Ibrutinib, a first-in-class oral Bruton tyrosine kinase (BTK) inhibitor, was  considered a transformative therapy for treatment-naive or relapsed/refractory chronic lymphocytic leukemia (CLL).

If well tolerated, ibrutinib is typically given indefinitely; however, given that the median age at diagnosis of CLL is almost 70 years, comorbidities or poor performance status often lead to discontinuation in real-world settings.

“We have to learn more and more from the clinical use of these new agents that have changed the natural history of CLL,” Stefano Molica, MD, of Azienda Ospedaliera Pugliese-Ciaccio, Italy, told Cancer Therapy Advisor.

Dr Molica and colleagues recently published data from an analysis looking at changes in glycemia, cholesterol, triglycerides, and HDL in 43 patients with CLL who received single-agent ibrutinib.1 This real-world analysis had several interesting outcomes.


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First, 35 of 43 patients had a fasting glucose concentration of less than 100 mg/dL at baseline. Within 3 months of ibrutinib initiation, 3 patients developed type 2 diabetes, with 2 requiring insulin. However, among 8 patients with type 2 diabetes prior to starting therapy, no changes in insulin requirements were observed.

“This finding would support the idea that some tyrosine kinase inhibitors cause a hyperinflammatory response,” said Christian A. Koch, MD, PhD, FACP, MACE, of the division of endocrinology at Fox Chase Cancer Center, Philadelphia, Pennsylvania.

According to Dr Koch, there is evidence that ibrutinib directly causes inflammation of pancreatic islet cells, eventually leading to a lack of insulin and causing an imbalance of glucose. The results of the study by Dr Molica and colleagues goes against this theory because the 8 patients with diabetes did not experience a change in their insulin requirement.

“This shows that we really do not quite understand yet what causes some of these adverse effects,” Dr Koch said.

Dr Molica also pointed out that the pancreatic lesions seen in animal studies are likely a class effect of BTK inhibitors, are mainly due to hemorrhage and subsequent inflammation and fibrosis, which may exacerbate an islet-centered pathology that may not be relevant in humans.

Next, the study showed a significant increase in high-density lipoprotein (HDL) concentration at 6 months and 12 months.

“In the general population there are data demonstrating an inverse association between HDL levels and atrial fibrillation risk,” Dr Molica said.