high-risk genomic subgroups, its lower rate of adverse effects, and its compatibility with the complex comorbid- ity profile common among older veterans have elevated it in the VA’s national treatment guidelines as the only pre- ferred drug in the first line.1 Acalabrutinib is a second-generation, covalent BTK inhibitor designed with greater selectivity than ibrutinib, the first approved agent in its class. Acalabrutinib blocks downstream B-cell receptor signaling critical to the proliferation and survival of malignant CLL/SLL cells. Its engineered selectivity reduces off-target kinase inhibition that has been associated with the atrial fibrillation, bleeding, and arthralgia that limited ibrutinib tolerability in some patients. That refinement translates into practical clinical advantages for older veterans with multiple comorbidities. For cardiovascular comorbidities, in particular, the lower incidence of atrial fibrillation observed with acalabrutinib relative to ibrutinib in head-to-head data has shifted prescribing patterns at many VA medical centers. The drug is administered orally twice daily, which, while requiring twice-daily adherence, maintains the convenience of an entirely outpatient regimen. ELEVATE-TN and ASCEND Demonstrate Extended PFS The pivotal ELEVATE-TN trial established acalabrutinib as a front-line option, randomizing previously untreated CLL/SLL patients to acalabrutinib alone, acalabrutinib combined with the anti-CD20 monoclonal antibody obinutuzumab, or chlorambucil plus obinutuzumab. Both acalabrutinib-containing arms demonstrated markedly superior progression-free survival compared with chemoimmunotherapy. At six years of follow-up, median progression-free survival (PFS) had not been reached in either acalabrutinib arm, while the chemoimmunotherapy comparator arm showed a median of roughly 27 months.2,3 Notably, responses were durable regardless of whether patients harbored del(17p), del(11q), or unmutated IGHV status, genomic features that historically predicted poor outcomes with alkylating agent-based regimens. That genomic agnosticism is particularly meaningful in the VA, where physicians may be reluctant to delay treatment of older patients while waiting for comprehensive molecular profiling, especially given the number of veterans who face travel and mobility challenges. ASCEND, the relapsed/refractory counterpart trial, randomized patients who had received at least one prior therapy to acalabrutinib or investigator’s choice of ide- lalisib plus rituximab or bendamustine plus rituximab. Acalabrutinib again demonstrated superior outcomes at 46 months with PFS not reached vs. 16.8 months for the investigator’s choice. Similarly, 42-month PFS rates were 62% for acalabrutinib vs. 19% for the chemoimmunother- apy option.4 The ELEVATE-RR Head-to-Head: Acalabrutinib vs. Ibrutinib Perhaps the most consequential dataset for VA formulary and clinical pathway decisions comes from ELEVATE-RR, which directly compared acalabrutinib and ibrutinib in patients with previously treated, high-risk CLL/SLL defined by del(17p) or del(11q). The trial was designed as a noninferiority study with respect to progression-free sur- vival, and acalabrutinib met that endpoint convincingly. At a median of four years, median PFS was not reached for acalabrutinib vs. 16.8 months for ibrutinib and the esti- mated 42-month OS was 78% vs. 65%, for acalabrutinib and ibrutinib, respectively.5 On the adverse event side, acalabrutinib demonstrated a statistically significant reduction in all-grade atrial fibril- lation, with rates of approximately 9% vs. 16% for ibruti- nib. Any-grade hypertension also occurred at lower rates with acalabrutinib. In a population where many patients already take anticoagulants or manage cardiovascular disease, those differences indicate improved tolerability while reducing downstream resource utilization and safety monitoring burdens on busy VA hematology services.6 Progression-free survival, response rate, and overall survival per independent review committee assessment. 1 6 Source: Ibrutinib increases the risk of hypertension and atrial fibrillation: systematic review and meta-analysis. PLoS One.
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