High lymphocyte count and bleeding risk in patients with chronic lymphocytic leukemia treated with Bruton’s tyrosine kinase inhibitors

Bruton’s tyrosine kinase inhibitors (BTKi) are being increasingly used to treat patients with chronic lymphocytic leukemia (CLL). Pathological bleeding is a well-known side effect of BTKi but identifying its predictors remains a challenge. This retrospective multicenter study analyzed whether baseline absolute lymphocyte count (ALC) may be associated with bleeding risk in CLL patients treated with BTKi. Time to bleeding (TTB) was the primary outcome of interest. A total of 108 CLL patients treated with BTKi (ibrutinib, n = 86, acalabrutinib, n = 22) were included. The median age was 70 years (range 41–88 years) and 48 (44.4%) were female. The median follow-up time was 32 months (range 1–108 months) and 17 (15.7%) bleeding events occurred during this time. Receiver operating curve analysis set the optimal cut-off value of the ALC at > 77.4 × 10⁹/L. Patients with higher ALC presented with higher total white blood cell count (p < 0.001), lower hemoglobin (p = 0.012), higher Rai stages (p = 0.037) and higher total tumor mass (p < 0.001). Univariately, patients with higher ALC had an inferior TTB when compared to those with lower ALC (hazard ratio, HR 3.27, p = 0.016); this effect persisted in the multivariate Cox regression analysis where higher ALC (HR 4.59, p = 0.032), higher Cumulative Illness Rating Scale (CIRS, HR 4.21, p = 0.040) and the use of antiplatelets/anticoagulants (HR 3.96, p = 0.046) remained independently of each other associated with an inferior TTB. This study provides an important signal regarding the higher risk of bleeding in CLL patients treated with BTKi who present with higher ALC and higher CIRS. Further studies are needed to validate our findings and to unravel the exact pathophysiological mechanisms behind this interesting observation.