PAPER SPOTLIGHT

Previous studies have indicated that treatment with ibrutinib , a Bruton tyrosine kinase ( BTK ) inhibitor , is associated with a 5 to 15 percent increase in the incidence of atrial fibrillation ( AF ), and , in a Letter to the Editor published in Blood , researchers cited a risk of cardiac symptoms in these patients , suggesting that clinicians should consider the possibility of ventricular arrhythmia ( VA ) when weighing the risk-benefit ratio of ibrutinib therapy .

“ Clinicians should be aware of the cardiac risk profile of patients starting on ibrutinib , and take seriously and evaluate any potential cardiac symptoms that occur on ibrutinib , including palpitations , dizziness , or syncope ,” corresponding author Jennifer R . Brown , MD , PhD , told ASH Clinical News . “ I would be particularly concerned about those patients at higher

clinical risk of ventricular arrhythmias .”

Benjamin L . Lampson , MD , PhD , from the Division of Hematologic Malignancies and Department of Medical Oncology at the Dana- Farber Cancer Institute in Boston , Massachusetts , and co-authors used data from the U . S . Food and Drug Administration ’ s ( FDA ) Adverse Event Reporting System ( FAERS ) to identify episodes of VA in patients receiving ibrutinib between November 2013 ( after the FDA

– JENNIFER R . BROWN , MD , PhD

approved ibrutinib for the treatment of mantle cell lymphoma [ MCL ]) and December 2015 . The authors then estimated incidence rates of VA from reported data on clinical trials of ibrutinib .

Data were collected on cases related to VA , ventricular fibrillation ( VF ), Brugada syndrome , right bundle branch block , cardiac arrest , cardiac death , cardiac fibrillation ,

cardio-respiratory arrest , conduction disorder , sudden death , sudden cardiac death , ventricular extrasystoles , and ventricular tachycardia . If ibrutinib discontinuation , cardiac events , or deaths were redacted , the researchers used the date when the patient was last seen alive or when the event was filed . Cases without enough information were excluded from the study .

The authors detailed four patient cases in their report :

• The index case was a 60-year-old man with chronic lymphocytic leukemia ( CLL ) who had no prior cardiac history . Two months after beginning ibrutinib , he reported new palpitations , and , 86 days after treatment , he experienced syncope . He had frequent premature ventricular contractions and non-sustained ventricular tachycardia ( VT ). He then started anti-arrhythmic agents , and a cardioverter-defibrillator was implanted . After discharge , he was maintained on ibrutinib , quinidine , and metoprolol for 28 months and experienced occasional non-sustained VT according to device interrogation .

• The second case was a 55-year-old man with refractory CLL , primary sclerosing cholangitis , and no

prior cardiac disease . He collapsed one year after initiating ibrutinib and was resuscitated . While hospitalized , he had an R-on-T phenomenon , resulting in polymorphic VT followed by VF . Coronary angiography , echocardiogram , cardiac magnetic resonance imaging , and genetic testing all failed to identify any cardiac abnormalities .

• The third case involved a 53-yearold man with CLL , AF , coronary artery disease , and a history of smoking 30 packs per year who reported palpitations and pre-syncope 19 days after starting ibrutinib . Holter monitoring showed frequent ventricular ectopic beats , and he was found to have polymorphic VT 9 days later .

• The fourth case of VF in a patient on ibrutinib may have been triggered by an acute ischemic event .

“ In all cases , ibrutinib was stopped , and in three instances , was resumed 10 to 50 days later ,” the authors reported . “ Two patients had recurrent VAs .”

Overall , the median time to event from ibrutinib initiation was 65 days ( range = 6-698 days ), and the median age at event was 61 years ( range = 49- 85 years ). “ In all FAERS cases that reported further cardiac work-up , no clear cause could be identified ,” Dr . Lampson and co-authors noted .

The authors then estimated incidence rates of VA in clinical trials

of ibrutinib , identifying seven additional instances of VT / VF and six sudden deaths . Ten of the 13 patients had no prior cardiac history , and none of the patients was taking other medications known to induce cardiac arrhythmias .

In the group of 10 patients , the weighted average of sudden death incidence rate was 788 events per 100,000 person-years , compared with 200 to 400 events per 100,000 person-years for the typical 65-year-old patient ( p = 0.025 ).

Unfortunately , Dr . Lampson and colleagues noted , the current report is not able to define the mechanisms behind the associations between ibrutinib and VA incidence . “ Ibrutinib is an arrhythmogenic molecule , although the arrhythmogenic mechanism is not well understood ,” they wrote . However , “ the kinase responsible for these changes is unknown and may not be BTK .”

The study is limited by its retrospective design , the self-reported nature of the FAERS data , and the lack of access to primary trial data . “ Nevertheless , future trials of ibrutinib should report VAs and sudden deaths ,” the authors concluded . “ Clinicians should inquire about symptoms of VAs in ibrutinib-treated patients [ and use ] a low threshold for cardiac work-up if they are present .”

REFERENCE

Lampson BL , Yu L , Glynn RJ , et al . Ventricular arrhythmias and sudden death in patients taking ibrutinib . Blood . 2017 February 10 . [ Epub ahead of print ]

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