Farrukh T. Awan, M.D.
Associate Professor of Internal Medicine
Director of Lymphoid Malignancies Program
Harold C. Simmons Comprehensive Cancer Center
University of Texas Southwestern Medical Center
The development of ibrutinib for the treatment of various B-cell malignancies has been a significant advance in the field. It is currently approved for the treatment of patients with mantle cell lymphoma (MCL), chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL), marginal zone lymphoma (MZL), Waldenstrom’s macroglobulinemia (WM), and chronic graft vs. host disease (cGVHD).
Ibrutinib is generally well tolerated and results in excellent disease control. However, patients have to continue taking the treatment for an indefinite duration until it stops working or causes intolerable side effects. Over the last few years, there has been a number of publications detailing the side effects of ibrutinib. Specifically, there has been a lot of attention paid to the risk of cardiovascular side effects with the ongoing use of ibrutinib. In general, these side effects can be grouped into abnormal heart rhythms like atrial and ventricular arrhythmias; and vascular issues like hypertension.
Atrial fibrillation was one of the first abnormal heart rhythm that was seen in patients on ibrutinib. In this disorder the upper heart chamber beats abnormally and irregularly fast. Patients can experience palpitations, chest pounding, fatigue, shortness of breath, and light headedness. The abnormal rhythm also increases the risk of blood clots and strokes. The use of ibrutinib significantly increases the risk of atrial fibrillation and this risk continues to increase over time. This complication is also seen more frequently in patients with a prior history of this condition. Various risk scores can be used to predict this risk and patients need to be monitored closely for this particular side effect. Patients should ideally be seen by a cardiologist prior to starting ibrutinib especially if they have a prior history of atrial fibrillation. We also recommend a baseline EKG to document the heart rhythm prior to starting the drug. In the event that patient develops atrial fibrillation, we recommend aggressive management to optimally control the heart rate with specific medications that do not interact with ibrutinib. Some patients may also require holding the drug or decreasing the dose to control or reverse the side effect.
Another issue that complicates the management of atrial fibrillation in patients on ibrutinib is the use of blood thinners. Most patients with atrial fibrillation need concomitant treatment with blood thinners to decrease the risk of blood clots and strokes. However, blood thinners should be used very cautiously in patients on ibrutinib since ibrutinib significantly increases the risk of bleeding. Patients are advised to discuss this issue with their oncologist and cardiologist prior to starting anti-platelet agents or blood thinners.
Ventricular tachycardia or fibrillation are abnormal rhythm of the bottom chambers of the heart that can cause palpitations, chest pain, shortness of breath, lightheadedness, or loss of consciousness by limiting the amount of blood being pumped to vital body organs. These arrhythmias can also cause sudden cardiac arrest and death in some patients. Ibrutinib use has been shown to increase the risk of this rare arrhythmia and sudden cardiac death as compared to a similar population of people who are not on ibrutinib. These abnormal arrhythmias are therefore an extremely serious condition and need to be managed emergently. While the specific risk factors are not well known for this life-threatening complication, its risk is increased in patients with a history of atrial fibrillation. We therefore recommend close monitoring of patients with any cardiac arrhythmias in conjunction with an experienced cardiology team familiar with the complications seen in patients on ibrutinib. All patients with any prior cardiac history should have a thorough cardiac assessment prior to starting ibrutinib. Patients are also advised to keep a symptom diary while on ibrutinib.
Hypertension or elevated blood pressure is a well-recognized side effect of ibrutinib. This happens in more than 70% of the patients on ibrutinib and mostly within the first six months of starting treatment. This results in more than a third of patients requiring a new blood pressure medicine or increasing the dose of an existing medication. This not only results in an increased risk of abnormal cardiac rhythms but also results in new heart failure, stroke, heart attack, and sudden cardiac death in patients who develop new or worsened hypertension as compared to patients who don’t develop hypertension. The risk of developing new or worsening hypertension is also significantly increased when compared to a comparable population not on ibrutinib. Importantly, the risk of developing serious complications can also be reduced by aggressively controlling hypertension while on ibrutinib. We therefore recommend close follow up with a primary care physician and cardiologist with frequent blood pressure monitoring for patients on ibrutinib.
In conclusion, ibrutinib is a BTK inhibitor that is an effective treatment for the management of patients with various B-cell malignancies. However, better understanding and consistent practice guidelines are required to manage the adverse events related to the use of this drug. This will allow us to identify and optimally manage the side effects related to this drug to maximize benefit and minimize toxicity. We also recommend consulting with a specialized CLL physician and cardiology team experienced in the management of patients with ibrutinib. In addition, it remains to be seen whether these issues will be observed at similar frequency with newer BTK inhibitors which are being developed for various B-cell malignancies.