Improved Innate Immune Function upon Preemptive Short-Term Acalabrutinib and Venetoclax in Newly Diagnosed CLL Patients with High Risk of Infections: Translational Findings from the Prevent-Acall Clinical Trial

Background: Patients with chronic lymphocytic leukemia (CLL) exhibit considerable risk of severe infections already prior to needing treatment. Despite this, clinical tools identifying patients-at-risk are an unmet need along with management strategies for high-risk CLL patients who do not fulfill iwCLL treatment criteria. PreVent-ACaLL (NCT03868722) is a phase 2 clinical trial applying the machine learning-based CLL treatment infection model (CLL-TIM) to identify newly diagnosed CLL patients with high risk of severe infections and/or early treatment (Agius et al., Nat Comm, 2020). High-risk patients are randomized between 3 cycles of preemptive acalabrutinib+venetoclax (A+V) or watch and wait (WW). We recently demonstrated that CLL patients needing treatment exhibited innate immune dysfunction characterized by excessive granulocyte activation and monocyte “exhaustion” with skewed cytokine response to toll-like receptor (TLR) stimulation. Immune function was restored upon treatment with BTK- and BCL2 inhibitors in parallel with a reduced infectious burden (Teglgaard et al., CCR, 2024). We here investigate innate immune dysfunction changes upon preemptive A+V or WW in context of the PreVent-ACaLL phase 2 trial.

Methods: Fifteen patients included thus far in PreVent-ACaLL were randomized 1:1 between preemptive A+V or WW. Blood samples were assessed at baseline, after 12 weeks (end of treatment), and after 24 weeks. Innate immune function was assessed in fresh whole-blood samples by TruCulture, a clinically implemented functional assay quantifying cytokine release in response to standardized immune stimuli (lipopolysaccharide [LPS] for TLR4; single-stranded RNA-virus analogue resiquimod [R848] for TLR7/8) and an unstimulated control. Concurrently, extensive immunophenotyping of immune cell subsets in fresh whole blood was assessed by an 8-tube, 10 color flow cytometry panel (DuraClone). Baseline data were compared to previous data from 35 CLL patients needing treatment (outside the trial). All patients provided written informed consent, and the study was approved by the Ethics Committee and the Data Protections Agency.

Results: At baseline, LPS- and R848 stimulated release of IFN-γ and IL-10 was reduced and R848-stimulated release of IL-8 and TNF-α was elevated in CLL patients included in PreVent-ACaLL (n=15) compared to normal reference levels, with cytokine levels comparable to CLL patients needing treatment. Unstimulated IL-8 and TNF-α were also elevated in PreVent-ACaLL patients, similar to- or exceeding the levels observed for CLL patients needing treatment. In the treatment arm (n=8), R848-stimulated IL-10 release normalized during the 24 weeks (p=0.02). R848 stimulated- and unstimulated IL-8 and TNF-α normalized upon A+V while remaining elevated in patients from the WW arm (n=7) (A+V vs WW at 24 weeks: p=0.02 [R848-IL8], 0.04 [R848-TNFα], and 0.04 [Unstim-IL-8]). Notably, normalization of unstimulated cytokines first occurred at 24 weeks (12 weeks post treatment). Immunophenotyping data will be included for the presentation.

Conclusion: Functional immune assessment of the first fifteen patients enrolled in the phase 2 PreVent-ACaLL trial for newly diagnosed patients with CLL at high risk of infection and/or treatment indicates increased inflammatory activity along with dysregulated innate immune responses similar to patients with progressive CLL needing treatment. Despite a small sample size, we observed signs of innate immune restoration and reduced inflammation in patients receiving preemptive A+V for 12 weeks as compared to the WW arm. These findings are coherent with our previous observations of innate immune restoration upon treatment with acalabrutinib monotherapy or ibrutinib+venetoclax in CLL patients needing treatment (Teglgaard et al., CCR, 2024). Thus, we here for the first time provide early data indicating that preemptive treatment may improve immune function and thus reduce infectious risk in high-risk newly diagnosed CLL, further emphasizing the role of data-driven decision support tools for CLL infectious risk assessment and management. The PreVent-ACaLL trial is ongoing, awaiting clinical results within the coming years.