Feature

‘Surprising’ link between ibrutinib, hypertension spurs further study

Daniel Addison, MD
Daniel Addison

Ibrutinib, a paradigm-changing drug for the treatment of various blood cancers, appeared to be more closely associated with new or worsened hypertension than previously thought, according to results of a study published in Blood.

Researchers also found that patients with B-cell malignancies who experienced hypertension associated with ibrutinib (Imbruvica; Pharmacyclics, Janssen) were more than twice as likely to develop heart problems, including arrhythmias, compared with those without new-onset or worsening hypertension.

“We noticed in our clinical practice that there seemed to be a high number of patients [taking ibrutinib] who subsequently developed high blood pressures, which were often difficult to treat,” Daniel Addison, MD, assistant professor of cardiovascular medicine and co-director of the cardio-oncology program at The Ohio State University, said in an interview with HemOnc Today. “My cancer colleagues often would ask for insights into treating this challenging high blood pressure, and because of this, we embarked on this collaborative study in conjunction with our cancer colleagues and cancer center pharmacists here at Ohio State.”

Incidence ‘higher than we think’

In the single-center study, Addison and colleagues reviewed medical records of 562 consecutive patients (mean age, 63.8 years; 70.6% men; 92.7% white) who received ibrutinib for B-cell cancers at their institution between 2009 and 2016. The researchers evaluated the prevalence of new hypertension or hypertension that increased in severity after ibrutinib initiation. They also assessed the correlation between high blood pressure and other cardiovascular measures.

Researchers defined new hypertension as systolic blood pressure of 130 mm Hg observed on two separate visits within 3 months.

They found that over median follow-up of 30 months, 71.6% of ibrutinib users developed new-onset hypertension. Among these patients, 17.7% had blood pressure that exceeded 160/100 mm Hg.

The development of new hypertension occurred early in the treatment regimen among patients without pre-existing hypertension, 54.1% of whom reached the hypertension threshold within 6 months. This equated to an overall average increase in systolic blood pressure of 13 mm Hg.

In a comparison of this increase with the projected increase using a traditional risk prediction model, researchers found that hypertension was almost 13 times higher at 1 year among ibrutinib-treated patients compared with age-matched individuals with similar heart conditions who did not take ibrutinib.

Sameh Gaballa, MD
Sameh R. Gaballa

“This study is somewhat surprising, because it’s showing that the incidence of hypertension is actually higher than we think it is,” Sameh R. Gaballa, MD, assistant professor of medical oncology, hematologic malignancies and bone marrow transplantation at Thomas Jefferson University, said in an interview with HemOnc Today. “It’s affecting more than 70% of patients.”

Gaballa, who was not involved with the study, cited the new-onset hypertension rates seen in the RESONATE trials of ibrutinib, which also were conducted at Ohio State. He noted that those rates were closer to 40%.

“They did use different cutoffs for blood pressure, compared with the initial trials,” Gaballa said. “They used 130 mm Hg systolic blood pressure, and the previous studies used 140, but I’m not sure if that small of a difference would really account for these findings.”

More than one-third of the ibrutinib-treated patients initiated antihypertensive medication or had their dose increased; one in five patients needed three or more medications to control their hypertension.

Although no specific class of antihypertensive appeared associated with control or prevention of ibrutinib-related hypertension, initiation of these medications correlated with a reduced risk for major adverse cardiovascular events (HR = 0.4, 95% CI, 0.24-0.66).

Patients treated with ibrutinib who developed new or worsened hypertension had twice the rate of cardiovascular complications (19.1%) than those who did not experience an increase in blood pressure (8.2%). Complications during ibrutinib therapy included atrial fibrillation (13.6%), new heart failure (3.7%), cerebrovascular accidents (2.1%), myocardial infarction (1.4%), and other heart rhythm issues or sudden cardiac death (1.1%).

“Generally, I do look at hypertension as a potential signal that some alterations to the heart and the blood vessels may be ongoing after drug initiation,” Addison said. “Because of this, I usually have a lower threshold to start a blood pressure medicine, if the patient can tolerate it.”

Implications of the study

Although these findings are cause for concern and further study, Gaballa said he does not believe they warrant changes in clinical practice.

