Real-world analysis of patients with CLL treated with ibrutinib: a retrospective analysis of Brazilian Registry of CLL Open Access

Before the development of targeted oral therapies, systemic cytotoxic chemotherapies were the cornerstone of chronic lymphocytic leukemia (CLL) treatment.^1,2 These included chemoimmunotherapy regimens such as fludarabine, cyclophosphamide, and rituximab; or bendamustine and rituximab.^3-5 However, the efficacy of these approaches is limited by significant toxicity, especially in older patients.⁶ 

Ibrutinib, a small molecule inhibitor of Bruton tyrosine kinase, a nonreceptor kinase essential for leukemic B-cell survival in CLL,⁷ was approved for use in CLL after positive results from the phase 3 RESONATE trial. This study demonstrated significant improvements in overall survival (OS) and progression-free survival (PFS) compared to ofatumumab in patients with previously treated CLL.⁸ In the subsequent RESONATE-2 trial, ibrutinib demonstrated a significantly higher overall response rate and lower risk of progression or death than chlorambucil in treatment-naive patients.⁹ 

Treatment with ibrutinib is typically continued until disease progression or death, although some patients may discontinue therapy due to adverse events (AEs).¹⁰ Observational studies have shown an association between early discontinuation of ibrutinib and poor outcomes, such as reduced survival.^11,12 

Although randomized clinical trials (RCTs) remain the gold standard for evidence-based medicine, real-world evidence is critical to fill knowledge gaps and inform decision-making. Real-world studies provide insight into the routine use of oral targeted therapies after approval for CLL treatment. Previous real-world observational studies of ibrutinib in CLL have been conducted in different countries.^12-26 However, RCTs often include selected patient populations that may not fully represent the heterogeneity seen in routine clinical practice, in which patients are typically older and have a higher comorbidity burden and more adverse prognostic features.²⁷ Therefore, real-world evidence from observational studies is essential to validate RCT findings and assess the efficacy and safety of ibrutinib in broader, more diverse patient populations.

This study analyzes real-world outcomes in a Brazilian cohort to further our understanding of the role of ibrutinib in CLL treatment in different health care settings. By examining treatment patterns, clinical efficacy, and safety profiles in a diverse and representative population, this study aims to provide comprehensive evidence to complement existing clinical trial data and inform best practices in routine CLL management.

We performed a retrospective analysis using data from the Brazilian Registry of Chronic Lymphocytic Leukemia (BRCLL) to determine real-world experience with continuous ibrutinib monotherapy in Brazil. The BRCLL is affiliated with the Brazilian Association of Hematology, Hemotherapy, and Cell Therapy and includes 4864 patients from 66 centers. This analysis includes patients enrolled between January 2015 and July 2024. The analysis included patients from 32 BRCLL centers, as listed in the supplemental Appendix. This study was approved by institutional review boards of all participating centers and conducted in accordance with the Declaration of Helsinki.

The following criteria were used to determine which patients were eligible for inclusion in this analysis: diagnosis of CLL according to International Workshop on Chronic Lymphocytic Leukemia (IWCLL) criteria, age ≥18 years, receipt of continuous ibrutinib monotherapy in any line of treatment, and a minimum of 3 months of clinical follow-up after ibrutinib initiation. We identified 310 patients who met the inclusion criteria, and in 3 cases, patients received ibrutinib in 2 different lines of therapy. Therefore, we analyzed a total of 313 treatments with ibrutinib in 310 patients from 32 centers.

Continuous variables were expressed as median and range, and categorical variables were expressed as percentages. OS was calculated from the date of ibrutinib initiation to the date of death or last visit. Time to next treatment (TTNT) was calculated from the date of ibrutinib initiation to the earliest onset of next-line treatment, evidence of disease progression, death, or last visit. OS and TTNT were estimated using the Kaplan-Meier method and compared between groups using log-rank tests. Adjusted probabilities for outcomes were estimated using the Cox proportional hazards method, with results expressed as hazard ratios and 95% confidence intervals. For all statistical methods used, a P value <.05 was considered statistically significant. Statistical analyses were performed using the SPSS software package, version 20 (SPSS Inc, Chicago, IL).

