Though drug ibrutinib has been linked to the development of atrial fibrillation (AF) and atrial flutter (AFl), with an observed incidence of AF among patients taking ibrutinib of 6 to 9 percent. Two pooled analyses presented at the 2016 ASH Meeting on Hematologic Malignancies confirm the risk of AF/AFl development with ibrutinib treatment, and highlight the need for further evidence about anticoagulation in these patients.1,2
In the first study, Jennifer R. Brown, MD, PhD, of the Chronic Lymphocytic Leukemia Center at the Dana-Farber Cancer Institute in Boston, Massachusetts, and authors conducted a pooled analysis of the following trials:
- RESONATE (median follow-up = 9.4 months)
- RESONATE-2 (median follow-up = 18.4 months)
- HELIOS (median follow-up = 17 months)
- RAY (median follow-up = 20 months)
Together, the trials included 1,505 patients: 756 received ibrutinib either alone or with bendamustine + rituximab, and 749 received a comparator treatment (COM). The median patient age for both groups was 71 years. The median treatment exposure was 11.3 months for those treated with ibrutinib (range = 1.81-27.4 months) and 9.1 months for the COM cohort (range = 0.03-27.37 months).
Sixty-one patients developed treatment-related AF (defined as events occurring after the first dose of the study drug until 30 days after the last dose): 49 ibrutinib-treated patients (6.5%) and 12 COM-treated patients (1.6%).
Dr. Brown and colleagues found that patients treated with ibrutinib had a four-times higher risk for developing AF than those in the COM cohort (multivariate hazard ratio [HR] = 4.0; 95% CI 1.94-8.29; p=0.0002). Prior history of AF (27% vs. 25%) and hypertension (63% vs. 83%) were other risk factors for AF in the ibrutinib and COM groups, respectively.
While most patients developed AF in the first four months of treatment (61% with ibrutinib and 75% with COM), the authors describe “events reported among all time intervals through 18 months.” Most AF events were grade 1/2 in both the ibrutinib and COM groups (67.3% vs. 66.7%, respectively), though serious cases of AF were reported in 49 percent of ibrutinib-treated patients and 50 percent of COM-treated patients.
No AF events resulted in a dose reduction of ibrutinib, though dose interruptions occurred in both the ibrutinib (32.7%) and COM (33.3%) groups. Seven patients in the ibrutinib cohort (14.3%) discontinued treatment due to AF. “AF events that occurred in these studies appeared to be manageable, with the majority of patients remaining on ibrutinib,” the authors concluded, adding that “the incidence of AF in this pooled analysis is consistent with ibrutinib prescribing information.”
In the second study, Seongseok Yun, MD, PhD, of the H. Lee Moffitt Cancer Center in Tampa, Florida, and authors conducted a pooled analysis of four trials that assessed the risk of AF/AFl and bleeding associated with ibrutinib use.
A search of PubMed, EMBASE, Cochrane Database, and meeting abstracts for trials comparing ibrutinib and chemoimmunotherapy (CIT) agents through May 15, 2016, identified four trials, which enrolled a total of 1,509 patients with chronic lymphocytic leukemia/small lymphocytic leukemia (CLL/SLL; n=1,231) or mantle cell lymphoma (MCL; n=278).
In the ibrutinib arms:
- 330 patients were treated with ibrutinib
- 289 patients were treated with ibrutinib and bendamustine + rituximab
In three studies, ibrutinib was dosed at 420 mg/day, and the other study evaluated a dose of 560 mg/day.
In the CIT arms:
- 191 patients were treated with ofatumumab
- 132 patients were treated with chlorambucil
- 289 patients were treated with bendamustine + rituximab
- 139 patients were treated with temsirolimus
The median patient age ranged from 64 to 72.5 years, and 31.7 percent of patients were female.
Compared with CIT, ibrutinib was associated with a significantly higher incidence of serious AF/AFl (risk ratio [RR] = 3.8; 95% CI 1.56-9.29; p=0.003), as well as all-grade AF/AFl (RR=8.81; 95% CI 2.7-28.75; p=0.0003) and all-grade bleeding (RR=2.93; 95% CI 1.14-7.52; p=0.03).
There were, however, no significant differences in major bleeding rates between the two groups (RR=1.72; 95% CI 0.95-3.11; p=0.07). Subgroup analyses also revealed no significant differences in the risk of serious AF/AFl and major bleeding between patients with CLL/SLL or MCL, treatment-naïve and relapsed/refractory disease, or the length and dose of ibrutinib treatment.
“The risks of AF/AFl and all-grade bleeding were significantly higher in the ibrutinib group,” Dr. Yun and colleagues concluded. “These results indicate the need for clinical vigilance in ibrutinib-treated patients with prior or treatment-emergent AF/AFl requiring anticoagulation until further evidence on anticoagulation protocols emerges and the understanding of this adverse event and its management grow.”
- Brown JR, O’Brien SM, Moslehi J, et al. Pooled analysis of atrial fibrillation adverse events in ibrutinib randomized controlled registration trials. Abstract #89587. Presented at the ASH Meeting on Hematologic Malignancies, September 16-17, 2016; Chicago, IL.
- Yun S, Vincelette ND, Acharya U, Abraham I. Risk of atrial fibrillation and bleeding diathesis associated with ibrutinib treatment: A pooled-analysis of four randomized trials. Abstract #89302. Presented at the ASH Meeting on Hematologic Malignancies, September 16-17, 2016; Chicago, IL.