Background Acalabrutinib is currently approved for use as a single agent or in combination with obinutuzumab in patients with previously untreated chronic lymphocytic leukemia (CLL). However, the clinical benefit of combination therapy versus monotherapy remains unclear – while the ELEVATE-TN study showed improved outcomes with the addition of obinutuzumab in a subset analysis, it was not designed to evaluate this difference. Here, we present a retrospective real-world comparison of acalabrutinib monotherapy (AM) and acalabrutinib-obinutuzumab combination therapy (AO) in CLL, assessing efficacy, safety, and toxicity.

Methods We conducted an IRB-approved, retrospective review of 81 adult CLL patients treated with front-line acalabrutinib +/- obinutuzumab from 2018-2024 at our tertiary academic medical center. The following data were collected for patients receiving AM (n=21) and AO (n=60): demographics, adverse events (AEs), dose modifications, best overall response, rates of negative minimal residual disease (MRD(-)), and progression-free survival (PFS).

Results Baseline characteristics were comparable between AM and AO cohorts in median age (65 vs 63 years, respectively), ECOG performance status ≤1 (90.5% vs 96.7%), and presence of anemia (HGB ≤11.0 in 57.1% vs 53.3%) and neutropenia (ANC ≤1500 in 9.5% vs 10%). High-risk features were prevalent in both cohorts, including the presence of del17p13.1 and/or TP53 mutation (33.3% vs 25.0%) and unmutated IGHV (61.9% vs 61.7%). A greater proportion of the AM cohort exhibited impaired renal function (GFR <60 in 66.7% vs 26.7%). In the AO cohort, the majority (86.7%) were able to complete ≥6 cycles of obinutuzumab, and 91.8% were able to complete 6 cycles within 6 months.

Toxicities were more common in AO compared to AM, including CTCAE grade ≥3 AEs (56.7% vs 38.1%), bleeding (35.0% vs 23.8%), and cardiac events (23.3% vs 9.5%). Infusion reactions also occurred in 10.0% of AO patients. Infections were common across both cohorts (55.0% vs 57.1%), and other commonly reported any-grade AEs in both cohorts included fatigue, headache, anemia, decreased platelet count, and bruising. Dose modifications (e.g., treatment holds, dosage adjustments, discontinuation) due to AEs were observed in similar proportions of both cohorts (AO: 60.0% vs AM: 57.1%), although rates of discontinuation were greater in AM (23.8%) than AO (16.7% discontinued one or both agents). Causes of discontinuation observed in both cohorts included arrhythmias, cytopenia, fatigue, and end-organ dysfunction.

The AO group had higher rates of complete response (CR) compared to AM (80.0% vs 19.0%), while the majority of AM patients achieved only a partial response (61.9% vs 16.7% of AO). Among patients who achieved CR, median time to CR was also shorter in AO (12 vs 16 months). MRD was assessed in 35 AO patients; 40.0% achieved MRD(-), with a median time of 14 months (IQR 9–24). At median follow-up of 25 months from treatment initiation, overall survival (OS) was greater in AO (95%) than AM (85.7%), as well as progression-free survival (PFS) (88.3% vs 81%). Three deaths were recorded in each cohort: causes in AO were attributed to infectious (2) and thromboembolic (1), while AM included CLL progression (1), a secondary malignancy (1), and intracranial hemorrhage (1).

Conclusions In this real-world cohort, AO was associated with better clinical responses, particularly greater rates of CR and MRD(-), and shorter time to CR, compared to AM. However, these improved clinical outcomes were also associated with increased rates of toxicity and infusion-related events that are absent with AM. Notably, while rates of OS and PFS were modestly greater for AO than AM, OS and PFS were over 80% with AM, indicating that AM may still offer durable disease control while remaining more appropriate in select populations with greater concerns for possible treatment-related toxicity. Importantly, the retrospective nature of our study (i.e., non-randomization) does introduce the potential for selection bias, as patients with greater tolerability concerns were more likely to receive monotherapy, potentially exaggerating both the rates of toxicities and improved outcomes seen with AO. These limitations underscore the need for prospective trials to more definitively identify which patients may derive the most benefit from AO combination therapy.

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2025
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