“Ibrutinib is still an excellent choice for the vast majority of patients,” he said. “Obviously, we have other options now, including venetoclax [Venclexta; AbbVie, Genentech] plus obinutuzumab [Gazvya, Genentech] in the upfront setting and venetoclax plus rituximab [Rituxan; Genentech, Biogen] in the relapsed setting, but in our experience, the vast majority of patients who were treated with ibrutinib tolerated it well.”

Addison agreed, saying that he is unlikely to suggest discontinuation of ibrutinib treatment for a patient due to hypertension issues alone.

“I don’t generally suggest that patients stop taking it, as this still remains very much a life-saving drug for a growing number of patients,” he said. “Typically, we in the cardio-oncology community try to work hand-in-hand with our cancer colleagues to better allow these patients to successfully continue their life-saving cancer treatments.”

Addison said his group and others are conducting additional studies on the correlation between ibrutinib and hypertension/cardiovascular issues. He said understanding the underlying driver of this association will yield insight into how to manage it.

“We’re looking at ways of detecting meaningful changes in the cardiovascular system after patients start this therapy, as well as better predicting who is most likely to develop other heart problems like atrial fibrillation, arrhythmias and even sudden death,” he told HemOnc Today. “Additionally, we are trying to determine the best treatment strategies for the growing number of ibrutinib users. This has been a large focus of my work and the work of our research team.”

In the meantime, these findings serve to further inform hematologists and oncologists about a potential risk their patients may face when taking ibrutinib.

“I think this study is alerting oncologists to look at the blood pressure issue and preemptively manage it,” Gaballa told HemOnc Today. “This is something we need to look at a little closer, because it hasn’t been looked at very closely in the past.” – by Jennifer Byrne

Reference:

Dickerson T, et al. Blood. 2019;doi:10.1182/blood.2019000840.

For more information:

Daniel Addison, MD, can be reached at 473 W. 12th Ave, Suite 200, Columbus, OH 43210; email: daniel.addison@osumc.edu.

Sameh Gaballa, MD, can be reached at 834 Chestnut St., Suite 320, Philadelphia, PA 19107; email: sameh.gaballa@jefferson.edu.

Disclosures: Addison reports no relevant disclosures. Please see the study for all other authors’ relevant financial disclosures. Gaballa reports research funding from Pharmacyclics and a speakers/advisory board role with Janssen and Pharmacyclics.

 

Daniel Addison, MD
Daniel Addison

Ibrutinib, a paradigm-changing drug for the treatment of various blood cancers, appeared to be more closely associated with new or worsened hypertension than previously thought, according to results of a study published in Blood.

Researchers also found that patients with B-cell malignancies who experienced hypertension associated with ibrutinib (Imbruvica; Pharmacyclics, Janssen) were more than twice as likely to develop heart problems, including arrhythmias, compared with those without new-onset or worsening hypertension.

“We noticed in our clinical practice that there seemed to be a high number of patients [taking ibrutinib] who subsequently developed high blood pressures, which were often difficult to treat,” Daniel Addison, MD, assistant professor of cardiovascular medicine and co-director of the cardio-oncology program at The Ohio State University, said in an interview with HemOnc Today. “My cancer colleagues often would ask for insights into treating this challenging high blood pressure, and because of this, we embarked on this collaborative study in conjunction with our cancer colleagues and cancer center pharmacists here at Ohio State.”

Incidence ‘higher than we think’

In the single-center study, Addison and colleagues reviewed medical records of 562 consecutive patients (mean age, 63.8 years; 70.6% men; 92.7% white) who received ibrutinib for B-cell cancers at their institution between 2009 and 2016. The researchers evaluated the prevalence of new hypertension or hypertension that increased in severity after ibrutinib initiation. They also assessed the correlation between high blood pressure and other cardiovascular measures.

Researchers defined new hypertension as systolic blood pressure of 130 mm Hg observed on two separate visits within 3 months.

They found that over median follow-up of 30 months, 71.6% of ibrutinib users developed new-onset hypertension. Among these patients, 17.7% had blood pressure that exceeded 160/100 mm Hg.

The development of new hypertension occurred early in the treatment regimen among patients without pre-existing hypertension, 54.1% of whom reached the hypertension threshold within 6 months. This equated to an overall average increase in systolic blood pressure of 13 mm Hg.

In a comparison of this increase with the projected increase using a traditional risk prediction model, researchers found that hypertension was almost 13 times higher at 1 year among ibrutinib-treated patients compared with age-matched individuals with similar heart conditions who did not take ibrutinib.

