Chronic lymphocytic leukaemia (CLL) is the most common type of leukaemia in adults in Western countries.1 It occurs more frequently in older patients,1–3 who often have other comorbidities and have undergone treatment with immunochemotherapy-based regimens.4 This disease is characterised by marked immune dysfunction. Although CLL is considered an indolent disease, its clinical course is highly heterogeneous owing to variations in patient clinical characteristics, cytogenetic alterations, and genetic mutations.

In this context, Bruton tyrosine kinase inhibitors (iBTK), such as ibrutinib, acalabrutinib and zanubrutinib, have emerged as key therapeutic options, demonstrating superior efficacy and a more favourable tolerability profile than immunochemotherapy regimens in both first-line and refractory or relapsed (R/R) settings.

Clinical studies, including RESONATE5 and RESONATE-2,6 as well as real-world studies, have shown that ibrutinib, the first approved iBTK, significantly prolongs progression-free survival and overall survival.7 Acalabrutinib and zanubrutinib are second-generation inhibitors and offer greater selectivity and a more favourable toxicity profile, thereby addressing some of the limitations of ibrutinib-related adverse events (AEs), such as atrial fibrillation (AF) and bleeding complications.8

The primary objective of this study was to describe the safety profile of first- and second-generation iBTKs as monotherapy in patients receiving first-line treatment and in those with R/R CLL at our hospital. We also analysed how the safety and tolerability profile, as well as the need to interrupt treatment, influences outcomes in these patients when iBTKs are used in routine clinical practice.

A single-centre, retrospective, cross-sectional observational study was conducted at the Hospital Universitario Miguel Servet (Zaragoza, Spain). Inclusion criteria: patients 18 years or older with a diagnosis of CLL, followed up in the haematology and haemotherapy department, whose iBTKs were dispensed by the hospital pharmacy department.

The following demographic variables were collected: functional status and tumour burden at diagnosis, genetic characteristics, previous treatments, dosage and dosage adjustments, treatment duration, temporary or permanent treatment interruptions and their reasons, as well as AEs and their consequences.

The reasons for dose adjustment were as follows: the onset of AEs, deterioration of renal function, inclusion in a clinical trial, and the presence of drug interactions. The reasons for treatment interruption are as follows: AEs, disease progression, patient decision, transformation to Richter syndrome, unacceptable toxicity, and death from the latter and other causes. Adverse events were categorised by system: infectious, digestive, vascular, cardiac, haematological, dermatological, oncological, central nervous system (CNS), ophthalmological, and general.

Demographic and clinical variables were obtained from electronic medical records. For this purpose, we used the Modulab laboratory information system and the corporate application of the Aragon Health Service, serving as the official sources for laboratory results and clinical data, respectively. Drug data were supplemented by analysing dispensing records in the Farmatools Outpatient Dispensing Module.

The frequency of each event was calculated as the proportion of patients experiencing the event between the initiation of iBTK therapy and the end of the study. Non-parametric statistical tests were employed to analyse categorical variables, and the Fisher Exact Test was used to compare proportions between cohorts. A P-value of <0.05 was used as the cut-off point for statistical significance. Depending on the nature of the analysis, percentages were expressed as a proportion of either the total number of patients or the total number of events. Treatment continuity was analysed using Kaplan–Meier curves, which were compared using the log-rank test. A univariate Cox regression model was used to estimate the hazard ratio (HR) between cohorts. All statistical analyses were conducted using the Jamovi software package version 2.3.21.

This study was conducted in accordance with the principles of the Declaration of Helsinki and was approved by the Aragón Drug Research Ethics Committee (code EOM24/038) on 10 July, 2024. The committee granted an exemption from the obligation to obtain informed consent for the retrospective collection of data from deceased patients or those who did not attend the hospital during the study period. In accordance with current regulations, all suspected medicine-related ADRs were reported to the Spanish Pharmacovigilance System for Medicines for Human Use.

The study included 83 patients treated with iBTKs from 1 May, 2015 to 1 June, 2024 (42 [50.6%] male). The mean age at diagnosis was 67.2 years. Regarding prior lines of treatment, 48 patients (58%) received iBTKs as first-line treatment, with 30 (62.5%) receiving ibrutinib, 15 (31.3%) acalabrutinib, and 3 (6.3%) zanubrutinib, while 35 patients (42%) initially received immunochemotherapy before initiating iBTKs, of whom 74.1% had received a single line of therapy (range: 1–4). Of the 35 patients with R/R CLL, 31 (88.6%) received ibrutinib and 4 (11.4%) received acalabrutinib. Table 1 shows the baseline demographic, clinical, and genetic characteristics of the patients stratified by line of treatment.

