Long‐term follow‐up of a phase 2 trial of single agent lenalidomide in previously untreated patients with chronic lymphocytic leukaemia

Lenalidomide has emerged as an active agent for the treatment of chronic lymphocytic leukaemia (CLL) and is currently under investigation in novel combinations. Early experience with single-agent lenalidomide in CLL identified unexpected toxicities, such as tumour flare (TF) and tumour lysis (Chanan-Khan et al, 2006; Ferrajoli et al, 2008; Badoux et al, 2011; Chen et al, 2011; Wendtner et al, 2012). As a result, lowered daily doses of lenalidomide (median 5–15 mg) were used, achieving moderate overall response rates (ORRs) of 11·5–65%, with few complete responses (CR). In our phase 2 study of single agent lenalidomide in 25 untreated CLL patients (Chen et al, 2011), we reported an ORR of 56%, stable disease (SD) 40% and no CR. Toxicities, such as TF (88%) and grade 3–4 neutropenia (72%) were common. We have now extended our follow-up from a median of 20·7 to 53·2 months, evaluating the prolonged use of single agent lenalidomide and focusing on optimal dosing, efficacy and cumulative toxicity. Trial design, eligibility and study treatment have been described previously (Chen et al 2011). Briefly, 25 previously untreated patients with symptomatic B cell CLL were enrolled in this single arm phase 2 trial. The original study protocol used a starting lenalidomide dose of 10 mg daily for 21 d of a 28-d cycle, escalating weekly by 5 mg to a target of 25 mg daily. Tumour lysis and grade 4 cytopenia/sepsis toxicities reported with the first two enrolled patients led us to decrease the starting dose to 2·5 mg daily, with dose escalations every 4 weeks. A lowered target daily dose of 10 mg was implemented, although dose escalation to 25 mg was permitted to optimize response. Patients continued lenalidomide until progression. In our updated analysis, median follow-up from the start of study drug was 53·2 months (range 6·3–66·7 months) with a median of 34 cycles (range, 2–71 cycles) administered to all 25 patients. Thirteen patients have discontinued lenalidomide to date due to treatment-related toxicity (n = 8), lack of response/progressive disease (n = 4), and recurrence of lung cancer (n = 1). Twelve patients have remained on therapy for at least 12 cycles, with a median number of 62 cycles received (range 52–71). Seven patients were able to tolerate dose-escalation to the maximum 25 mg daily dose but the median dose sustained was only 15 mg (range, 2·5–25 mg). Long-term use of lenalidomide did not appear to lead to cumulative toxicities, particularly myelosuppression. Although grade 3–4 neutropenia and thrombocytopenia were common in our study (76% and 28% of all patients, respectively), most events occurred in the first year of therapy, after which the rate of recurrence fell dramatically (Fig 1). Only three patients discontinued therapy due to cytopenias, all early within the first four cycles of therapy, and not due to cumulative myelosuppression. The most common non-haematological toxicities (all grades) were TF (88%), fatigue (76%), rash (60%), muscle cramping (40%) and diarrhoea (40%). TF was mild (all grade 1–2) but using our intermittent dosing schedule of lenalidomide, cyclical recurrence of TF symptoms was noted in 15% of all cycles, occurring as late as cycle 28. Prolonged exposure to lenalidomide did not appear to predispose to opportunistic infections (only one disseminated zoster) and infections were generally mild (mostly upper respiratory/skin). Furthermore, there did not appear to be an increased risk of secondary cancers with long-term lenalidomide use. With a median follow-up of over 4 years, we observed only two patients with non-invasive squamous cell carcinoma of the skin and one patient with recurrent lung cancer almost 8 years after resection. With relatively short follow-up, previous front-line trials of single agent lenalidomide in CLL reported moderate efficacy (ORR 11·5–65%; CR 0–10%). With follow-up extended from 20·7 months originally to 53·2 months in this update, we report that prolonged lenalidomide improved ORR from 56% to 72%, with five patients upgrading from partial response to CR (20%). The median time to best response was 18·1 months (range up to 63·4), significantly longer than the 7·7 months required for first response. Though dose escalation to 25 mg was allowed to optimize response, CR in the five patients was achieved even at doses as low as 5 mg. Hence, escalation to maximum doses may not be necessary to achieve high quality responses and aiming for a tolerable, sustainable lower dose may be preferable. Our 3-year progression-free survival (64·6%) and overall survival (85·3%) are comparable to survival outcomes reported with first-line FCR (fludarabine, cyclophosphamide, rituximab), widely considered the standard of care for fit patients with CLL (Hallek et al, 2010). The median duration of response for all 25 patients was 40·4 months. Of the eight patients with high-risk fluorescence in situ hybridization cytogenetics (deletions 17p/11q), six responded (two CR), with a median response duration for all eight patients of 35·9 months (range 34·2–64·6 months). Therefore, durable responses with single agent lenalidomide can be achieved, even in those with high-risk disease. Recent studies have identified cereblon (CRBN) as a direct physical target of the immunomodulatory drug (IMiD) compounds (Ito et al, 2010). CRBN expression is reportedly required for IMiD activity and its downregulation has been postulated as a mechanism of resistance to lenalidomide (Zhu et al, 2011; Lopez-Girona et al., 2012). Gene-expression profiling (GEP) for days 1 (pre-dosing) and 8 (post-dosing) of cycles 1 and 2, was performed on CD19 selected cells derived from 22 of the 25 patients in our study. In this patient set, the CRBN gene was uniformly expressed regardless of lenalidomide response, and expression was not modulated with therapy as confirmed by Western blot analysis (Fig 2). Therefore, unlike in myeloma, CRBN expression pretreatment does not appear to be a predictive biomarker of primary lenalidomide resistance in untreated CLL. In conclusion, our long-term follow-up of patients receiving single-agent lenalidomide suggests that high quality, durable responses can be achieved even with low doses, but requires prolonged therapy. Prolonged therapy does not predispose to cumulative toxicity and appears feasible in this patient population. Lessons learned from our experience may be exploited to direct future trial designs using low dose, sustained treatment and provides rationale for the use of lenalidomide as maintenance therapy in CLL. Research support from Celgene Corporation and Ontario Cancer Institute for Cancer Research. CIC designed the research, contributed patients, analysed data and wrote the paper. HP, TW, ND, LWL, AL analysed data and wrote the paper. VK contributed patients and wrote the paper. ENW and PLB performed correlative studies, analysed data and wrote the paper. ST performed correlative studies, analysed data, designed research and wrote the paper. CIC, VK and ST have received research funding and honoraria from Celgene. PLB has a consultant/advisory relationship with Onyx.

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