The data from ELEVATE-RR led several major guide- lines, including the VA and National Comprehensive Cancer Network, to list acalabrutinib as a preferred BTK inhibitor option in relapsed/refractory CLL/SLL with high-risk features, with front-line use similarly supported in appropriate candidates. Combination Strategies and Emerging Data Investigators have also studied acalabrutinib in combina- tion fixed-duration regimens for treatment-naïve CLL/ SLL patients. ELEVATE-TN and ASCEND data showed that the acalabrutinib plus obinutuzumab (AO) deepened responses compared to acalabrutinib monotherapy, with a higher rate of undetectable minimal residual disease in the combination arm. In ELEVATE-TN, the AO com- bination showed a 90% reduction in the risk of progres- sion or death, while acalabrutinib alone reduced the risk of progression or death 80%. ASCEND showed a 65% improvement in PFS. Median OS was not reached in any arm in either trial. The FDA approved AO for CLL/SLL in November 2019. The AMPLIFY study, which compared acalabruti- nib-venetoclax (AV) with or without obinutuzumab to chemoimmunotherapy with investigators’ choice of fludarabine-cyclophosphamide-rituximab or bendamus- tine-rituximab (FCR/BR), also demonstrated improved outcomes for the acalabrutinib combo regimens in 867 treatment-naïve patients without a 17p deletion or TP53 mutation. At a median follow-up of 40.8 months, median PFS was not estimable in the AV arm and reached 47.6 months in the FCR/BR arm. With a median follow-up of 41.0 months, there were 18 (6%) deaths in the AV arm and 42 (14%) in the FCR/BR arm. The results led to FDA approval in February 2026 for the acalabrutinib-veneto- clax combination for CLL/SLL.7 For VA patients with comorbidities that complicate long-term continuous therapy, the concept of fixed- duration acalabrutinib-based regimens has great appeal. Reducing the duration of therapy diminishes cumulative toxicity, simplifies medication management in patients on complex polypharmacy, and may reduce direct drug costs over the treatment episode. Tolerability in the Older Veteran The VA CLL/SLL population differs significantly from typical clinical trial populations. Patients often present at hematology clinics with diagnoses of hypertension, type 2 diabetes, chronic kidney disease, obstructive sleep apnea, and post-traumatic stress disorder, among other condi- tions. Polypharmacy is the rule rather than the exception, and functional status varies widely. Against that backdrop, the most common adverse effects associated with acala- brutinib, headache in the first weeks of therapy, bruising, and transient mild diarrhea are generally manageable without dose modification. The headache phenomenon, which occurs in up to half of patients during the initial weeks, can often be mitigated with caffeine supplementation or low-dose analgesics. Rates of treatment discontinuation due to adverse events in clinical trials were lower for acalabrutinib than for ibru- tinib, a finding of practical relevance when evaluating long-term therapy in patients who may already struggle with medication adherence. VA oncologists and hematologists treating CLL/SLL in older veterans now have robust prospective data to support acalabrutinib as a first-line or relapsed/refractory choice, with a tolerability advantage over the first-generation BTK inhibitor class and efficacy data that extend across the high-risk genomic subgroups most likely to be iden- tified in symptomatic patients presenting for treatment. As CLL/SLL continues to disproportionately affect veter- ans, the quality of that evidence base will remain central to guideline adherence and treatment decision-making across VA facilities nationwide. 1VA Clinical Pathway CLL and SLL. April 2026. 2Sharman JP, Egyed M, Jurczak W, et al. Acalabrutinib with or without obinutuzumab versus chlorambucil and obinutuzumab for treatment- naive chronic lymphocytic leukaemia (ELEVATE TN): a randomised, controlled, phase 3 trial. Lancet. 2020 Apr 18;395(10232):1278-1291. doi: 10.1016/S0140-6736(20)30262-2. Erratum in: Lancet. 2020 May 30;395(10238):1694. doi: 10.1016/S0140-6736(20)31018-7. PMID: 32305093; PMCID: PMC8151619. 3Sharman JP, et al. Acalabrutinib-obinutuzumab improves survival vs chemoimmunotherapy in treatment-naive CLL in the 6-year follow-up of ELEVATE-TN. Blood. 2025 Sep 11;146(11):1276-1285. doi: 10.1182/ blood.2024024476. PMID: 40198878; PMCID: PMC12824692. 4Jurczak W, Pluta A, Wach M, et al. Acalabrutinib versus investigator’s choice in relapsed/refractory chronic lymphocytic leukemia: final ASCEND trial results. HemaSphere. 2022 Nov 14;6(12):e801. doi: 10.1097/HS9.0000000000000801. PMID: 36398134; PMCID: PMC9666115. 5Byrd JC, Hillmen P, Ghia P, et al. Acalabrutinib versus ibrutinib in previously treated chronic lymphocytic leukemia: results of the first randomized phase III trial. J Clin Oncol. 2021;39(31):3441–3452. 2021 Nov 1;39(31):3441-3452. doi: 10.1200/JCO.21.01210. Epub 2021 Jul 26. PMID: 34310172; PMCID: PMC8547923. 6Ghia P, et al. Detailed safety profile of acalabrutinib vs ibrutinib in previously treated chronic lymphocytic leukemia in the ELEVATE-RR trial. Blood. 2023 Aug 24;142(8):687-699. doi: 10.1182/blood.2022018818. PMID: 37390310; PMCID: PMC10644206. 7Brown JR, Seymour JF, Jurczak W, et al. Fixed-Duration Acalabrutinib Combinations in Untreated Chronic Lymphocytic Leukemia. NEJM. 2025 Feb 20;392(8):748-762. doi: 10.1056/NEJMoa2409804. Epub 2025 Feb 5. PMID: 39976417. 2 0 2 6 C O M P E N D I U M O F F E D E R A L M E D I C I N E 1 7
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