Table 1 shows the baseline clinical characteristics of the study population. The cohort was predominantly male (61%), with a median age of 67 years (range, 35-95). According to the Binet staging system, 41% of patients were classified as stage A, 37% as stage B, and 22% as stage C, with staging data available for 78% of participants. Binet stage was recorded at diagnosis as a baseline prognostic score and was not reassessed at the time of ibrutinib initiation. At least 1 comorbidity was present in 233 patients (74%) at the time of ibrutinib initiation (Table 2), and most patients had ≥2 comorbidities. Several patients had cardiovascular disease: hypertension (29%), arrhythmia (7%), and heart failure (6%). Some patients also had kidney disease (3%), diabetes (3%), and psychiatric disorders (3%).

Elevated β2-microglobulin levels were observed in 48% of the 118 patients tested. Immunoglobulin heavy-chain variable region gene (IGHV) status was available for 101 patients (33%), 70 of whom (69%) had unmutated IGHV. Del(17p) was analyzed using fluorescence in situ hybridization and/or TP53 mutation analysis in 191 patients (62%), of whom 40 (21%) tested positive. The prevalence of del(17p) and/or TP53 mutations was higher among patients treated with ibrutinib as first-line therapy (17/77 [22%]) than those treated with ibrutinib as second-line therapy (11/77 [14%]) or later-line therapy (12/104 [12%]). However, this comparison should be interpreted with caution, given the incomplete availability of molecular data.

Ibrutinib was administered as first-line therapy in 25% of patients, as second-line therapy in 42% of patients, as third-line therapy in 20% of patients, and as fourth- or later-line therapy in 13% of patients. The median duration of ibrutinib therapy was 27 months in the first line, 40 months in the second line, 28 months in the third line, and 14 months in the fourth or later line. Patients treated in the first or second line had a longer median treatment duration (32 months) than those treated in the third line or beyond (23 months).

Ibrutinib was discontinued in 173 of 313 patients (55%). The most common reasons for discontinuation were disease progression in 57 patients (33% of those who discontinued), toxicity in 55 patients (32%), and death during treatment in 45 patients (26%). Other reasons, including physician decision or access issues, accounted for 16 cases of discontinuation (9%). A subsequent line of therapy was initiated in most patients for whom ibrutinib was discontinued (93 patients [54%]). Among those who received another treatment, the median time between stopping ibrutinib and starting the next therapy was 3 days (range, 0-54 months). Among patients who discontinued ibrutinib due to disease progression, venetoclax ± rituximab was the most common subsequent treatment, used in 68% of patients. For those who discontinued due to toxicity, the next line of treatment included another Bruton tyrosine kinase inhibitor in 40% of patients and venetoclax ± rituximab in 34%.

Most patients (51%) experienced at least 1 treatment-emergent toxicity. AEs were less common in patients who received ibrutinib in the first or second line than in those who received it in later lines (42% vs 59%; P = .02). The most common toxicities were infections (27%), bleeding (12%), hematologic toxicity (9%), cardiac toxicity (6%), and diarrhea (4%). Atrial fibrillation was reported in 5% of patients.

The median follow-up period was 50 months (range, 3-105). The median TTNT was 56 months for patients treated with first-line ibrutinib, 68 months for second-line therapy, 47 months for third-line therapy, and 32 months for fourth- or later-line therapy. TTNT at 4 years was 67% in patients who received first-line ibrutinib, 69% in patients who received it in second line, 48% in patients who received it in third line, and 48% in patients who received it in fourth or later lines. TTNT was significantly shorter in patients who received ibrutinib in later lines than those treated in first or second line (TTNT at 4 years, 48% vs 72%; P < .0001; Figure 1). Patients with del(17p)/TP53 mutations had a reduced TTNT at 4 years compared to patients without these genetic alterations (43% vs 68%; P = .002). In addition, TTNT was significantly shorter in older patients, but it was not affected by IGHV mutation status (Table 3). Due to the limited availability of IGHV and TP53 status for a significant portion of the cohort, we chose not to perform a multivariate analysis to prevent biased or underpowered conclusions.