Duration and treatment continuity

The median treatment duration was significantly longer in patients receiving first-line iBTKs (34.7 months, 95% CI, 31.4-NA) than in R/R patients (20.8 months, 95% CI, 11.5–35.0).

Analysis of treatment continuity using Kaplan–Meier curves (see Fig. 1) demonstrated a statistically significant advantage for the first-line cohort (log-rank p = 0.01). Treatment continuity was 86.8% in the first-line cohort and 64.0% in R/R patients at 1 year, decreasing to 78.2% and 40.7%, respectively, at 2 years. As illustrated in Table 5, the continuity values are shown for 12, 24, 36, and 60 months.

Figure 1.

Treatment continuity in patients with CLL treated with iBTKs as first-line treatment or for R/R disease.

iBTKs, Bruton tyrosine kinase inhibitors; CLL, chronic lymphocytic leukaemia; R/R, refractory or relapsed disease.

*p < 0.05 (log-rank test).

Table 5.

Treatment continuity in patients with chronic lymphocytic leukaemia receiving Bruton tyrosine kinase inhibitors as first-line treatment or for refractory/relapsed disease.

	First line % (95% CI)(n = 35)	R/R % (95% CI)(n = 48)
Continuity at 12 months	86.8 [77.5–97.3]	64.0 [49.6–82.6]
Continuity at 24 months	78.2 [66.4–92.2]	40.7 [26.6–62.2]
Continuity at 36 months	44.5 [29.5–67.1]	26.4 [14.4–48.3]
Continuity at 60 months	44.5 [29.5–67.1]	18.8 [8.8–40.5]

CLL, chronic lymphocytic leukaemia; iBTKs, Bruton tyrosine kinase inhibitors; R/R, refractory or relapsed.

In the univariate Cox regression analysis, treatment in R/R patients was associated with a 2.15-fold higher risk of treatment interruption (HR: 2.15; 95% CI, 1.18–3.89; p = 0.012).

Our study provides real-world clinical evidence on the safety profile and treatment continuity of iBTKs in patients with CLL. More than three-quarters of patients experienced at least one AE. Infections were the most common type of AE across all grades and in AEs greater than grade 3. Within this category, respiratory infections were the most common AE subtype and occurred significantly more frequently in R/R patients than in those receiving first-line treatment. This finding is consistent with the results of comparative trials, which also reported that infectious events were among the most common AEs associated with both ibrutinib and second-generation iBTKs.5,6,9,10 Long-term follow-up shows that infections remain the main toxicity, due to the immunodeficiency intrinsic to CLL and the effects of treatment.11

The most common reasons for treatment interruption in the R/R cohort were disease progression and unacceptable toxicity, whereas first-line patients experienced greater treatment continuity. This finding is consistent with the results of clinical practice series and comparative trials, which reported that prior exposure was associated with higher rates of treatment interruption due to disease progression or toxicity.8,12 In addition, the median duration of first-line treatment (34.7 months) is comparable to that reported in international series, suggesting that early use favours greater therapeutic continuity and sustained clinical benefit.13

The numerical differences observed in the total number of AEs and in AEs greater than grade 3 between first-line and R/R patients may be explained, at least in part, by the higher burden of prior therapies—primarily immunochemotherapy—in the R/R cohort. Regimens such as FCR, R-bendamustine, or R-chlorambucil can induce persistent immune alterations, including hypogammaglobulinaemia, which can increase the risk of infections and complications in subsequent treatment lines. This effect is well documented and persists in the era of targeted therapies.14 In real-world ibrutinib cohorts, previously treated patients exhibit higher rates of treatment interruption due to disease progression or toxicity than de novo patients, which is consistent with greater cumulative clinical frailty after previous treatment lines.15 In our series, treatment discontinuation was more frequent in R/R patients despite similar overall AEs, suggesting that the cumulative impact of prior therapies may reduce patients' tolerance and contribute to therapy interruption.

