Five years ago, chemoimmunotherapy was the standard first-line treatment for chronic lymphocytic leukemia (CLL).^1-3 Now, 2 additional classes of novel agents, including Bruton’s tyrosine kinase (BTK) inhibitors and B-cell lymphoma 2 (BCL2) antagonists, are available in the first-line setting. “We actually have high-grade evidence to show that the use of novel agents can actually be as good or even better than the conventional chemoimmunotherapy,” remarked Prof. Tse, Wai-Choi Eric.

For young and fit patients, the previous best chemoimmunotherapy regimen was a fixed cycle of fludarabine, cyclophosphamide and rituximab (FCR) with a significant 3-year progression-free survival (PFS) benefit over chemotherapy alone (65% vs. 45%; HR=0.56; 95% CI: 0.46-0.69; p<0.0001).¹ Comparatively, the BTK inhibitor ibrutinib can be dosed with rituximab (IR) until disease progression with a further improved 3-year overall survival (OS) and PFS of 98.8% and 89.4%, respectively, versus 91.5% and 72.9%, respectively, with FCR (HR=0.17 and 0.35, respectively; both p<0.001).⁴ Notably, this 3-year PFS benefit was extended to high-risk patients with unmutated-IGHV (90.7% vs. 62.5%; HR=0.26; 95% CI: 0.14-0.50).⁴ In terms of safety, IR was associated with a significantly lower risk of grade ≥3 infection complications (10.5% vs. 0.3%; p<0.001) but a higher risk of grade ≥3 atrial fibrillation (7.4% vs. 3.2%) and hypertension (18.8% vs. 8.2%) when compared to chemoimmunotherapy.⁴

For older (>65-years-old) or less fit patients, bendamustine and rituximab (BR) was the preferred chemoimmunotherapy regimen with less pronounced infectious complications than FCR.² Demonstrating a superior 2-year PFS to BR, IR is now preferred treatment over chemoimmunotherapy in practice (88% vs. 74%; HR=0.38; 95% CI: 0.25-0.59; p<0.001).⁵ Interestingly, ibrutinib monotherapy achieved a 2-year PFS of 87% that was not significantly different than IR (HR=1.00; 95% CI: 0.62-1.62; p=0.49), suggesting that the BTK inhibitor alone is already highly efficacious especially among high-risk patients.⁵

For frail and elderly patients with significant comorbidities, obinutuzumab plus chlorambucil (G-Chl) was the standard-of-care with a prolonged PFS (HR=0.39; 95% CI: 0.31-0.49; p<0.001) and a higher rate of complete response (CR; 20.7% vs. 7.0%) than rituximab plus chlorambucil.3 With ibrutinib now available, ibrutinib plus obinutuzumab (IG) had demonstrated an even longer PFS (median not reached [NR] vs. 19.0 months; HR=0.23; 95% CI: 0.15-0.37; p<0.0001] and a higher rate of CR (19% vs. 8%; RR=2.51; 95% CI: 1.21-5.21; p=0.0096) than G-Chl that was consistent across patients with poor prognostic factors.⁶

In addition to IG, the BTK inhibitor acalabrutinib had also demonstrated a significantly longer PFS than G-Chl with (median NR vs. 22.6 months; HR=0.10; 95% CI: 0.06-0.18; p<0.0001) or without obinutuzumab (median NR vs. 22.6 months; HR=0.20; 95% CI: 0.13-0.31; p<0.0001).⁷ With a greater specificity than ibrutinib, acalabrutinib monotherapy was associated with a low rate of atrial fibrillation of any grade (4%) and hypertension of grade ≥3 (2%).⁷

Other than BTK inhibitors, the BCL2 antagonist venetoclax plus obinutuzumab was also shown to have a longer PFS (median NR vs. 39.6 months; p<0.0001), a higher objective response rate (ORR; 84.7% vs. 71.3%; p<0.001) and a remarkably higher CR rate (49.5% vs. 23.1%) than G-Chl in frail and elderly patients.⁸ After 3 months of treatment, more patients receiving venetoclax plus obinutuzumab achieved measurable residual disease (MRD) negativity than G-Chl (75.5% vs. 35.2%; p<0.001) that was maintained after the fixed treatment cycle of 1 year.⁸

Although venetoclax plus obinutuzumab had demonstrated a consistent PFS benefit in both patients with mutated- and unmutated-IGHV, frontline ibrutinib had a better 5-year PFS and OS among those with del(17p) and/or TP53 mutations.^9,10 When considering treatment for CLL patients, Prof. Tse prefer BTK inhibitors over standard chemoimmunotherapy with venetoclax plus obinutuzumab to be considered for frail and elderly patients with significant comorbidities, except for those with del(17p) or TP53 mutations. Importantly, Prof. Tse summarized, “Standard chemoimmunotherapy should not be used in patients with high-risk features such as unmutated IGHV and del(17p) and/ or TP53 mutations.”