Research Summary
This study1 evaluated the Medicare cost impact of choosing among covalent Bruton tyrosine kinase inhibitors (cBTKis) for treatment-naïve (TN) and relapsed/refractory (RR) chronic lymphocytic leukemia (CLL). The analysis focused on differences in drug acquisition and management of grade 3 or greater adverse events (AEs) between acalabrutinib, ibrutinib, and zanubrutinib. A United States (US) Centers for Medicare and Medicaid Services (CMS) payer perspective was applied to patients eligible to initiate a cBTKi in TN or second-/third-line RR settings who were cBTKi-naïve.
A Markov model used 28-day cycles with four pathway states: on cBTKi; venetoclax plus rituximab (fixed two-year duration); subsequent treatment (pooled pirtobrutinib, chimeric antigen receptor T-cell therapy with lisocabtagene maraleucel, and best supportive care); and death. Grade 3 or greater AE management costs were applied over one year of cBTKi therapy using weighted monthly costs for atrial fibrillation, hypertension, neutropenia, thrombocytopenia, infections, hemorrhage, and diarrhea, informed by cumulative grade 3 or greater AE rates from extended Phase III follow-up for each cBTKi at similar duration. Drug costs reflected 2024 wholesale acquisition cost (WAC) and label dosing; monthly WACs were $11,165 for ibrutinib, $9,770 for acalabrutinib, and $9,578 for zanubrutinib, corresponding to annual WACs of $213,677, $186,979, and $183,303, respectively. Clinical inputs governing discontinuation, post-cBTKi transitions, and mortality were drawn from real-world data and literature and held equal across cBTKi. Commercial cost sources were converted to Medicare using published commercial-to-Medicare ratios and inflated to 2024 US dollars. The CMS subpopulations included disabled, terminally ill, and end-stage renal disease (ESRD). Uncertainty was examined via deterministic sensitivity analysis (±20% on key parameters), probabilistic analysis (5,000 simulations), and scenario analyses using matching-adjusted indirect comparison (MAIC)–informed AE rates.
In the base case, 13,726 patients with CLL on Medicare were modeled (44% TN, 56% RR). Infections were the most frequent grade 3 or greater AE across cBTKis in TN and RR settings, followed by neutropenia. Aggregate grade 3 or greater AE rates favored acalabrutinib in both settings, at a rate of 35.8 percent with acalabrutinib among TN patients compared to 61.6 percent with ibrutinib (−25.8% difference) and 56.4 percent with zanubrutinib (−20.6% difference) and of 75.0 percent with acalabrutinib among RR patients compared to 83.0 percent with ibrutinib (−8.0% difference) and 86.1 percent with zanubrutinib (−11.1% difference). Specific differences included lower rates of grade 3 or greater hypertension and atrial fibrillation in TN CLL and lower hypertension and diarrhea in RR CLL.
Combining pharmacy and AE costs, acalabrutinib saved $15,478 per patient in one year versus ibrutinib, driven by a $12,076 lower treatment cost and a $3,402 lower AE cost. Compared with zanubrutinib, acalabrutinib saved $1,901 per patient in one year, as a $1,663 higher treatment cost was offset by a $3,563 lower AE cost. Per-patient savings with acalabrutinib persisted at three and five years, at $23,735 and $25,545 versus ibrutinib, and $764 and $515 versus zanubrutinib, respectively. Among patients with CLL on Medicare, acalabrutinib was associated with total cost savings of $212 million, $326 million, and $351 million versus ibrutinib over one, three, and five years, respectively, and $26 million, $10 million, and $7 million versus zanubrutinib, respectively. Expected annualized CMS savings with acalabrutinib were $64 million versus ibrutinib and $2 million versus zanubrutinib.
Across CMS special subpopulations within the modeled cohort, with an estimated 4,875 individuals in the disabled group, 1,849 in the terminally ill group, and 560 in the ESRD group, acalabrutinib was associated with 1,186, 292, and 95 fewer grade 3 or greater AEs than ibrutinib, respectively, and 966, 282, and 89 fewer AEs than zanubrutinib, respectively, over one year. The corresponding annualized savings with acalabrutinib were $26 million, $9 million, and $3 million versus ibrutinib and $1.6 million, $0.3 million, and $0.1 million versus zanubrutinib.
Scenario analyses using MAIC-informed AE rates yielded acalabrutinib savings of $15,142 per patient versus ibrutinib and $1,501 per patient versus zanubrutinib over one year. Varying discontinuation from any cause produced one-year savings of $19,872 and $2,267 per patient versus ibrutinib and zanubrutinib, respectively, with acalabrutinib. In probabilistic analysis, lower AE cost with acalabrutinib was maintained in all simulations, while lower pharmacy cost was maintained in 68.5 percent of simulations compared to ibrutinib and 46.8 percent compared to zanubrutinib. Deterministic sensitivity analysis identified drug prices as the principal driver of uncertainty.
Under the model’s assumptions, acalabrutinib’s cost advantage arose from the combination of lower treatment cost than ibrutinib and fewer severe AEs than both ibrutinib and zanubrutinib. The data indicated that, for Medicare beneficiaries with TN or RR CLL initiating a cBTKi, acalabrutinib was associated with lower expected one-, three-, and five-year total costs compared with ibrutinib and with smaller but persistent savings compared with zanubrutinib, driven by lower AE-related costs and, versus ibrutinib, lower drug cost. Findings were consistent across CMS special populations and robust to multiple sensitivity and scenario analyses.
Reference
- Kittai AS, Patel DA, Shafrin J, et al. Cost impact of Bruton’s tyrosine kinase inhibitor selection in Medicare patients with chronic lymphocytic leukemia. J Comp Eff Res. 2025;14(8):e250035.