Kinetics of Lymphocytosis during First-Line Treatment with BTK Covalent Inhibitors in Chronic Lymphocytic Leukemia Patients: An Italian Multicenter Experience of Real Life
Authors: Innocenti Idanna , Mosca Antonio , Tomasso Annamaria , Galitzia Andrea , Scarfo Lydia , Galli Eugenio , Laureana Roberta , Benintende Giulia , Mattiello Veronica , Morelli Francesca , Chiriu Sabrina , Del Principe Maria Ilaria , Frustaci Annamaria , Zamprogna Giulia , Gentile Massimo , Fabbri Nicole , Autore Francesco , Montalbano Maria Chiara , Farina Giuliana , Innao Vanessa , Patti Caterina , Sportoletti Paolo , Fresa Alberto , Catania Gioacchino , Coscia Marta , Tedeschi Alessandra , Sanna Alessandro , Visentin Andrea , Trentin Livio , Varettoni Marzia , Ghia Paolo , Murru Roberta , Laurenti Luca 
Published: December 2023

CONCLUSIONS
In chronic lymphocytic leukemia (CLL) patients (pts) the first phase of treatment with covalent Bruton's tyrosine kinase inhibitors (cBTKi), Ibrutinib or Acalabrutinib, is characterized by an increased absolute lymphocyte count (ALC), regardless of previous lines of treatment. Ibrutinib, as first-line therapy, induces lymphocytosis in about 57% of pts, and it is more prominent in IGHV mutated CLL patients. This phenomenon, due to the spread of neoplastic lymphocytes from the nodal compartment into peripheral blood, is transient in most patients, resolving within 8 months, but can rarely persist over 12 months, without any impact on survival: the criterion of Partial Response with Lymphocytosis (PR-L) was introduced for this phenomenon. Despite lymphocytosis in Ibrutinib has been widely investigated, little is known about the effective presence, kinetics and duration of lymphocytosis in patients treated with Acalabrutinib.
The main purpose of this multicentric study was to define, in a real-life setting, the kinetics of drug-induced lymphocytosis in CLL patients treated with Acalabrutinib or Ibrutinib, in order to discover any possible differences in terms of entity and duration of this phenomenon.
In our multicentric retrospective study we enrolled 204 pts (127 male and 77 female), treated in first line with cBTKi (136 Ibrutinib and 68 Acalabrutinib), from 16 different Italian centers, between April 2016 and November 2022, with last follow up in April 2023. For each patient we collected data about the burden of disease at baseline (in terms of staging, lymph nodes involvement, presence of splenomegaly), and about the biological features of the disease (cytogenetic aberrations and molecular mutations, IGHV status). Then we evaluated the ALC at the baseline and at well-defined time-points (after two weeks, 1, 2, 3, 6, 9, 12 months) over an observation period of 1 year. Patients' characteristics are reported in Figure 1.
The main differences between the two groups were observed in FISH and molecular biology, with a prevalence of del17p and mutated TP53 among Ibrutinib-treated patients. We observed a median ALC increase after the beginning of therapy in both groups. Median lymphocytosis was higher than baseline during the first month of treatment in both cohorts. A progressive decline in median ALC occurred from the second month of treatment in both groups: at this time-point, median lymphocyte count was 62% of baseline in Acalabrutinib cohort versus 84% in Ibrutinib cohort (p=0.025). From the sixth month to the end of the study we found a statistical difference in the ALC with higher counts in the Ibrutinib group. In fact, at this time point, median ALC was 6960/microL in Acalabrutinib compared to 11010/microL in Ibrutinib group (13% vs 30% of baseline), at the ninth month it was 4550/microL vs 8230/microL (10% vs 20% of baseline) and after twelve months it was 2740/microL vs 5520/microL (8% vs 13% compared to baseline) in the Acalabrutinib versus Ibrutinib group, respectively. Besides, we evaluated the percentage of lymphocytosis resolution in both arms at different timepoints and we observed a quicker restoration of an ALC &lt; 5000/mmc in the Acalabrutinib arm. The results are illustrated in Figure 1.
Acalabrutinib seems to determine, like Ibrutinib, an increase of ALC immediately after the starting of treatment. Therefore, lymphocytosis appears as a cBTKi-class effect. Despite this, the kinetics of lymphocytosis are not overlapping in the two groups: since the sixth month of therapy ALC reaches almost-normal values in the Acalabrutinib group, with significant statistical differences compared to Ibrutinib.
These data suggest that lymphocytosis seems to be less long-lasting in patients treated with Acalabrutinib than in those ones treated with Ibrutinib and the response criterion of PR-L may have a less scope for applicability during treatment with Acalabrutinib.