Abstract
Introduction: The Brutons Tyrosine Kinase (BTK) inhibitor ibrutinib has dramatically improved treatment of patients with chronic lymphocytic leukemia (CLL) resulting in markedly increased progression free and overall survival (OS), particularly for those with chemoimmuno-refractory or TP53-mutated disease. However, pivotal clinical studies, such as the RESONATE trial, have also identified ibrutinib-associated complications including infections, hemorrhagic events and atrial arrythmias. Real-world evidence using nationwide-wide records have so far been scarce. Here we present population-based data extracted from multiple national registers on ibrutinib-treated CLL patients with focus on OS and adverse events.
Methods: Using the Swedish portion of the Scandinavian Donations and Transfusions (SCADAT3-S) database, which includes all individuals blood typed in Sweden, we identified a nationwide cohort of patients with a diagnosis of CLL registered in the Swedish Cancer register and who had expedited prescriptions of ibrutinib, according to the Swedish Prescribed Drug Register. Patients were followed from their first date of ibrutinib expedition until death, emigration, or end of follow-up (31st December 2018). Information on adverse events were collected from the Swedish Patient Registry, with information on inpatient and specialized out-patient care. The ibrutinib treatment duration was defined as up to 90 days after last expedition of ibrutinib, end of follow-up, death or emigration, whichever occurred first. OS as well as selected adverse events were calculated from initiation of ibrutinib therapy and displayed using crude Kaplan-Meier estimates (KM). Descriptive statistics were used to describe demographics and treatment duration.
Results: We identified 378 patients with a diagnosis of CLL and a prescription of ibrutinib. The median age at diagnosis of 64 years and 117 (30%) were female patients. The median follow-up from initiation of ibrutinib therapy was 1.4 years (interquartile range [IQR], 0.6 to 2.5) with a median time of diagnosis until treatment initiation of 6.7 years (IQR, 4-10) (Table 1).
OS at 12 and 24 months from start of ibrutinib treatment was 86% (95% confidence interval [95% CI], 82 to 90%) and 74% (95% CI, 68% to 79%), respectively. Kaplan-Meier estimates are displayed in Figure 1A.
For patients without a previous diagnosis of atrial fibrillation or flutter (AF) (n=238), the 12-month cumulative incidence of AF was 11% (95% confidence interval 7 to 16%) (Figure 1B). During follow-up, invasive aspergillus infection, requiring treatment, occurred in 4 patients (cumulative incidence at 12 months 0.02 (95% CI, 0.01 to 0.05). Influenza/pneumonia was the most commonly identified infection (59 events [12 month cumulative incidence of 0.20, 95% CI 0.15 to 0.26], of which 11 events were lower respiratory infections, excluding invasive aspergillosis), followed-by sepsis with a cumulative incidence at 12 months of 0.13 (95% CI, 0.10 to 0.19).
Conclusions: Our nationwide population-based register data support previous results from prospective studies on ibrutinib-treated CLL patients in terms of OS. Regarding adverse events, however, our data clearly identify atrial fibrillation and flutter as a significant problem, although the risk seems to diminish after the first year of treatment. Furthermore, invasive aspergillosis, although uncommon, is a serious adverse event worth considering in patients subjected to ibrutinib therapy.
Dahlen: Novartis: Research Funding. Edgren: Cellgene: Research Funding. Stenke: Incyte: Membership on an entity's Board of Directors or advisory committees.
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