The median OS was also not achieved, with an OS of 68% at 4 years. Of the 102 patients who died, the most common cause was infection (n = 57 [56%]), including 37 deaths (36%) during ibrutinib therapy and 20 (20%) after treatment discontinuation. Nineteen deaths (19% of all deaths) were related to complications from severe acute respiratory syndrome coronavirus 2, of which 14 occurred during or shortly after ibrutinib use. Other causes of death during treatment included disease progression (n = 22 [22%]) and cardiac events (n = 7 [7%]).

This study presents, to our knowledge, the largest retrospective cohort of Brazilian patients with CLL who were treated with ibrutinib monotherapy in a real-world clinical setting. Our findings provide insight into the efficacy and safety of ibrutinib across multiple treatment regimens in a diverse, comorbid patient population. The cohort included 310 patients (313 treatments), predominantly male, with a median age of 67 years. A substantial proportion of patients had cardiovascular comorbidities, and 22% presented with TP53 mutations or del(17p), which is comparable to rates in Canadian and Italian real-world cohorts.^22,28 

Ibrutinib was administered as first-line treatment in 25% of patients, as second-line treatment in 42%, as third-line treatment in 20%, and as fourth- or subsequent-line treatment in 13%. The median treatment duration was 29 months. Despite the real-world setting, survival outcomes were similar to those observed in clinical trials. The RESONATE-2 trial excluded del(17p) patients and reported a PFS at 7 years of 59% in treatment-naive patients.²⁷ The RESONATE trial showed that PFS varied by treatment line: not reached in the second line, 67 months in the third line, 44 months in the fourth line, and 27 months in later lines.²⁹ Our data align with these findings, even in a more heterogeneous population.

The EVIdeNCE trial had a higher proportion of patients with only 1 prior treatment than the RESONATE trial, likely affecting the observed differences in survival. Similar outcomes were seen in a Canadian cohort, which reported a 2-year OS of 83.9% in patients with adverse genetics, and in the Italian Medicines Agency analysis of 740 patients with TP53 abnormalities, which showed a 2-year OS of 83% with frontline ibrutinib. These results reinforce the prognostic importance of genetic features and comorbidities.

UK data further contextualize our findings. In United Kingdom, ibrutinib was primarily used in the second- or third-line setting, with first-line use reserved for select high-risk patients according to National Institute for Health and Care Excellence guidelines.³⁰ The 12-month OS after ibrutinib initiation ranged from 84% to 100% across UK studies,^11,31 whereas the RESONATE trial reported 90%.²⁹ The RESONATE-2 trial showed an OS of 85% at 4 years and 78% at 7 years, compared to 71% at 4 years in our study. A real-world comparison from the Platform for Haematology in EMEA: Data for Real World Analysis database suggested that first-line ibrutinib improves survival compared to chemoimmunotherapy or later-line use.³² 

In our cohort, more than one-quarter of patients with del(17p) or a TP53 mutation received ibrutinib as a first-line treatment, often due to limited access to novel agents. Additionally, 19 deaths from severe acute respiratory syndrome coronavirus 2 infection may have contributed to the reduced OS.

AEs were reported in 51% of patients, occurring more frequently in later lines (59% vs 42% in first line/second line; P = .02). Common AEs included infections (27%), bleeding (12%), hematologic (9%) and cardiac problems (6%), and diarrhea (4%). Atrial fibrillation occurred in 5% of patients, which is lower than the rates observed in RESONATE-2 (10%) and RESONATE (22%). This difference may reflect surveillance or reporting discrepancies. Hypertension occurred in only 4.2% of patients, which is much lower than the 20% observed in clinical trials and may be due to underreporting. Although ibrutinib has been associated with ventricular arrhythmias, there was only 1 case of sudden death, and no arrhythmias were reported. Importantly, patients with cardiovascular comorbidities had PFS comparable to the overall cohort, supporting careful management rather than exclusion.

