Ibrutinib and acalabrutinib ± obinutuzumab are preferred first-line therapy options for all patients including in high-risk subgroups such as those with del(11q) or del(17p)/TP53 mutation and unmutated IGHV.

Pts were randomized 1:1, stratified by IGHV mutation and del(11q) status, to I+V (3 cycles ibrutinib 420 mg/d, followed by 12 cycles I+V with venetoclax... At 3 mo after end of treatment (EOT+3), rate of uMRD was significantly higher for I+V vs Clb+O in BM (51.9% vs 17.1%; p < 0.0001) and peripheral blood (PB; 54.7% vs 39.0%; p = 0.0259).

Overall, this integrated analysis of data with up to 6 years of long-term follow-up demonstrates that using single-agent ibrutinib in earlier lines of treatment results in better PFS, OS, and ORR with sustained efficacy for patients with CLL, including patients with high-risk prognostic features. During this extended follow-up, only 6% of patients treated in the first-line setting discontinued due to progressive disease. Ibrutinib was well tolerated with only 19% of patients across all lines of therapy discontinuing due to AEs.

At 42 months a significantly higher proportion of ibrutinib-treated patients with deletion(17p)/TP53 mutations, deletion(11q), or unmutated IGHV were progression-free compared to patients with these genomic features who were treated with chlorambucil (Figure).

...- Del11q22.3 ataxia telangiectasia mutated (ATM) as detected by FISH...

...- At least one high-risk cytogenetic feature defined by the presence of 17p deletion, 11q deletion and/or p53 mutation...

Among patients who experienced disease progression on ibrutinib treatment (n = 19), 11 (57.9%) patients carried del(17p)/TP53 mutation, 4 (23.5%) patients had del(11q), and 3 (27.3%) patients harbored unmutated IGHV.

Patients with high-risk prognostic features were defined as having TP53 mutation, del(11q), and/or unmutated IGHV....For patients with high-risk prognostic features, median PFS was NR for first-line or 1-2 prior lines and was 42.5 months for ≥3 prior lines (Figure 1B); treatment in earlier lines resulted in better PFS for these patients (first-line vs 1-2 prior, HR: 0.64 [95% CI, 0.35-1.18]; first-line vs ≥3 prior, HR: 0.33 [95% CI, 0.19-0.57]; 1-2 prior vs ≥3 prior HR: 0.51 [95% CI, 0.30-0.87])....this integrated analysis of data with up to 6 years of long-term follow-up demonstrates that using single-agent ibrutinib in earlier lines of treatment results in better PFS, OS, and ORR with sustained efficacy for patients with CLL, including patients with high-risk prognostic features

The 5-year PFS rate was 92% in TN patients and 44% in R/R patients. Median PFS in R/R patients was 51 months; in those with del(11q), del(17p), and unmutated IGHV, it was 51, 26, and 43 months, respectively, demonstrating long-term efficacy of ibrutinib in some high-risk subgroups....efficacy and acceptable tolerability of ibrutinib over an extended time, providing the longest experience for Bruton tyrosine kinase inhibitor treatment in patients with CLL/SLL.