Atrial fibrillation link to ibrutinib highlights urgent need for guidelines

Blood cancers

16 Sep 2016

There is a “clear and pressing need” to improve the management of patients with chronic lymphocytic leukaemia who develop atrial fibrillation as a result of ibrutinib (Imbruvica) treatment, Sydney experts have claimed.

Haematologists Professor Stephen Mulligan and Professor Christopher Ward, with electrophysiologist Dr David Whalley and pharmacologist Professor Sarah Hilmer, said it is essential to document and follow up all patients who develop AF on treatment, regardless of whether it is symptomatic or asymptomatic.

The need for more data and better treatment guidelines reflects the fact that up to 40% of patients discontinue ibrutinib because of AF. The related clinical challenges of rate control, anticoagulant stroke prophylaxis and bleeding risk are complicated by multiple drug interactions.

Professor Mulligan and his colleagues wrote a commentary in the British Journal of Haematology on a separate review of 56 ibrutinib-related AF cases, including six identified at the Peter MacCallum Cancer Centre in Melbourne.

Although 15 cases had a history of prior AF, all the patients were in sinus rhythm when they commenced ibrutinib at the standard dose of 420 mg/day.

AF emerged a median of 3.8 months after starting treatment, and in 75% of cases it occurred within a year.

Three patients developed severe cardiac failure, which was fatal in one case, one patient had a stroke, and eight non-thrombocytopenic patients had grade 3-4 bleeding events, ranging from gastrointestinal haemorrhage to cardiac tamponade and intrapulmonary haemorrhage.

AF was classified as grade 3-4, being symptomatic and/or requiring urgent medical intervention, in 23 cases.

“AF was persistent in 35 of 56 cases despite treatment,” wrote the international research team that included Constantine Tam from the Peter MacCallum Centre. “Ibrutinib was permanently discontinued in 26 cases.”

Even though the cases occurred in major research centres, there was a very inconsistent approach to management with highly variable anticoagulation regimens and a range of treatments aiming for AF rate or rhythm control.

“Increasingly, physicians less experienced in its use will prescribe ibrutinib,” they said.

“We believe this highlights the urgent need to establish clinical practice guidelines, in collaboration with expert cardiologists, haematologists, oncologists and clinical pharmacologists.”

Longitudinal long-term follow-up of large populations with CLL receiving ibrutinib is also needed to determine thromboembolic and bleeding risk in this population.

“Our study… highlights the critical need for collaborative management of such patients with an expert cardiologist,” they said.

“Any pre-disposing or precipitating factors (eg hyperthyroidism, infection, electrolyte disturbance, ischaemia, heart failure or valvular disease) should be identified and corrected, if possible.”

As outcomes after cessation of ibrutinib are poor, it is desirable to continue therapy, whenever possible, they concluded.


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