PORTUGUESE REAL‐LIFE EXPERIENCE WITH IBRUTINIB OUTSIDE CLINICAL TRIALS – A MULTICENTER ANALYSIS

Abstract

Introduction: Bruton's tyrosine kinase inhibitor, ibrutinib, was recently approved for treatment-naïve, relapsed/refractory and del(17p)/TP53 mutated chronic lymphocytic leukemia (CLL). Discrepancies between clinical trials and routine healthcare are commonly observed in hematology-oncology. We aimed to evaluate the real-world clinical characteristics and drug-related toxicities of patients with CLL treated with ibrutinib in Portugal. Methods: We conducted a multicenter (13 institutions) retrospective observational study of 70 patients diagnosed with CLL that began treatment with ibrutinib between May 2014 and January 2017. We evaluated patient characteristics, biological features of the disease, previous therapy, toxicities, and overall survival (OS). All patients received ibrutinib as a single agent, all but 5 at an initial dose of 420 mg daily. Clinical data were analyzed using IBM® SPSS® Statistics version 22.0. Results: Median age of the cohort was 68 years (IQR: 63-74); 41 patients (58.6%) were male. Median CIRS score was 4 (2-6); ECOG performance status score was 0-1 in 90.5% and 2-4 in 9.5% of evaluable patients; 65.7% were staged as Rai III/IV and 61.4% as Binet C; 54.4% had del(17p) and 11.9% del(11q); 15.7% were treatment naïve; median number of previous lines of therapy for CLL was 2 (1-3); 50% were previously treated with fludarabine and 74.3% with rituximab-containing regimens. Median duration of Ibrutinib treatment was 7.7 months (3-15.5); median follow-up was 8.7 months (4-18.3). Adverse events (AEs) were identified in 87.1% of patients; 51.4% had severe AEs (SAEs - CTCAE grade ≥ 3). The most frequent AE was infection, in 41.4% of patients (69% SAEs), followed by thrombocytopenia (40%-21.4% of which SAEs), neutropenia (35.7%-48% of which SAEs), anemia (28.6%), diarrhea (25.7%), bleeding (21.4%-40% of which SAEs), and arthralgia (20%). AEs led to ibrutinib dose reduction in 18.6% and temporary suspension in 31.4% of patients. Discontinuation-free survival at median follow-up was 82.9%. Ibrutinib was discontinued in 16 patients (22.9%): 5 due to progression, 2 prior to allogeneic hematopoietic stem cell transplantation, 1 due to loss of follow-up, and the remaining 8 because of AEs (50% infectious). OS at median follow-up was 82.9%. 14 patients died, 6 due to disease progression, 5 due to infection, 2 due to hemorrhage, and 1 of sudden death. ECOG 2-4 was significantly associated with an increased risk of death (log-rank p-value 0.013; HR 4.06, 95% CI: 1.22-13.5). OS wasn't significantly different in patients with and without del(17p). Conclusions: The incidence of SAEs was similar to the one reported in the RESONATE trial, proving the safety of ibrutinib as a single agent in CLL. As suggested in the literature, ibrutinib seems to overcome the negative prognostic impact of del(17p). ECOG performance status remains an important predictor of mortality in this population.