Ibrutinib-associated Arthralgias/Myalgias in Patients With Chronic Lymphocytic Leukemia: Incidence and Impact on Clinical Outcomes

The Bruton’s tyrosine kinase (BTK) inhibitor ibrutinib has transformed the treatment of chronic lymphocytic leukemia (CLL), leading to unprecedented improvements in progression-free and overall survival for all patients, including those with poor prognostic features. The side effect profile of ibrutinib is unique compared with chemoimmunotherapy and includes atrial fibrillation, increased bleeding risk, and arthralgias/myalgias. Although common, arthralgias/myalgias and their management are poorly described. We identified 214 patients with CLL treated with ibrutinib (as a single agent or in combination) from 2011 to 2018 at the University of Pennsylvania. In this cohort, 36% (76/214) of patients developed arthralgias/myalgias during follow-up with a median onset of 34.5 months. Most (79%) events were grade 1 or 2. Risk factors for developing arthralgias/myalgias included younger age at start of ibrutinib, female gender, and ibrutinib use as first treatment. Twenty-eight percent of patients with grade 1 or 2 toxicity continued ibrutinib and had resolution of symptoms. Dose holds were frequently used to manage this toxicity, and this strategy was more successful than dose reduction. Sixty-two percent of patients with grade 3 toxicity ultimately discontinued ibrutinib. Supportive care measures such as discontinuing statins or use of non-steroidal anti-inflammatory drugs, acetaminophen, or corticosteroids were not used frequently enough in this cohort to evaluate their efficacy. Additional studies to determine the mechanism of ibrutinib-related arthralgias/myalgias are needed to develop optimal management strategies. Ibrutinib-associated arthralgias/myalgias are a frequent adverse event that can occur late in the treatment course and are mostly grade 1 or 2. For patients with grade 1 or 2 arthralgias/myalgias, dose reductions can frequently mitigate the side effects and allow patients to continue on therapy, whereas the majority of patients with grade 3 toxicity ultimately discontinue therapy. Further study is needed to determine their pathogenesis in order to develop best practice management strategies.