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 progression-free 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. Clinical trial information: NCT01578707 and NCT01744691