Cardiovascular and vascular AEs, including bleeding, were infrequent and showed no significant differences between cohorts. The most frequent AE of this type was AF, particularly in patients treated with ibrutinib, with no significant differences between first- and second-generation iBTKs. This finding is consistent with the results of comparative trials such as ELEVATE-RR, in which fewer patients receiving acalabrutinib experienced AF compared with those receiving ibrutinib, as well as with the ALPINE study, in which fewer patients receiving zanubrutinib developed AF.16

A notable finding was the higher frequency of CNS-related AEs, specifically headaches, in patients treated with second-generation iBTKs. All of these patients received acalabrutinib, and this difference reached statistical significance. This finding is in line with the results of previous studies, in which headache has been recognised as one of the most common and specific AEs associated with acalabrutinib.17

Second-generation iBTKs have shown a more favourable safety profile, resulting in fewer treatment interruptions due to AEs while maintaining comparable efficacy.8,12,18,19 Thus, their increased use as first-line treatment is a plausible explanation for the trend towards relatively fewer serious AEs in this cohort.

The frequency of second neoplasms (6.2%) was slightly lower than that reported in the literature. In the 6-year update of the RESONATE trial, approximately 11% of patients developed second neoplasms; solid tumours and non-melanoma skin cancer were the most common.11 Similarly, second neoplasms have been reported during follow-up in first-line clinical trials, such as those by Woyach et al. and Shanafelt et al. This finding suggests that their occurrence may be related to both the prolonged immunosuppression intrinsic to CLL and previous exposure to chemotherapy.20,21 This hypothesis is supported by the observation that half of our patients with second neoplasms had received immunochemotherapy.

This study has several limitations. Firstly, its retrospective, single-centre design and limited sample size may have led to an underestimation of infrequent events and restricted the generalizability of the results. However, the study provides relevant information on a routine clinical practice setting, where patients exhibit greater clinical heterogeneity and comorbidities than in clinical trials. The strength of this study lies in its detailed characterisation of AEs and evaluation of treatment continuity over an extended follow-up period, thereby providing information applicable to the daily management of CLL in our setting.

Overall, our results confirm that iBTKs demonstrate a manageable safety profile in real-world practice, with infections as the main toxicity and no significant differences between drug generations. Greater treatment continuity in first-line patients than in R/R patients underscores the importance of considering the previous treatment history in therapeutic decision-making and of reinforcing close follow-up to optimise adherence and minimise toxicity.

In this real-world cohort, iBTKs exhibited a manageable safety profile consistent with that reported in the literature, with a frequency of AEs similar to that reported in pivotal trials and other observational series. Infections were the most frequent AEs, predominantly respiratory, and occurred significantly more frequently in R/R patients than in those receiving first-line treatment. Cardiovascular and vascular AEs were uncommon and showed no significant differences between drug generations, although AF occurred mainly in patients treated with ibrutinib. Tolerance to continuous treatment was higher in the first-line cohort, suggesting that clinical context and prior therapies influence treatment continuity. Greater use of second-generation iBTKs may contribute to a lower frequency of serious AEs, consistent with patterns reported in comparative trials. Despite the methodological limitations of this study, these findings are applicable to daily clinical practice and support close, multidisciplinary monitoring in order to optimise safety, adherence, and treatment continuity.

This study compares the safety profiles and treatment continuation rates of 2 generations of Bruton tyrosine kinase inhibitors in patients with chronic lymphocytic leukaemia. It provides real-world clinical evidence that may inform treatment personalisation.

All authors have accepted and fulfilled the responsibilities defined by the International Committee of Medical Journal Editors (available at http://www.icmje.org/).

In the event of publication, the authors exclusively transfer the rights of reproduction, distribution, translation, and public communication (by any means or audio, audiovisual, or electronic medium) of the work to Farmacia Hospitalaria and, by extension, to the SEFH. To this end, a letter of transfer of rights will be signed at the time of submission of the work through the online manuscript management system.

Rocío Bello-Calvo: Software, Project administration, Methodology, Formal analysis. Rita González-Resina: Writing – original draft, Methodology, Investigation. Araceli Rubio-Martínez: Validation, Supervision. Itziar Larrodé-Leciñena: Validation, Supervision. María Pilar Delgado-Beltrán: Validation, Supervision. María Reyes Abad-Sazatornil: Visualization, Validation, Supervision.

None declared.