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 (CLL), research is focused on developing fixed-duration strategies to improve long-term outcomes while sparing patients from serious toxicities. The ICLL-07 trial evaluated a fixed-duration (15-month) immunochemotherapy approach in which after 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 84 of 135 (62.2%) patients enrolled achieved CR with a BM MRD <0.01%. Here, we report follow-up at median 63 months. Peripheral blood (PB) MRD was assessed 6 monthly beyond the 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 the PB MRD status were apparent per 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.

Graphical abstract

Figure 1.

Longitudinal follow-up of PB MRD based on the arm. (A) I arm. (B) I-FCG arm. MRD is expressed as the percentage of evaluable patients, with MRD+ ≥0.01%, low-level positive MRD+ <0.01%, or undetectable MRD subdivided into mutually exclusive (not cumulative) categories depending on the LOD. Undetectable MRD was subdivided as follows: MRD4 for 10^-4 ≥ LOD >10^-5, MRD5 for 10^-5 ≥ LOD >10^-6, and MRD6 for LOD ≤10^-6. PB MRD was assessed until month 64. N above each bar represents the number of evaluable patients at that time point. ND, not determined.

Figure 2.

Longitudinal follow-up of PB MRD in the I-FCG arm, based on the IGHV mutational status. (A) IGHV-mutated status. (B) IGHV-unmutated status. MRD is expressed as percentage of evaluable patients, with MRD+ ≥0.01%, low-level positive MRD+ <0.01%, or undetectable MRD subdivided into mutually exclusive (not cumulative) categories depending on the LOD. Undetectable MRD was subdivided as follows: MRD4 for 10^-4 ≥ LOD >10^-5, MRD5 for 10^-5 ≥ LOD >10^-6, and MRD6 for LOD ≤10^-6. PB MRD was assessed until month 64. N above each bar represents the number of evaluable patients at that timepoint.

Figure 3.

Survival outcomes in the overall trial population from induction treatment start (n = 133 evaluable). (A) PFS (14 progression events). (B) OS (12 deaths). The dashed lines represent the CIs.