A Phase II Study of the Combination of FCR-Lite and Lenalidomide Followed By Lenalidomide Maintenance in Front-Line CLL: The FCR² Regimen

Introduction: Fludarabine, cyclophosphamide, rituximab (FCR) remains the standard of care for the treatment of newly diagnosed, fit CLL pts requiring therapy. However, the FCR side effects profile is non-trivial and CLL pts with poor risk features have inferior outcomes. Strategies aimed at minimizing toxicity without compromising efficacy have been reported including modifications of the optimal dosing and duration of FCR using a dose-reduced approach (Foon et al, “FCR lite”) or reduction in number of FCR cycles based on MRD status (Strati et al). In the era of biological agents, both preclinical and clinical data have shown the efficacy of lenalidomide (Len) in CLL likely through its role as an immunomodulator and interference with interactions between CLL and its microenvironment. In CLL, Len presents a clinical opportunity both in combination with chemotherapy and as maintenance strategy. This was the rationale for our trial using Len in combination with FCR and as maintenance to improve outcomes and shorten therapy.

Methods: We conducted a phase 2 cohort study examining the combination of dose-reduced FCR and Len (“FCR^2”) followed by Len maintenance for treatment naïve, CLL pts requiring therapy (NCIWG criteria). Eligible pts (age ≥18 yr, ECOG 0-2, CrCl ≥30 ml/min, absence of AIHA) 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). Len was administered on D 8-28 of each cycle (starting dose of 5 mg increasing to 10 mg and 15 mg in cycle ≥ 2 based on toxicity algorithm). Pts who were MRD (-) in PB and BM (multicolor flow cytometry) initiated Len maintenance after cycle 4 FCR² (otherwise proceeded to 6 cycles). Supportive care included asa 81 mg, pegfilgrastim, and antimicrobial prophylaxis (ciprofloxacin, bactrim, fluconazole, acyclovir). Daily Len maintenance started two months after FCR² completion in responding pts for a total of 12 months (5-15 mg based on toxicity algorithm). The primary study endpoint was the proportion of CR pts after cycle 4 of FCR² with ≥ 8/19 (≥ 40%) CR+CRi considered a positive result and worthy of further study (α 0.05, β 90%). Secondary endpoints included MRD status, ORR, OS, PFS and toxicity (CTCAE V. 4.0). We report the primary endpoint and preliminary data on non-survival secondary 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 FCR² cycles due to pt preference n=1, physician preference n=2, one additional pt withdrew consent after cycle 5 to proceed with Allo SCT.) Baseline characteristics expressed as median (range) 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), IgG 602 mg/dL (294-1018), β2mg 2.8 μg/mL (1.74-6.69), LDH u/L 471 (132-1022), BM % lymphs 75 (25-100%), baseline SPD 23.4 (2.9-63.5). In addition 30% pts had Rai stage III-IV, 53% unmutated-CLL, 5% del17p and 30% del11q. After 4 cycles of FCR² (n=19) response rates were as follows CR 47%, CRi 5%, PR 42%, SD 5% (pts were MRD neg in 29% BM and 56% PB samples, 3 pts (16%) were MRD neg in both PB and BM). After 6 cycles of FCR² (n=16), response rates improved and were as follows: 63% CR, 13% CRi, 19% PR, 5% PD (pts were MRD neg in 50% BM and 72% PB samples). Table 1 shows MRD status following 4 and 6 cycles of FCR². During induction, 12 pts required a treatment interruption or dose reduction of Len per protocol (median dose of len was 10 mg). The most common grade 3-4 toxicities were as follows (% events): neutropenia (51%), leukopenia (20%), hyperglycemia (5%), NTP fever (5%). Grade 3-4 TLS and tumor flare were not noted. The med follow up for the entire cohort is 13.1 months (7.3-22.5 months). One progression has occurred in a pt who withdrew from study after 2 cycle of FCR². One death has occurred in a pt with del17p who died on D+255 following allogeneic SCT in CR from the complications of cGVHD. 10 pts have gone on to initiate Len maintenance.

Conclusions: FCR-lite in combination with Len is feasible and demonstrates encouraging clinical activity in a high-risk, CLL pt population with an acceptable toxicity profile. A significant proportion of pts are MRD neg in PB and/or BM following FCR². Addition of Len to FCR may minimize chemotherapy exposure without compromising outcome.