7-10.9); normal <3.2), bulky nodes 3 pts (10%), organomegaly 16 pts (52%). High risk features included: del17p/del11q on FISH in 6 pts (19%), ZAP70+ in 17 of 27 pts tested (63%) and unmutated IgVH in 16 of 26 pts tested (62%). All 31 pts received at least 1 cycle and were evaluable for toxicity and response.

Hematologic toxicity: 19pts (61%) developed Gr 3-4 neutropenia during at least 1 cycle; 6 pts (19%) developed febrile neutropenia. Nine pts (29%) developed Gr 3-4 thrombocytopenia, without bleeding. Gr 3-4 neutropenia occurred in 14% and Gr 3-4 thrombocytopenia in 5% of the 431 cycles administered to all patients. Nonhematologic toxicity: Most common toxicities (all grades) included: non-desquamating rash (64%), diarrhea (61%), insomnia (55%), fatigue (52%), and edema (51%). Infections (all grades) were frequent (25 pts; 80%) but Grade 3-4 infections developed in only 4 pts (13%), including pneumonia (3 pts), and bacteremia (1 pt). Other common grade 3-4 toxicities included rash (3 pts), tumor flare (3 pts), abdominal pain (2 pts), and fatigue (2 pts). In contrast to the high rate of TF from our previous single-agent lenalidomide trial (88%), TF was considerably less common (9 pts; 29%). No TLS was noted.

Dose modifications/study withdrawals: The median number of cycles received was 18 (range 1-18), with 58% completing protocol treatment. A median daily dose of 20mg (range 2.5-25mg) was reached. Dose reductions of lenalidomide were required in 14 pts (45%), most due to cytopenias. Reasons for early study discontinuation: toxicity (5 pts), patient withdrawal (5 pts), progressive disease (1 pt), and unrelated death (1 pt).

Efficacy: All 31 pts achieved stable disease (SD) or better on study. Overall response rate was 74%: 21 PR (68%), 8 SD (26%), 2 CR (6%). Responses were reached at a median of 3.7 mos (range 0.8-13.7), though best response was not achieved until median 5 mos (range 0.8-25). At a median follow-up of 26 mos, 9 pts have progressed, only one during the treatment period. Duration of response was prolonged with greater depth of response: CR 28.6 mos, PR 17.9 mos, SD 4.6 mos. Median PFS was 27.8 months (95%CI: 22.1%-NA). The median OS has not been reached.

Correlatives: Cereblon (CRBN) is a direct target of lenalidomide with expression required for anti-tumor activity. CRBN protein was detected by Western blot analysis in CD19-selected cells from screening blood samples of all 28 pts evaluated. Expression of CRBN substrates IKZF1 (Ikaros) and IKZF3 (Aiolos) pre and post-treatment and correlation with response and PFS are under evaluation and will be reported.

Conclusion: Final 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 approach facilitates dose escalation beyond the 10mg daily dose used in our previous single agent study and achieves durable responses, without continuing therapy until progression.