KEY TAKEAWAYS
- The PK-E3I observational study aimed to investigate how transient vs pHL affects outcomes in patients with CLL treated with ibrutinib.
- Researchers noted that tHL is linked to reduced response duration, indicating the need for therapy adjustment after 3 months.
One of the 1 clinical observations of ibrutinib activity in the treatment of chronic lymphocytic leukemia (CLL) is a rapid decline in lymph node size. This phenomenon is accompanied by hyperlymphocytosis, either transient or prolonged, which is associated with distinct clinical responses and thus impacts long-term outcomes. Understanding the factors that determine different disease courses upon ibrutinib treatment remains a scientific challenge.
Sarah Cadot and the team aimed to assess the effects of transient versus prolonged hyperlymphocytosis (pHL) on clinical outcomes and pharmacodynamic parameters in patients with CLL undergoing ibrutinib treatment.
They performed an inclusive analysis from 2016 to 2021 with 2 cohorts of patients with CLL (cohort 1, n = 41; cohort 2, n = 81), reflecting the typical clinical characteristics of CLL. Such as a Male/Female sex ratio of 2/1, a median age of 70 years at diagnosis, and patients in first-line (1L) therapy (27%) or relapsed/refractory (R/R) patients (73%).
The study tracked blood cell counts over 2 years of ibrutinib treatment and included immunophenotyping and whole-body magnetic resonance imaging (MRI) in cohort 1. Data were integrated into a newly developed mathematical model, combining dynamical and statistical approaches, to identify biological mechanisms associated with different clinical responses.
The analysis revealed that ibrutinib-induced lymphocytosis delineates 2 patients with CLL subgroups: transient hyperlymphocytosis (tHL) and pHL.
Differences between the two groups were determined by baseline parameters such as absolute counts of CD4+ T lymphocytes (P = 0.026), regulatory CD4 T cells (P = 0.007), programmed cell death protein 1 (PD1), and CD69 expression on B leukemic cells, CD19/CD5high/CXCR4low levels (P = 0.04), and lymph node cellularity.
The study found that patients with tHL had a lower duration of response and poorer clinical outcomes. The mathematical modeling reproduced patient-specific dynamics and highlighted that differences between the 2 groups were largely due to the production of leukemic B cells in lymph node compartments and, to a lesser extent, T lymphocytes and leukemic B cell egress into the bloodstream.
Access to additional longitudinal MRI data could further elucidate leukemic B cell dynamics in lymph nodes and validate the relevance of the 2 distinct patient groups.
The study concluded that the multidisciplinary approach improved the understanding of ibrutinib response by identifying new pharmacodynamic parameters before and during treatment. It highlighted that tHL is associated with reduced duration of response and poorer clinical outcomes. Consequently, the findings support the need for adjusted management of ibrutinib therapy after 3 months.
The study was funded by Institut National du Cancer within the framework of C15093BS-Cancer Plan (SC, SK, LD, LY, AQM); Agence Nationale de la Recherche within the framework of LABEX-TOUCAN (SC, CL, LY, AQM); Centre National de la Recherche Scientifique within the framework of EDYLE (SC, CA, CD, LD, LY, FC, AQM); La Ligue contre le Cancer, within the framework of Comites 11,32,65 (LY, AQM).
Source: https://pubmed.ncbi.nlm.nih.gov/39037964/
Clinical Trial: https://clinicaltrials.gov/study/NCT02824159
Cadot S, Audebert C, Dion C, et al. (2024). “New pharmacodynamic parameters linked with ibrutinib responses in chronic lymphocytic leukemia: Prospective study in real-world patients and mathematical modeling.” PLoS Med. 2024 Jul 22;21(7):e1004430. doi: 10.1371/journal.pmed.1004430. PMID: 39037964.
