Presentation (CTI)

OBJECTIVES: Ibrutinib, acalabrutinib, and zanubrutinib are indicated as monotherapy for chronic lymphocytic leukaemia (CLL). Comparative cost-effectiveness analyses have historically favoured second-generation BTK inhibitors (BTKis) over ibrutinib, owing to ibrutinib's inferior safety profile (atrial fibrillation: 16-17% vs 7-9% for acalabrutinib/zanubrutinib). In January 2026, ibrutinib became the first oncology drug subject to Medicare price negotiation under the Inflation Reduction Act (IRA), reducing its price from $14,934 to $9,319 per 28-day supply (38% reduction). We present a conceptual framework for a PROSPERO-registered systematic review and network meta-analysis (NMA; PROSPERO CRD420261419098) to quantify whether IRA-negotiated pricing alters the comparative BTKi cost-effectiveness in CLL.
METHODS: A systematic review will search MEDLINE, Embase, Cochrane CENTRAL, and ClinicalTrials.gov from database inception to July 2026 for published economic evaluations of ibrutinib, acalabrutinib, and zanubrutinib in CLL, following PRISMA and CHEERS 2022 guidance. A de novo partitioned survival model will integrate NMA-derived progression-free survival hazard ratios across four pricing scenarios (wholesale acquisition cost, Medicare negotiated price, projected future negotiation, generic entry) with adverse-event cost offsets, stratified by del(17p)/TP53 mutation status. Bayesian NMA methods will be applied.
RESULTS: Systematic scoping identified 13 published economic evaluations (2018 to 2026); none incorporated IRA-negotiated pricing. Historical ICERs were highly heterogeneous across healthcare systems: ibrutinib vs chemoimmunotherapy, $189,000/QALY (US); acalabrutinib vs ibrutinib, £61,941/QALY (UK NHS). At ibrutinib's negotiated price of $9,319/month, the gap relative to standard US willingness-to-pay thresholds of $100,000 to $150,000/QALY narrows but remains unresolved. Adverse-event cost offsets remain unquantified across all identified studies.
CONCLUSIONS: Despite a 38% price reduction, ibrutinib's cost-effectiveness relative to second-generation BTKis remains context-dependent and unresolved. This NMA-based synthesis, the first to incorporate IRA pricing, adverse-event offsets, and biomarker stratification, will inform BTKi formulary decisions for US payers, NICE, and international HTA bodies. The authors declare no conflicts of interest.