Table 3.
Evidence of BTK inhibitors in patients with CLL/SLL
| Patients type | Treatment regimen | Efficacy | Study | Phase | Patients (N) |
|---|---|---|---|---|---|
| Patients with treatment naïve CLL/SLL | |||||
| Without del(17p) and TP53 mutation | IR vs. FCR (fludarabine 25 mg/m2, cyclophosphamide 50 mg/m2, rituximab 50 mg/m2) |
Statistically significant improvement in PFS and OS in the IR group compared with the FCR group (HR: 0.35; P < 0.001 and HR: 0.17; P < 0.001, respectively) |
E1912 [41] | 3 | 354 vs. 175 |
| Ibrutinib vs. chlorambucil |
PFS: median-NR vs. 15 months; 59% vs. 9% (HR: 0.154; 95% CI: 0.108–0.220) 7-year OS: median NR vs. 89 months; 78% in ibrutinib (HR: 0.453; 95% CI: 0.276–0.743) ORR: 92% vs. 37% |
RESONATE-2 [42] | 3 | 136 vs. 133 | |
| Zanubrutinib vs. BR | Better PFS improvement with zanubrutinib than BR regimen; 2-year PFS rate: 85.5% (HR: 0.42; 95% CI: 0·28–0·63; P < 0.0001) | SEQUOIA [38] | 3 | 241 vs. 238 | |
| BR vs. ibrutinib monotherapy vs. IR | 2-year PFS rate: 74% vs. 87% (HR: 0.39; 95% CI: 0.26–0.58; P < 0.001) vs. 88% (HR: 0.38; 95% CI, 0.25–0.59; P < 0.001) | Alliance [43] | 3 | 182 vs. 182 vs. 183 | |
| Ibrutinib plus obinutuzumab vs chlorambucil (0.5 mg/kg bodyweight on days 1 and 15 of each 28-day cycle) plus obinutuzumab (100 mg on day 1, 900 mg on day 2, 1000 mg on day 8, and 1000 mg on day 15 of cycle 1, then 1000 mg on day 1 of each 28-day cycle for cycles 2–6) |
30 months PFS: 79% vs. 31% Median PFS: HR: 0·23; 95% CI: 0·15–0·37; P < 0.0001 |
iLLUMINATE [44] | 3 | 113 vs. 116 | |
| Acalabrutinib + obinutuzumab vs. acalabrutinib monotherapy vs. obinutuzumab (day 1: 100 mg, 2: 900 mg, 8: 1000 mg, and 15: 1000 mg of cycle 1 and on day 1: 1000 mg of cycles 2–6) + chlorambucil (0.5 mg/kg on days 1 and 15 of each cycle) |
Median PFS at 48-month follow-up: NR vs. NR vs. 17.5 months; PFS rate: 87% vs. 77.9% vs. 25.1%; P < 0.0001, P < 0.0001, and P = 0.0296 OS rate: 92.9% vs. 87.6% vs. 88.0%; P = 0.064, P = 0.9164, P = 0.0836 |
ELEVATE-TN [51] | 3 | 179 vs. 179 vs. 177 | |
| With del(17p) and TP53 mutation | IR vs. Ibrutinib monotherapy vs. BR | Median PFS: NR vs. NR vs. 7 months | Alliance [43] | 3 | 11 vs. 9 vs. 14 |
| Zanubrutinib | ORR: 94.5%; 18-month PFS rate: 90.6%; 18-month OS rate: 95.1% | SEQUOIA [38] | 3 | 109 | |
| Acalabrutinib | 48-month PFS rate: 74.8% | ELEVATE-TN [51] | 3 | 25 | |
| IGHV unmutated | IR vs. FCR | 5-year PFS rates: 75% vs. 33% | E1912 [41] | 3 | 210 vs. 71 |
| Acalabrutinib + obinutuzumab vs. acalabrutinib monotherapy vs. obinutuzumab + chlorambucil |
48-month PFS rates: 77.1% vs. 85.7% (P < 0.0001 for A + O vs. O + C, P < 0.0001 for A vs. O + C) |
