Abstract
BackgroundIbrutinib demonstrated remarkable efficacy and favorable tolerability in patients with untreated or relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL), including those with high-risk genetic alterations. The IBRORS-CLL study assessed the characteristics, clinical management and outcome of CLL patients receiving ibrutinib in routine clinical practice in Spain. PatientsObservational, retrospective, multicenter study in CLL patients who started single-agent ibrutinib as first-line treatment or at first or second relapse between January 2016 and January 2019. ResultsA total of 269 patients were included (median age: 70.9 years; cardiovascular comorbidity: 55.4%, including hypertension [47.6%] and atrial fibrillation [AF] [7.1%]). Overall, 96.7% and 69% of patients underwent molecular testing for del(17p)/TP53 mutation and IGHV mutation status. High-risk genetic features included unmutated IGHV (79%) and del(17p)/TP53 mutation (first-line: 66.3%; second-line: 23.1%). Overall, 84 (31.2%) patients received ibrutinib as first-line treatment, and it was used as second- and third-line therapy in 121 (45.0%) and 64 (23.8%) patients. The median progression-free survival and overall survival were not reached irrespective of del(17p)/TP53, or unmutated IGHV. Common grade ≥3 adverse events were infections (12.2%) and bleeding (3%). Grade ≥3 AF occurred in 1.5% of patients. ConclusionThis real-world study shows that single-agent ibrutinib is an effective therapy for CLL, regardless of age and high-risk molecular features, consistent with clinical trials. Additionally, single-agent ibrutinib was well tolerated, with a low rate of cardiovascular events. This study also emphasized a high molecular testing rate of del(17p)/TP53 mutation and IGHV mutation status in clinical practice according to guideline recommendations.
Highlights
Chronic lymphocytic leukemia (CLL) is characterized by a marked immune dysfunction 1 and a heterogeneous clinical outcome mainly determined by the patients clinical features, cytogenetic alterations and gene mutations. 2,3 Deletions in chromosome 17p [del(17p)] and mutation in TP53 gene, deletion of 11q [del(11q)], and unmutated immunoglobulin heavy chain variable (IGHV) region gene status is associated with poor response and outcome to chemoimmunotherapy (CIT). 4-9 Testing of these alterations is of paramount importance for guiding treatment decisions in routine clinical practice in chronic lymphocytic leukemia (CLL).[10,11,12]
CLL is characterized by substantial immune dysfunction, which increases the incidence of infections. 1,40 Ibrutinib has been shown to confer significant improvement on immunological parameters, 41,42 and the increase in immunoglobulin A (IgA) levels during ibrutinib treatment has been associated with a reduction of infection rate. 42,43 We found that mean IgA levels significantly increased from the initiation of ibrutinib to the end of treatment, a finding which is consistent with the significant rise in IgA levels observed in clinical trials. 41,42 T-cell dysfunction in CLL is characterized by abnormalities in the proportion of CD4 and CD8 T cells, including the inverted CD4/CD8 ratio (< 1), which has been associated with poor outcomes
This real-world study shows that single-agent ibrutinib is an effective treatment option in TN and R/R patients, regardless of age and high-risk genetic features, in line with clinical trials
Summary
Chronic lymphocytic leukemia (CLL) is characterized by a marked immune dysfunction 1 and a heterogeneous clinical outcome mainly determined by the patients clinical features, cytogenetic alterations and gene mutations. 2,3 Deletions in chromosome 17p [del(17p)] and mutation in TP53 gene, deletion of 11q [del(11q)], and unmutated immunoglobulin heavy chain variable (IGHV) region gene status is associated with poor response and outcome to chemoimmunotherapy (CIT). 4-9 Testing of these alterations is of paramount importance for guiding treatment decisions in routine clinical practice in CLL.[10,11,12] Additional analysis as complex karyotype (i.e., ≥3 chromosomal abnormalities), that have an adverse prognostic significance, are still considered investigational. 10,11,13Ibrutinib is a first-in-class, oral once-daily, covalent inhibitor of Brutons tyrosine kinase (BTK), which has demonstrated higher efficacy and favorable tolerability profile compared to the most effective CIT regimens in both relapsed/refractory (R/R)[14,15] and treatment-naïve (TN) 16-19 patients. 22,26 realworld data from different healthcare systems across countries may be heterogeneous due to divergences in clinical practice, and nationwide experiences are of particular interest. This real-world study aimed to explore the clinical, genetic, and molecular characteristics of CLL patients receiving single-agent ibrutinib in earlier lines of therapy in Spain. We assessed the effectiveness of ibrutinib in terms of response and clinical outcome and the safety and tolerability profile of this agent when used under routine clinical practice conditions
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