Sameh Gaballa, MD
Sameh R. Gaballa

“This study is somewhat surprising, because it’s showing that the incidence of hypertension is actually higher than we think it is,” Sameh R. Gaballa, MD, assistant professor of medical oncology, hematologic malignancies and bone marrow transplantation at Thomas Jefferson University, said in an interview with HemOnc Today. “It’s affecting more than 70% of patients.”

Gaballa, who was not involved with the study, cited the new-onset hypertension rates seen in the RESONATE trials of ibrutinib, which also were conducted at Ohio State. He noted that those rates were closer to 40%.

“They did use different cutoffs for blood pressure, compared with the initial trials,” Gaballa said. “They used 130 mm Hg systolic blood pressure, and the previous studies used 140, but I’m not sure if that small of a difference would really account for these findings.”

More than one-third of the ibrutinib-treated patients initiated antihypertensive medication or had their dose increased; one in five patients needed three or more medications to control their hypertension.

Although no specific class of antihypertensive appeared associated with control or prevention of ibrutinib-related hypertension, initiation of these medications correlated with a reduced risk for major adverse cardiovascular events (HR = 0.4, 95% CI, 0.24-0.66).

Patients treated with ibrutinib who developed new or worsened hypertension had twice the rate of cardiovascular complications (19.1%) than those who did not experience an increase in blood pressure (8.2%). Complications during ibrutinib therapy included atrial fibrillation (13.6%), new heart failure (3.7%), cerebrovascular accidents (2.1%), myocardial infarction (1.4%), and other heart rhythm issues or sudden cardiac death (1.1%).

“Generally, I do look at hypertension as a potential signal that some alterations to the heart and the blood vessels may be ongoing after drug initiation,” Addison said. “Because of this, I usually have a lower threshold to start a blood pressure medicine, if the patient can tolerate it.”

PAGE BREAK

Implications of the study

Although these findings are cause for concern and further study, Gaballa said he does not believe they warrant changes in clinical practice.

“Ibrutinib is still an excellent choice for the vast majority of patients,” he said. “Obviously, we have other options now, including venetoclax [Venclexta; AbbVie, Genentech] plus obinutuzumab [Gazvya, Genentech] in the upfront setting and venetoclax plus rituximab [Rituxan; Genentech, Biogen] in the relapsed setting, but in our experience, the vast majority of patients who were treated with ibrutinib tolerated it well.”

Addison agreed, saying that he is unlikely to suggest discontinuation of ibrutinib treatment for a patient due to hypertension issues alone.

“I don’t generally suggest that patients stop taking it, as this still remains very much a life-saving drug for a growing number of patients,” he said. “Typically, we in the cardio-oncology community try to work hand-in-hand with our cancer colleagues to better allow these patients to successfully continue their life-saving cancer treatments.”

Addison said his group and others are conducting additional studies on the correlation between ibrutinib and hypertension/cardiovascular issues. He said understanding the underlying driver of this association will yield insight into how to manage it.

“We’re looking at ways of detecting meaningful changes in the cardiovascular system after patients start this therapy, as well as better predicting who is most likely to develop other heart problems like atrial fibrillation, arrhythmias and even sudden death,” he told HemOnc Today. “Additionally, we are trying to determine the best treatment strategies for the growing number of ibrutinib users. This has been a large focus of my work and the work of our research team.”

In the meantime, these findings serve to further inform hematologists and oncologists about a potential risk their patients may face when taking ibrutinib.

“I think this study is alerting oncologists to look at the blood pressure issue and preemptively manage it,” Gaballa told HemOnc Today. “This is something we need to look at a little closer, because it hasn’t been looked at very closely in the past.” – by Jennifer Byrne

Reference:

Dickerson T, et al. Blood. 2019;doi:10.1182/blood.2019000840.

For more information:

Daniel Addison, MD, can be reached at 473 W. 12th Ave, Suite 200, Columbus, OH 43210; email: daniel.addison@osumc.edu.

Sameh Gaballa, MD, can be reached at 834 Chestnut St., Suite 320, Philadelphia, PA 19107; email: sameh.gaballa@jefferson.edu.

Disclosures: Addison reports no relevant disclosures. Please see the study for all other authors’ relevant financial disclosures. Gaballa reports research funding from Pharmacyclics and a speakers/advisory board role with Janssen and Pharmacyclics.

 

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