ELEVATE-TN [51] | 3 | 103 vs. 119 vs. 116 | |
| Zanubrutinib vs. BR | Longer PFS with zanubrutinib than with BR (HR: 0.24; 95% CI: 0.13–0.43) | SEQUOIA [38] | 3 | 125 vs. 121 | |
| IGHV mutation | IR vs. FCR | 5-year PFS rates: 83% vs. 68% | E1912 [172] | 3 | 70 vs. 44 |
| Acalabrutinib + obinutuzumab vs. acalabrutinib monotherapy vs. obinutuzumab + chlorambucil | 48-month PFS rates: 87% vs. 77.9% vs. 25.1% (P = 0.0012 for A + O vs. O + C, P = 0.0551 for A vs. O + C) | ELEVATE-TN [51] | 3 | 58 vs. 74 | |
| Zanubrutinib vs. BR | Longer PFS with zanubrutinib than with BR (HR: 0.35; 95% CI: 0.19–0.64) | SEQUOIA [38] | 3 | 109 | |
| Patients with R/R CLL/SLL | |||||
| Without del(17p) and TP53 mutation | Acalabrutinib vs. idelalisib + rituximab or BR | 42-month PFS rate: 63% vs. 21%; HR: 0.30; 95% CI: 0.20–0.44; P < 0.0001 | ASCEND [58] | 3 | 155 vs. 155 |
|
Zanubrutinib vs ibrutinib |
24-month PFS rate: 78.4% vs. 65.9%; HR: 0.65; 95% CI: 0.49–0.86; P = 0.002 | ALPINE [55] | 3 | 207 vs. 208 | |
| With del(17p) and TP53 mutation | Acalabrutinib vs. ibrutinib | Median PFS of 38.4 months in both the groups | ELEVATE-RR [54] | 3 | 268 vs. 265 |
| Zanubrutinib vs. ibrutinib | 24-month PFS: 72.6% vs. 54.6%; HR: 0.53; 95% CI: 0.31–0.88 | ALPINE [55] | 3 | 75 vs. 75 | |
| Acalabrutinib vs. idelalisib + rituximab or BR | 42-month PFS: 57% vs. 10%; HR: 0.22; 95% CI: 0.12–0.39; P < 0.001 | ASCEND [58] | 3 | 22 vs. 13 | |
| Ibrutinib vs. ofatumumab | HR: 0.175; 95% CI: 0.115–0.258 | RESONATE [53] | 3 | 147 | |
| IGHV mutated | Acalabrutinib vs. idelalisib + rituximab or BR | 68% vs. 36%, HR: 0.34; 95% CI: 0.13–0.93; P = 0.027 | ASCEND [58] | 3 | 21 |
| Ibrutinib vs. ofatumumab | HR: 0.103; 95% CI: 0.067–0.159 | RESONATE [53] | 3 | 181 | |
| IGHV unmutated | Acalabrutinib vs. idelalisib + rituximab or BR | 59% vs. 17%, HR: 0.29; 95% CI: 0.20–0.41; P < 0.001 | ASCEND [58] | 3 | 109 vs. 119 |
| Zanubrutinib vs. ibrutinib | HR: 0.64; 95% CI: 0.47–0.87 | ALPINE [55] | 3 | 72 vs. 98 | |
| Ibrutinib vs. ofatumumab | HR: 0.200; 95% CI: 0.113–0.353 | RESONATE [53] | 3 | 85 | |
A, acalabrutinib; BR, bendamustine plus rituximab; BTK, Bruton tyrosine kinase; C, chlorambucil; CI, confidence interval; CLL, chronic lymphocytic leukemia; FCR, fludarabine, cyclophosphamide, rituximab; IR, ibrutinib + rituximab; HR, hazard ratio; IGHV, immunoglobulin heavy-chain variable-region; MZL, marginal zone B-cell lymphoma; NR, not reached; PFS, progression-free survival; SLL, small lymphocytic lymphoma; TN, treatment naïve; O, obinutuzumab; ORR, overall response rate; OS, overall survival