Ibromics: A Real-World Study of Clinical and Biological Parameters in Patients with Chronic Lymphocytic Leukemia (CLL) Treated in First Line with Single Agent Ibrutinib
Authors: Muñoz-Calleja Cecilia , Hernández-Rivas José Ángel , Bosch Francesc , Palomo Laura , Mosquera Orgueira Adrian , Ramirez Angel , Fernandez Alvarez Ruben , Oliveira Ana C , Amat Martinez Paula , Serrano Alicia , García-Grande Aránzazu , Yeguas Ana , Crespo Marta , Alcoceba Miguel , Ferrer Lores Blanca , Garcia Vela José Antonio , Espinosa-Hevia Luis , Bolumburu Celia , Villanueva Forero Miguel 
Published: December 2024

Background
Chronic Lymphocytic Leukemia (CLL) is influenced by the leukemic microenvironment and the competence of the immune system (IS). Treating the disease by restoring the anti-tumor activity of the patient's IS can lead to sustained and deep responses and reduce side effects. Ibrutinib elicits changes in the tumor microenvironment that both control CLL malignant B-cells proliferation and reestablish immune surveillance, through BTK and ITK inhibition. Understanding the relevance of the immune players in CLL and how different treatments affect them would have a direct impact in successfully managing the disease.
Aims
The aim of this study is to comprehensively analyze the baseline characteristics of 1L CLL patients treated with single-agent ibrutinib and investigate the dynamics of immune restoration during the first 6 months (6m) of treatment in a real-world setting.
Methods
This is an interim analysis of the multicenter, prospective, non-interventional real-world evidence study IBROMICS. Patients with active CLL according to iwCLL18 and starting 1L ibrutinib were included. We report the analysis of patients' clinical and immunological data at baseline and after 6m of treatment. A paired comparison (samples from the same patients) was used to evaluate lymphocyte subsets to assess the dynamics of immune restoration.
Results
Of the 91 patients recruited in 42 centers in Spain from September 2022 to September 2023, 57 (62.6%) were male, and median age was 71 years (62-78). 87/88 patients (98.9%) had an ECOG status of 0-1. Baseline comorbidities were present in 81/91 patients (89.0%), most commonly hypertension (40/91, 44.0%), dyslipidemia (23/91, 25.3%), and diabetes (20/91, 22.0%). Unmutated IGHV was reported in 60/87 patients (69.0%), 14/82 (17.1%) had del(17p), 19/85 (22.4%) had mutated TP53, and 7/65 (10.8%) had a complex karyotype with a median of 3.5 cytogenetic alterations.
Data on therapeutic response at 6m were available for 35 patients. The overall response rate (ORR) was 88.6% (n=31), with 25.7% (n=9) having complete response (CR), 17.1% (n=6) partial response (PR), and 45.7% (n=16) PR with lymphocytosis (PR-L). No significant differences in ORR were observed between patients with or without del(17p)/TP53 mutations, as well as in relation to the IGHV status.
The comparison of immunological parameters between baseline and after 6m of single-agent ibrutinib 420mg treatment revealed significant changes. The median percentage of lymphocytes decreased significantly from 87.1% at baseline (Q1-Q3, 71.0-93.1%), median change after 6m -19.2% (p&lt;0.0001). The absolute number of lymphocytes also decreased from a median of 66.2 cells ×109/L (Q1-Q3, 19.4 - 106.4×109/L) at baseline to 15.3 cells ×109/L (Q1-Q3, 6.7-36.4×109/L) after 6m (p&lt;0.001). CD3, CD4, and CD8 T lymphocytes showed a significant reduction in their absolute values, starting from 3.8×109/L (Q1-Q3, 3.0-4.1×109/L), 2.5×109/L (Q1-Q3, 1.2-19.1×109/L), and 2.5×109/L (Q1-Q3, 1.1-14.3×109/L), respectively, at baseline, to 1.2×109/L (Q1-Q3, 0.1-2.5×10 9/L), 1.6×10 9/L (Q1-Q3,0.8-3.6), and 1.3×109/L (Q1-Q3, 0.6-2.9×109/L), after 6m (p&lt;0.01). However, the relative values of the main T-lymphocyte subpopulations increased in this period, including CD4 (baseline 2.6% (Q1-Q3, 1.5-6.3%), median change +3.7% (p&lt;0.001)), CD8 (baseline 3.0% (Q1-Q3, 1.1-4.4%), median change +4.3% (p&lt;0.0001)), and gammadelta (baseline 1.5% (Q1-Q3, 0.5-3.9%), median change +1.0% (p&lt;0.005)), indicating a recovery of these cells. Additionally, there was a notable increase in naive lymphocytes CD4 (baseline 28.1% (Q1-Q3, 13.8-40.1%), median change +4.7% (p&lt;0.01)).
Conclusions
This real-world prospective study provides valuable insights into the utilization of single-agent ibrutinib in CLL, providing information on patients' characteristics and the dynamics of immune restoration after 6m of treatment in a clinical setting. The findings indicate a partial restoration of T cell competence, including both cytotoxic and T helper lymphocytes, along with an increase in naive cells, thus suggesting a broader repertoire of antigenic response. This restoration is vital as it may enable the IS to effectively respond to both tumor and infectious antigens. Additionally, these findings may contribute to a deeper understanding of the immunological mechanisms involved in the improved response to drug combinations with ibrutinib for CLL.