A fixed-duration immunochemotherapy approach in CLL: 5.5-year results from the phase 2 ICLL-07 FILO trial

Abstract

In previously untreated, medically fit patients with chronic lymphocytic leukemia, research is focused on developing fixed-duration strategies to improve long-term outcomes whilst sparing patients from serious toxicities. The ICLL-07 trial evaluated a fixed-duration (15-month) immunochemotherapy approach where, following obinutuzumab-ibrutinib induction for 9 months, patients (n=10) in complete remission (CR) with bone marrow (BM) measurable residual disease (MRD) <0.01% continued only ibrutinib 420 mg/day for 6 additional months (I arm), whereas the majority (n=115) received up to 4 cycles of fludarabine/cyclophosphamide-obinutuzumab 1000 mg alongside the ibrutinib (I-FCG arm). Primary analysis at month 16 showed that 62.2% (84/135) of all patients enrolled achieved CR with BM MRD <0.01%. Here we report follow-up at median 63 months. PB MRD was assessed 6 monthly beyond end of treatment using a highly-sensitive (10-6) flow cytometry technique. In the I-FCG arm, the PB MRD <0.01% rate (low-level positive <0.01% or undetectable with limit of detection ≤10-4) in evaluable patients was still 92.5% (74/80) at month 40 and 80.6% (50/62) at month 64. No differences in PB MRD status were apparent according to the IGHV mutational status. In the overall population, 4-year progression-free and overall survival rates were 95.5% and 96.2%, respectively. Twelve deaths occurred overall. Fourteen serious adverse events occurred beyond the end of treatment. Thus, our fixed-duration immunochemotherapy approach produced deep and sustained PB MRD responses, high survival rates, and low long-term toxicity. A randomized trial is needed to compare our immunochemotherapy approach with a chemotherapy-free strategy. This trial was registered at www.clinicaltrials.gov as #NCT02666898.

Five-year follow-up of a phase 2 study of ibrutinib plus fludarabine, cyclophosphamide, and rituximab as initial therapy in CLL

“… 21 The other study, reported by the French Innovative Leukemia Organization (FILO) group, used 9 months of ibrutinib plus obinutuzumab, followed by 4 cycles of fludarabine, cyclophosphamide, and obinutuzumab in CLL regardless of IGHV status. 22 Both studies demonstrated durable PFS (96%-98% at 3 or 4 years) and high rates of CR (60% in the MD Anderson study) or CR with BM-uMRD (62% in the FILO study). The FILO study also demonstrated that deep response was sustained, an 81% rate of PB-uMRD4 at 5 years.…”

“…To date, the rates of tMN are similar in our iFCR study (2.4% [2/85]; 5-year median follow-up), the study by Jain et al (2% [1/45]; 3-year median follow-up), 21 and the FILO study (2% [2/115]; 5-year median follow-up). 22 Likewise, a retrospective analysis of 3200 patients with CLL treated with FCR or fludarabine plus cyclophosphamide demonstrated no difference in the incidence of tMN in subgroups divided by ≤6 cycles of FCR. 26 Thus, the number of chemoimmunotherapy cycles added to ibrutinib may not be the most important factor contributing to tMN.…”