Prognostic role of beta-2 microglobulin (B2M) in relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL) patients (pts) treated with ibrutinib (ibr)

Background: B2M is often elevated in pts with CLL and correlates with disease stage and burden. Normalization of B2M at 6 mo during ibr treatment was associated with improved progressionfree survival (PFS) (Thompson et al 2016). We evaluated B2M changes over time, factors associated with B2M normalization, and correlations between B2M status and PFS in pts with R/R CLL treated with ibr. Methods: Data were pooled from 2 clinical trials of single‐agent ibr (420 mg/d) in pts with R/R CLL. Pts in RESONATE were randomized 1:1 to ibr or ofatumumab. All pts in RESONATE‐ 17 received ibr. Univariate (UVA) and multivariate (MVA) analyses were used to examine baseline (BL) factors associated with B2M normalization. PFS from time of the 6‐mo B2M visit was compared based on B2M status; exploratory analyses evaluated PFS by 9‐, 12‐, and 15‐mo B2M status. Results: In the combined ibr population (N = 339), BL elevated B2M (79% ≥3.5 mg/L; median 5.4 mg/L), del17p (61%), and unmutated IGHV (58%) were common; 15% had del11q, and 25% had creatinine clearance (CrCl) < 60 mL/min. Pts had a median of 2 prior lines of therapy. Median B2M decreased rapidly, by ∼40% at 3 mo, in all patients. Overall, 50% of pts normalized B2M during ibr. Median time to B2M normalization was 17 mo and was non‐significantly shorter for pts with del17p vs without del17p (14 vs 26 mo; P= 0.220). In UVA, BL B2M < 3.5 mg/L, age < 65 y, and CrCl ≥60 mL/min were significantly (P≤0.0002) associated with B2M normalization at 6 mo, while del17p was not significant. In MVA, BL B2M < 3.5 mg/L (P= 0.0002) and CrCl ≥60 mL/min (P= 0.034) were significant factors. PFS did not differ when assessed by 6‐mo B2M normalization status (HR 0.699 [95% CI 0.452, 1.080]; P= 0.105), nor by 12‐ or 15‐mo B2M status, but was significantly different by 9‐mo B2M status (HR 0.579 [95% CI 0.366, 0.915]; P= 0.018); median PFS was not reached in either group. For B2M normalization at 9 mo, CrCl was significant in MVA, but age and BL B2M were not. Conclusions: Pts treated with ibr had a rapid decrease in median B2M regardless of BL parameters. BL B2M < 3.5 mg/L and CrCl ≥60 mL/min were associated with B2M normalization at 6 mo in MVA. B2M normalization status at 9, but not 6, mo predicted PFS.