BACKGROUND Covalent Bruton's tyrosine kinase inhibitors (cBTKi) have revolutionized the treatment of Chronic Lymphocytic Leukemia (CLL), improving outcomes above all in patients with a poor prognosis. Currently, all cBTKi available in clinical practice can be used in the first line of CLL therapy, based on the results of the phase III clinical trials RESONATE‐2, ELEVATE‐TN and SEQUOIA, which demonstrated the superiority of Ibrutinib, Acalabrutinib and Zanubrutinib, respectively, over chemotherapy/chemoimmunotherapy in terms of progression‐free survival (PFS). BTK plays a pivotal role in B cell receptor (BCR) signal transduction, stimulating pathways involved in B lymphocytes survival, proliferation and adhesion. Modifying neoplastic lymphocytes' adhesion properties, cBTKi determine an increase in absolute lymphocyte count (ALC) during the initial phase of treatment, followed by a gradual reduction of ALC and lymphocytosis resolution in most cases. The kinetics of lymphocytosis in CLL treated with Ibrutinib monotherapy has been widely studied. In a multicenter retrospective study, we observed that ALC reduction over time was more rapid in patients treated with Acalabrutinib. Thus, the primary endpoint of this study is to describe the kinetics of lymphocytosis also in patients with CLL treated with Zanubrutinib, in order to highlight possible differences among all three cBTKi.MATERIALS AND METHODS We carried out a multicenter retrospective real‐life study involving 16 Italian centers. We included only those patients receiving cBTKi monotherapy, in front line, at the target dose of 420 mg/day for Ibrutinib, 200 mg/day for Acalabrutinib and 320 mg/day for Zanubrutinib and we considered only those patients who showed an increase of the lymphocytes count at day 15 (295/346, 85%). Subsequently, we assessed the ALC through serial blood count tests at different time points: first 2 weeks, 1 month, 2 months, 3 months, 6 months, 9 months, and 12 months after the beginning of treatment. For each timepoint we calculated the median ALC, expressing it as percentage of the baseline.RESULTS We observed a faster ALC reduction in the Acalabrutinib arm, while the curves of Ibrutinib and Zanubrutinib arms showed a complete overlap. This difference appeared statistically significant at month 3, month 6 and month 9. Subsequently, we examined if well‐defined clinical or biological features could independently have an impact. According to the IGHV mutational status, we observed a substantial overlap of the curves and no statistically significant differences among patients with unmutated IGHV, while a more rapid decrease of the lymphocytosis in the Acalabrutinib arm emerged among those with mutated IGHV, becoming statistically significant at 3, 6, 9 and 12 months. Stratifying patients according to the presence or the absence of splenomegaly at baseline, we observed that patients with splenic involvement presented a faster lymphocyte count reduction, statistically significant between month 3 and 12 of treatment in each group. Conversely, lymph node burden and TP53 disruption showed no impact on the kinetics of lymphocytosis. DISCUSSION We here describe for the first time the kinetics of lymphocytosis in patients treated in front line with Zanubrutinib. We confirmed that patients on treatment with Acalabrutinib show a faster decrease in ALC over time as compared to patients treated with Ibrutinib, and that this difference is due to the particular behaviour of the mutated IGHV subgroup. Patients with CLL treated with Zanubrutinib showed a kinetics of lymphocytosis different from the other second generation cBTKi Acalabrutinib, but similar to the first-in-class drug Ibrutinib. We also observed that, despite the administered cBTKi, the presence of splenomegaly at baseline seems to accelerate the “lymphocytes clearence” from the blood stream. In conclusion, differences in ALC modification over time seem to correlate to two factors: the presence of splenomegaly before starting treatment and having mutated IGHV status, the latter during therapy with Acalabrutinib. These evidences could have an important impact in the era of oral combination therapy, considering the role of BTKi as “demarginalizing agents” able to expose neoplastic lymphocytes to the pro-apoptotic action of BCL2 inhibitors in the peripheral blood.

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2025
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