A Phase I/II Study of Reduced Dose FCR (FCR-lite) in Combination with Lenalidomide Followed By Lenalidomide Maintenance (FCR2) for Initial Therapy of CLL: Final Results and Long-Term Follow-up

Introduction: Lenalidomide (Len) is an oral immunomodulatory agent with activity in CLL in both the front-line and relapsed settings. Recently Len has demonstrated significant improvements in PFS when studied as maintenance therapy following chemoimmunotherapy in the front-line and relapse settings (Fink, ASH 2016, Foa, ASH 2016) as well as in combination with R-fludarabine in the front-line setting (Rupert ASCO 2017, CALGB 10404). Here we present long-term follow-up of reduced-dose FCR (FCR-lite) in combination with Len followed by Len maintenance as a front-line CLL therapy. Methods: We conducted a phase 2 study (NCT 01723839) examining the combination of FCR-lite and Len ("FCR²") followed by Len maintenance for treatment naive, CLL pts requiring therapy. Eligible pts (age ≥18 yr, ECOG ≤ 2, CrCl ≥30 ml/min) were treated with 4-6 cycles of FCR² (D1-3 fludarabine 20 mg/m², D1-3 cyclophosphamide 150 mg/m², D1&15 rituximab 500 mg/m² every 28 days). Pts with del17p, del11q and/or unmutated IGHV were not excluded. Len was administered on D 8-28 of each cycle (starting dose of 5 mg increasing to 10-15 mg in cycle ≥ 2 based on toxicity). Pts who were MRD (-) in PB and BM (4 color flow cytometry) initiated Len maintenance after cycle 4, otherwise pts proceeded to 6 cycles FCR² followed by Len maintenance. Len maintenance started two months after FCR² completion in responding pts (≥ PR) for a total of 12 months (5-15 mg daily, dose based on toxicity). The primary study endpoint was the proportion of complete remissions (CR) after cycle 4 of FCR² (≥ 40% CR+CRi considered a positive result, α 0.05, β 90%). Secondary endpoints included MRD status, ORR, PFS, OS and toxicity profile. We report the final analysis of primary and secondary study endpoints. Results: 25 pts met inclusion criteria for enrollment of which 22 pts enrolled and 19 were evaluable (consent was withdrawn on 3 pts after ≤ 4 FCR cycles due to pt preference n=1, MD preference n=2, one additional pt withdrew consent after cycle 5 to proceed with SCT). Median baseline characteristics were as follows: age 62.5 yr (42-75 yr), ECOG PS 1 (0-2), WBC 115.4 x 109/L (8.7-301.7), Hb 12.2 g/dL (7.8-15.3), Plt 131 x 109/L (60-178), β2mg 2.8 μg/mL (1.74-6.69), LDH u/L 471 (132-1022), 30% pts had Rai stage III-IV, 53% unmutated IGHV, 5% del17p, 30% del11q. After 4 cycles of FCR (n=19) response rates were: ORR 94%, CR/CRi 52%, PR 42%, SD 5% (MRD (-) in 29% BM, 56% PB, 3 pts (16%) MRD (-) in PB and BM). After 6 cycles of FCR² (n=16), response rates were: ORR 95%, 76% CR/CRi, 19% PR, 5% PD (MRD (-) in 50% BM, 72% PB samples). During induction, 12 pts required a treatment interruption or dose reduction of Len (median Len dose = 10 mg) and the most common grade ≥3 toxicities were as follows (% events): neutropenia (51%), leukopenia (20%), hyperglycemia (5%), neutropenic fever (5%). Ten of 19 pts went on to receive Len maintenance (5 eligible pts withdrew consent, 3 pts were ineligible due to persistent cytopenias, 1 pt with PD). During maintenance, 8 pts required a treatment interruption or dose reduction of Len (median Len dose = 5mg, median number of monthly cycles = 12) and neutropenia was the only grade ≥ 3 toxicity (50%). With a median follow up of 39 months, median PFS was 43.8 months (figure 1). Median OS (figure 2) was not reached (one death recorded at the time of this analysis in allogeneic SCT patient in CR). One secondary malignancy has been recorded. Grade ≥ 3 TLS and tumor flare were not observed. Discussion: Len can safely be combined with FCR-lite in the front-line setting and subsequently administered as maintenance therapy for 1 year in a pt population that included high-risk CLL and advanced age. As compared to prior Len maintenance series, this series is unique in that it provides long-term follow-up period (nearly 40 months) assessing both efficacy and toxicity and addresses appropriate Len dose in combination and maintenance. Immunomodulatory agents, as a drug class, are active in CLL and should be further investigated in the management of patients with CLL. Disclosures Mato: Pharmacyclics: Research Funding; DTRM: Research Funding; Kite: Consultancy; Janssen: Consultancy; Portola: Research Funding; Gilead Sciences, Inc.: Membership on an entity9s Board of Directors or advisory committees; AstraZeneca: Consultancy; AbbVie: Consultancy, Research Funding; Celgene: Consultancy, Membership on an entity9s Board of Directors or advisory committees; Regeneron: Research Funding; TG Therapeutics: Membership on an entity9s Board of Directors or advisory committees, Research Funding; Acerta: Research Funding. Goy: Genentech: Research Funding; Pharmacyclics / JJ Seattle Genetics: Membership on an entity9s Board of Directors or advisory committees, Research Funding; Acerta: Consultancy, Honoraria, Membership on an entity9s Board of Directors or advisory committees; Takeda: Consultancy, Honoraria, Membership on an entity9s Board of Directors or advisory committees, Speakers Bureau; Celgene: Consultancy, Membership on an entity9s Board of Directors or advisory committees, Research Funding. Feldman: Bristol-Myers Squibb: Consultancy; Janssen: Speakers Bureau; Pharmacyclics: Speakers Bureau; Celgene: Speakers Bureau; Kite Pharma: Speakers Bureau; Seattle Genetics: Honoraria, Research Funding, Speakers Bureau; AbbVie: Speakers Bureau. Leslie: KITE pharma: Speakers Bureau; seattle genetics: Speakers Bureau; celgene: Speakers Bureau. Valentinetti: TG Therapeutics: Employment. Schuster: Gilead: Consultancy, Research Funding; Nordic Nanovector: Consultancy; Genentech: Consultancy, Research Funding; Janssen: Consultancy, Honoraria; Merck: Research Funding; Seattle Genetics: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Novartis: Consultancy, Research Funding. Svoboda: Kite: Consultancy; Merck: Research Funding; Celgene: Research Funding; Pharmacyclics: Research Funding; Seattle Genetics: Consultancy, Research Funding; BMS: Consultancy, Research Funding. Foon: Celgene: Employment. Skarbnik: Genentech: Speakers Bureau; Seattle Genetics: Speakers Bureau; Abbvie: Other: Ad board, Speakers Bureau; Gilead: Speakers Bureau; Novartis: Speakers Bureau.