Real-World Analysis of Patients with CLL Treated with Ibrutinib: A Retrospective Analysis of the Brazilian Registry of CLL
Authors: Pfister Verena , Marques Fernanda de Morais , de Molla Vinicius Campos , Parra Flavia , Yamamoto Mihoko , Santucci Rodrigo , Aranha Milton A. F. , Buccheri Valeria , Ribeiro Glaciano , Figueiredo Vera , Hamerschlak Nelson , Costa Neto Abel , Schmidt Filho Jayr , Silveira Talita , Scheliga Adriana , Goncalves Matheus Vescovi , Perobelli Leila , Chiattone Carlos , Arrais-Rodrigues Celso 
Published: December 2024

Introduction: Ibrutinib, a Bruton's tyrosine kinase (BTK) inhibitor approved for all lines of treatment in chronic lymphocytic leukemia (CLL), is associated with increased survival and prolonged response, even in high risk scenarios, with relatively low toxicity compared to chemoimmunotherapy. However, a significant number of patients discontinue therapy due to intolerance and toxicity. It is essential to comprehend the factors contributing to treatment discontinuation and the subsequent impact on clinical outcomes. This is the first large real-world analysis of patients from Latin America.

Objective: This analysis aims to utilize real-world data to assess ibrutinib's effectiveness and to examine factors contributing to discontinuation and the subsequent impact on clinical outcomes in Brazil.

Methods: The Brazilian Registry of CLL is an ambispective non-interventional data collection tool. All patients who received ibrutinib as continuous monotherapy at any therapy line between January 2015 and March 2024, with essential minimum data on patient and treatment characteristics, clinical outcomes, and a minimum follow-up of three months, were included.

Results/Discussion: A total of 278 patients from 29 centers were included. Ibrutinib was used in the first line of treatment (LoT) in 23%, second LoT in 42%, third line in 21%, and fourth or subsequent lines in 14%. The majority were male (63%), with a median age of 68 years (range: 35-95), and most (44%) had significant comorbidities. TP53 mutation or del(17p) status was assessed in 173 patients (62%), with 38 (22%) testing positive. The median duration of ibrutinib treatment was 28 months (range: 6 days - 103 months). The median interval between diagnosis and initiation of ibrutinib was 53 months (range: 0-330), shorter for those in 1st or 2nd lines (40 months) than later lines (89 months). Ibrutinib was discontinued in 51% of cases, primarily due to toxicity (32%), death (29%), disease progression (26%), and other factors (13%). In several cases, ibrutinib was replaced by another BTK inhibitor by the physician's preference A significant proportion (51%) experienced at least one treatment-related toxicity. Patients in the first or second line had fewer adverse events than those in later lines (46% vs. 59%, P=0.04). Common toxicities included infections (28%), bleeding (11%), hematologic toxicity (9%), cardiac toxicity (5%), and diarrhea (4%). Atrial fibrillation occurred in 5% of cases. Median PFS was not reached. After a median follow-up of 50 months (range: 3-105), PFS was 64% at 4 years, longer for patients in the first or second line compared to later lines (72% vs. 48%, P&lt;0.0001) and in those with del(17p)/TP53 mutations compared to those without (50% vs. 69%, P=0.008). The median time-to-next-treatment (TTNT) was 56 months: 17 months for patients who used ibrutinib for less than 2 years, 47 months for 2-4 years, and 84 months for more than 4 years. Overall survival (OS) at 4 years was 70%, shorter for patients in later lines (57% vs. 77% for 1st or 2nd lines, P=0.006). The most common causes of death were infections in 63% of cases (on ibrutinib in 45%, and after stopping ibrutinib in 18%), disease progression (18%), and cardiac complications (7%).

Conclusions: Ibrutinib shows favorable effectiveness in Brazilian CLL patients across all treatment lines. Intolerance and discontinuation were relatively common, affecting treatment effectiveness, especially in patients receiving ibrutinib late in the disease course, possibly related to cumulative adverse events from previous lines. These results should be interpreted considering the limitations of a registry-based retrospective analysis, including lack of details on comorbidities and the impact of these factors on outcomes and adverse events.