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Ibrutinib-Associated Adverse Events

Insights From:Jennifer R. Brown, MD, PhD, Harvard Medical School; Richard R. Furman, MD, Weill Cornell Medical College; Brad S. Kahl, MD, UW Carbone Cancer Cente
Published: Friday, Aug 14, 2015


Ibrutinib is a highly effective therapy that is FDA-approved for patients with chronic lymphocytic leukemia (CLL), mantle cell lymphoma, and Waldenström's macroglobulinemia. Ibrutinib is generally a well-tolerated oral therapy, although it is common for patients to experience some gastrointestinal issues, comments Jennifer Brown, MD. The most common adverse event (AE) is diarrhea, which tends to be limited and occurs early in therapy. However, in many instances, diarrhea will resolve on its own within the first one to two months.

Ibrutinib is primarily considered an inhibitor of Bruton's tyrosine kinase (BTK); however, other kinases, such as EGFR, are also blocked, which could be the cause of AEs like diarrhea, notes Richard Furman, MD. To help ameliorate these events, patients should take ibrutinib at bedtime when there is no food in the gastrointestinal tract, adds Furman.

Other AEs associated with ibrutinib include arthralgia, easy bruising, and delayed wound healing. Arthralgia can generally be resolved with a short course of corticosteroids; however, some patients will find this AE intolerable, resulting in treatment discontinuation, notes Brown. Other AEs with ibrutinib include low-grade bleeding, with occasional reports of intracranial hemorrhages and gastrointestinal bleeds. Given this risk, ibrutinib should not be administered with concomitant warfarin, Brown advises.

Many of the AEs associated with ibrutinib are related to the inhibition of BTK, which is present on platelets and is required for platelet aggregation induced by collagen or shear stress. Long-term BTK inhibition with ibrutinib (1 to 3 years) has been shown to cause increased levels of megakaryocytes, which can lead to large platelets in peripheral blood. These platelets are probably hyperfunctional, which may lead to impairment of microcirculatory function, suggests Furman.

The phase III RESONATE trial evaluated the use of single-agent ibrutinib versus ofatumumab and the phase III HELIOS trial assessed whether adding ibrutinib to bendamustine and rituximab provided benefit over bendamustine and rituximab alone. In both studies, the risks of grade 3 and 4 hemorrhage were equivalent in both arms. The HELIOS study did confirm that there was an increased risk of atrial fibrillation with ibrutinib compared with placebo; however, the etiology or mechanism behind this AE remains unclear, notes Furman.

Other novel agents approved for patients with CLL are associated with distinct AEs, including the PI3 kinase inhibitor idelalisib, which is associated with transaminitis and diarrhea. Idelalisib-related transaminitis typically begins between weeks 4 and 12 of therapy and is always asymptomatic, states Furman. Idelalisib-related diarrhea can present as early or late diarrhea, and tends to be fulminant and severe.
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Ibrutinib is a highly effective therapy that is FDA-approved for patients with chronic lymphocytic leukemia (CLL), mantle cell lymphoma, and Waldenström's macroglobulinemia. Ibrutinib is generally a well-tolerated oral therapy, although it is common for patients to experience some gastrointestinal issues, comments Jennifer Brown, MD. The most common adverse event (AE) is diarrhea, which tends to be limited and occurs early in therapy. However, in many instances, diarrhea will resolve on its own within the first one to two months.

Ibrutinib is primarily considered an inhibitor of Bruton's tyrosine kinase (BTK); however, other kinases, such as EGFR, are also blocked, which could be the cause of AEs like diarrhea, notes Richard Furman, MD. To help ameliorate these events, patients should take ibrutinib at bedtime when there is no food in the gastrointestinal tract, adds Furman.

Other AEs associated with ibrutinib include arthralgia, easy bruising, and delayed wound healing. Arthralgia can generally be resolved with a short course of corticosteroids; however, some patients will find this AE intolerable, resulting in treatment discontinuation, notes Brown. Other AEs with ibrutinib include low-grade bleeding, with occasional reports of intracranial hemorrhages and gastrointestinal bleeds. Given this risk, ibrutinib should not be administered with concomitant warfarin, Brown advises.

Many of the AEs associated with ibrutinib are related to the inhibition of BTK, which is present on platelets and is required for platelet aggregation induced by collagen or shear stress. Long-term BTK inhibition with ibrutinib (1 to 3 years) has been shown to cause increased levels of megakaryocytes, which can lead to large platelets in peripheral blood. These platelets are probably hyperfunctional, which may lead to impairment of microcirculatory function, suggests Furman.

The phase III RESONATE trial evaluated the use of single-agent ibrutinib versus ofatumumab and the phase III HELIOS trial assessed whether adding ibrutinib to bendamustine and rituximab provided benefit over bendamustine and rituximab alone. In both studies, the risks of grade 3 and 4 hemorrhage were equivalent in both arms. The HELIOS study did confirm that there was an increased risk of atrial fibrillation with ibrutinib compared with placebo; however, the etiology or mechanism behind this AE remains unclear, notes Furman.

Other novel agents approved for patients with CLL are associated with distinct AEs, including the PI3 kinase inhibitor idelalisib, which is associated with transaminitis and diarrhea. Idelalisib-related transaminitis typically begins between weeks 4 and 12 of therapy and is always asymptomatic, states Furman. Idelalisib-related diarrhea can present as early or late diarrhea, and tends to be fulminant and severe.
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