In our study, older patients had worse outcomes, likely due to a higher burden of comorbidities, such as hypertension and arrhythmias. Although age is not an independent factor in other studies, comorbidity burden may have influenced the prognosis in our study.

More than half of the patients in the UK cohort experienced AEs (58%), which is similar to our findings and those of previous studies.^12,31 Bruising, hematologic toxicity, diarrhea, and arthralgia were common, consistent with RESONATE, RESONATE-2, and observational data.

Dose reductions and interruptions were more prevalent in our real-world population (25%) than in trials, likely due to broader dose adjustment criteria. Although interruptions may negatively affect outcomes, dose reductions do not seem to affect efficacy. These findings support educational efforts to ensure appropriate dose management. Real-world data increasingly support adaptive dosing.^33-35 One pooled analysis of 7 trials showed no loss of PFS or OS after early cardiac AE-related dose reductions,³⁴ reinforcing our findings and encouraging flexible dosing.³⁶ Although dose reductions were uncommon in our cohort, over half of the patients permanently discontinued treatment, mainly due to progression, toxicity, or death. This underscores the importance of tolerability in long-term treatment.

Compared to the EVIdeNCE trial, our cohort had similar comorbidities and adverse genetics but had more later-line use, which may explain the slightly lower survival rate. Differences in health care infrastructure, access to molecular testing, and support services between Brazil and Italy may also influence outcomes. Discontinuation rates in our study align with those in long-term clinical trials but differ from rates in other real-world reports. These variations reflect differences in patient populations and access to treatment. UK studies reported lower discontinuation rates due to AEs, possibly due to guideline adherence and proactive AE management.^12,31,37,38 In our study, a small subset of patients remained treatment free for an extended period after ibrutinib discontinuation. This may be because some patients started therapy based on subjective or evolving symptoms rather than overt disease progression, which allows for delayed re-treatment.

The alignment of our AE profile with both clinical trials and real-world data supports the external validity of our findings. Including UK data further underscores the impact of regional practices on ibrutinib’s safety and efficacy.

The strengths of our study include its multicenter design and the use of eletronic case report forms to collect detailed data, which enhances the representativeness and reliability of findings for Brazilian patients. Limitations include relatively short follow-up periods and incomplete genetic profiling, reflecting real-world constraints.

In conclusion, our study confirms the efficacy of ibrutinib in treating Brazilian patients with CLL across therapy lines. However, we observed high discontinuation rates (55%) and increased toxicity in later lines of treatment (59%), underscoring the importance of personalized treatment plans, management of comorbidities, and flexible dosing. To optimize care in diverse settings, broader access, longer follow-up, and comprehensive molecular testing remain essential.

The authors thank all the physicians, nurses, and data managers participating in the Brazilian CLL registry, as well as the team at the Brazilian Association of Hematology and Hemotherapy for their support and funding, especially Aline Pimenta and Renata Fava.

This collaborative study was sponsored by the Brazilian Association of Hematology, Hemotherapy, and Cell Therapy and was financially supported by Johnson & Johnson. V.P. was supported by the Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq process number 141099/2021-6). The study was partially funded by Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES process number 001).

Contribution: V.P., M.V.G., C.S.C., and C.A.-R. contributed to conception and design; V.P., F.d.M.M., T.S., J.S.F., V.C.d.M., M.V.G., R.S., M.A., D.L.C.d.F., P.S., H.N.P., G.R., V.P.F., L.P., V.B., A.S., N.H., A.C., C.S.C., and C.A.-R. collected and assembled data; and V.P., M.Y., M.V.G., C.S.C., and C.A.-R. analyzed and interpreted data; and all authors contributed to manuscript writing.

Conflict-of-interest disclosure: The authors declare no competing financial interests.

Correspondence: Verena Pfister, Brazilian Association of Hematology, Rua Doutor Diogo de Faria, 775 cj 133, São Paulo - SP, CEP 04037-002, Brazil; email: pfister.verena@gmail.com.