Background
Phase 3, open-label, randomized controlled trial (ELEVATE-RR). N=533 patients with R/R CLL/SLL after 1–3 prior lines, all with del(17p) and/or del(11q) by FISH (high-risk cytogenetics enriched). Randomized 1:1 to acalabrutinib vs ibrutinib (head-to-head). Primary endpoint: non-inferiority for PFS; key secondary: atrial fibrillation incidence (superiority). First head-to-head trial of a next-generation vs first-generation covalent BTK inhibitor.
Interventions and follow up
Arm A: Acalabrutinib 100 mg PO twice daily until progression or unacceptable toxicity
Arm B: Ibrutinib 420 mg PO once daily until progression or unacceptable toxicity
Primary endpoint: PFS (non-inferiority, acalabrutinib vs ibrutinib)
Median follow-up: 40.9 months
Arm B: Ibrutinib 420 mg PO once daily until progression or unacceptable toxicity
Primary endpoint: PFS (non-inferiority, acalabrutinib vs ibrutinib)
Median follow-up: 40.9 months
Results
PFS: 38.4 months (both arms equal), HR 1.00 (95% CI 0.79–1.27) — non-inferiority met
ORR: 81% vs 77%
OS: HR 0.82 — not significant
AFib/flutter (any grade): 9.4% (acalabrutinib) vs 16.0% (ibrutinib), P=.02 — superiority met
Hypertension (any grade): 9.4% vs 23.2%
ORR: 81% vs 77%
OS: HR 0.82 — not significant
AFib/flutter (any grade): 9.4% (acalabrutinib) vs 16.0% (ibrutinib), P=.02 — superiority met
Hypertension (any grade): 9.4% vs 23.2%
Adverse events
Cardiovascular: AFib any grade 9.4% (acala) vs 16.0% (ibrutinib); hypertension 9.4% vs 23.2%; major hemorrhage 3.4% vs 3.8%
Other: Headache any grade 34.6% (acalabrutinib, mostly grade 1–2, early); arthralgia 14.2% vs 22.6%
Overall: Grade ≥3 AEs 71.4% vs 78.1%; dose reductions 34.4% vs 48.7%
Discontinuation due to AEs: 14.7% vs 21.3%
Other: Headache any grade 34.6% (acalabrutinib, mostly grade 1–2, early); arthralgia 14.2% vs 22.6%
Overall: Grade ≥3 AEs 71.4% vs 78.1%; dose reductions 34.4% vs 48.7%
Discontinuation due to AEs: 14.7% vs 21.3%
Conclusions
Acalabrutinib demonstrated non-inferior PFS to ibrutinib in R/R CLL with del(17p) and/or del(11q), with significantly lower rates of atrial fibrillation (9.4% vs 16.0%) and hypertension (9.4% vs 23.2%), establishing acalabrutinib as a safer alternative to ibrutinib with equivalent efficacy.
Key Limitations
Non-inferiority design — acalabrutinib is not proven superior for efficacy. Enrichment for del(17p)/del(11q) limits generalizability to unselected R/R CLL. Open-label design; AFib ascertainment may be biased by differential monitoring. Headache was common with acalabrutinib (34%), managed with caffeine avoidance or schedule adjustment. Median follow-up 41 months; long-term ibrutinib toxicity differences may grow with longer follow-up. Neither agent addresses Richter transformation or BTKi-resistant disease, a gap filled by pirtobrutinib (BRUIN CLL-321).
Clinical Context
ELEVATE-RR supported preferred use of acalabrutinib over ibrutinib for R/R CLL on safety grounds, analogous to ASPEN (zanubrutinib vs ibrutinib in WM) and ALPINE (zanubrutinib vs ibrutinib in CLL). FDA approved acalabrutinib for CLL in 2019. ALPINE (Blood 2023) showed PFS superiority and lower AFib for zanubrutinib, making zanubrutinib the preferred covalent BTKi at many centers. For BTKi-pretreated patients, pirtobrutinib (BRUIN CLL-321) is now standard. ESMO-MCBS: not assigned.