Background
Phase III open-label RCT (n=310), relapsed/refractory CLL after ≥1 prior systemic therapy. Compared the BTK inhibitor acalabrutinib monotherapy against investigator's choice of idelalisib+rituximab or bendamustine+rituximab.
Interventions and follow up
Arm A: Acalabrutinib 100 mg PO BID until progression
Arm B: Investigator choice — IR (idelalisib 150 mg PO BID + rituximab 375→500 mg/m2) or BR (bendamustine 70 mg/m2 + rituximab); crossover to acalabrutinib allowed at progression
Primary endpoint: PFS (IRC-assessed)
Median follow-up: 16.1 mo
Arm B: Investigator choice — IR (idelalisib 150 mg PO BID + rituximab 375→500 mg/m2) or BR (bendamustine 70 mg/m2 + rituximab); crossover to acalabrutinib allowed at progression
Primary endpoint: PFS (IRC-assessed)
Median follow-up: 16.1 mo
Results
mPFS: NR vs 16.5 mo (A vs B); HR 0.31, 95%CI 0.20-0.49, P<.0001
12-mo PFS: 88% vs 68%
ORR: 81% vs 75%
1-yr OS: 94% vs 91%
12-mo PFS: 88% vs 68%
ORR: 81% vs 75%
1-yr OS: 94% vs 91%
Adverse events
Serious AEs: 29% (acala) vs 56% (IR) vs 26% (BR).
Hematologic/cytopenias (grade ≥3): Neutropenia 16% vs 39% vs 31%; anemia 12% vs 7% vs 9%; thrombocytopenia 4% vs 8% vs 3%.
Infections/GI (grade ≥3): Pneumonia 5% vs 8% vs 3%; diarrhea 1% vs 24% vs 0%.
Mortality: Deaths 10% vs 11% vs 14%.
Hematologic/cytopenias (grade ≥3): Neutropenia 16% vs 39% vs 31%; anemia 12% vs 7% vs 9%; thrombocytopenia 4% vs 8% vs 3%.
Infections/GI (grade ≥3): Pneumonia 5% vs 8% vs 3%; diarrhea 1% vs 24% vs 0%.
Mortality: Deaths 10% vs 11% vs 14%.
Conclusions
Acalabrutinib monotherapy significantly improved PFS over idelalisib+rituximab or bendamustine+rituximab in relapsed/refractory CLL, with a favorable tolerability profile.
Key Limitations
Open-label design; short median follow-up at primary analysis (OS immature). Heterogeneous comparator arm pooling IR and BR. No head-to-head comparison against ibrutinib or venetoclax-based regimens.
Clinical Context
Supported FDA (2019) and EMA approval of acalabrutinib for CLL. ESMO guidance positions second-generation BTK inhibitors (acalabrutinib, zanubrutinib) as preferred over idelalisib-based regimens in relapsed/refractory CLL given improved efficacy and tolerability.
References