High incidence of atrial fibrillation in patients treated with ibrutinib

Abstract

ObjectiveAtrial fibrillation (AF) is one of the most common side effects of ibrutinib, a drug that has dramatically improved the prognosis of chronic B-cell malignancies such as chronic lymphocytic leukaemia (CLL). The true incidence of ibrutinib-related AF (IRAF) is not well known and its therapeutic management poses unique challenges especially due to the inherent risk of bleeding. We aimed to determine the incidence and predictors of IRAF, and to analyse its management and outcome.MethodsA standardised monitoring was applied at two cardio-oncology clinics in consecutive patients referred before and during ibrutinib therapy. The primary endpoint was the incidence of IRAF. The excess of AF incidence with ibrutinib was studied by comparing the incidence of IRAF with the expected incidence of AF in general population and in patients with CLL not exposed to ibrutinib.Results53 patients were included. The incidence of IRAF was 38% at 2 years and the risk was 15-fold higher than the AF risk in both the general population and patients with CLL not exposed to ibrutinib (p<0.0001). The majority of cases occurred in asymptomatic patients within the first 6 months. Left atrial volume index ≥40 mL/m2 at treatment initiation identified patients at high risk of developing IRAF. No major bleeding events occurred in patients on ibrutinib, although the majority of patients with IRAF were treated with anticoagulants.ConclusionsThis cardio-oncology study showed that the risk of IRAF was much higher than previously reported. The majority of cases occurred in asymptomatic patients justifying close monitoring.

Treatment of Patients with Relapsed or Refractory Mantle–Cell Lymphoma with Zanubrutinib, a Selective Inhibitor of Bruton's Tyrosine Kinase

“…Ibrutinib, the first oral BTK inhibitor, is approved for the treatment of R/R MCL in the United States, European Union, and China on the basis of a phase II study that demonstrated overall and complete response (CR) rates of 68% and 21%, respectively (9). However, off-target inhibition of EGFR and other structurally similar kinases has been implicated in ibrutinib-associated toxicities, such as diarrhea, rash, bleeding (10,11), and atrial fibrillation (12,13).…”

Haematological malignancies: a guide to novel therapies

“…• Bleeding can range from epistaxis and petechiae to major events including fatal intracerebral and gastrointestinal bleeding 15 …”

“…• Ibrutinib may need holding if diarrhoea is ≥ grade 3 (7 stools a day over baseline) 18 Table 2. Adverse effects of the Bruton tyrosine kinase (BTK) inhibitor ibrutinib and how to manage them [15][16][17][18] therapy and so comprehensive geriatric assessments are increasingly utilised to risk stratify and guide treatment intensity in older patients or in those with complex co-morbidities. 12 Despite novel therapies, a minority of patients are still treated with a significantly immunosuppressive fludarabine-based regimen.…”

Utilizing left atrial strain to identify patients at risk for atrial fibrillation on ibrutinib

“…Ibrutinib is an irreversible Bruton tyrosine kinase inhibitor used in the treatment of various B‐cell malignancies, including chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL), relapsed or refractory Mantle cell lymphoma, relapsed or refractory marginal zone lymphoma, Waldenstrom macroglobulinemia, chronic graft‐versus‐host disease, and additional off‐label uses 1,2 . Ibrutinib has been associated with the development of atrial fibrillation (AF) in approximately 6%–16% of patients, 1 though a recent prospective multicenter cohort study suggests the incidence of ibrutinib‐related atrial fibrillation (IRAF) may be as high as 38% at 2‐year follow‐up 3 . A systematic review and meta‐analysis of four randomized control trials noted the pooled relative risk of AF in ibrutinib recipients was 3.5 (95% confidence interval 1.8–6.9, P < .0001) 4 .…”

“…prospective multicenter cohort study suggests the incidence of ibrutinib-related atrial fibrillation (IRAF) may be as high as 38% at 2-year follow-up. 3 A systematic review and meta-analysis of four randomized control trials noted the pooled relative risk of AF in ibrutinib recipients was 3.5 (95% confidence interval 1.8-6.9, P < .0001). 4 Cardiovascular adverse events related to ibrutinib were associated with a 10%-20% fatality rate (with the exception of ibrutinib-associated hypertension), as per a retrospective international analysis of 303 ibrutinib-associated cardiovascular deaths.…”