AT THE IWCLL MEETING

NEW YORK (FRONTLINE MEDICAL NEWS) – A left atrial abnormality on a pretreatment electrocardiogram (ECG) is a moderately specific and sensitive finding that independently predicts risk for developing atrial fibrillation in chronic lymphocytic leukemia patients starting on ibrutinib, findings from a retrospective cohort study indicate.

ECGs are inexpensive and available in most physician’s offices. Routinely checking for a left atrial abnormality before starting ibrutinib would identify a patient subgroup that would benefit from increased monitoring and allow for proactive intervention strategies to reduce complications should atrial fibrillation develop, Anthony Mato, MD , said at the annual meeting of the International Workshop on Chronic Lymphocytic Leukemia.

“Atrial fibrillation (AFib) is the most common toxicity leading to ibrutinib interruption or discontinuation in clinical practice,” said Dr. Mato of the Abramson Cancer Center at the University of Pennsylvania, Philadelphia. Further, patients who develop AFib are at increased risk for congestive heart failure, embolic stroke, and bleeding events in the setting of anticoagulation.

Prior studies, including the RESONATE and RESONATE 2 trials, have clearly demonstrated a link between ibrutinib exposure and the development of AFib. Long-term follow-up data suggest an estimated incidence of 9% to 11%.

Dr. Mato and his colleagues used a case-control design within a two-center retrospective cohort study to test the hypothesis that pre-ibrutinib left atrial abnormality, as determined by the ECG, can identify patients at increased risk for AFib during ibrutinib-based therapy.

Of 153 consecutive CLL patients who were treated with ibrutinib 420 mg/day, 11% developed new AFib at a median of 7 months after starting treatment. Discontinuation of ibrutinib because of AFib was low, with less than 2% of the entire cohort discontinuing treatment.

Based on findings in 20 case patients and 24 controls with an available pretreatment ECG, the presence of a left atrial abnormality before ibrutinib therapy was associated with a nine times increased risk of subsequently developing AFib.

“We looked at baseline hypertension, coronary disease, diabetes, age, and sex, and, although hypertension, coronary disease, and age appeared to have some effect, they weren’t as significant as left atrial abnormality” for predicting risk of AFib, Dr. Mato noted.

On multivariate analysis, controlling for hypertension, coronary disease, and age, a left atrial abnormality continued to be a significant predictor of AFib (odds ratio, 6.6).

“We then wanted to make this more practical for clinicians who may potentially perform an ECG to estimate risk,” he said, noting that ECG test characteristics associated with left atrial abnormality were defined: Sensitivity was estimated to be 79%, specificity was 71%, positive and negative likelihood ratios were 2.7 and 0.3, respectively. Positive predictive value was 68%, and negative predictive value was 81%.

The area under the ROC curve for this single predictor was 75%, he said.

The median age of the cohort at CLL diagnosis was 61 years, and the median age at ibrutinib start was 70. Patients had undergone a median of 2 prior lines of therapy, and 87% were treated in the relapsed/refractory setting.

The median follow-up was 17 months, and the median time from CLL diagnosis to the start of ibrutinib was 73 months.

Cardiovascular characteristics prior to treatment included smoking or former smoking in 49%, hypertension in 42%, hyperlipidemia in 39%, diabetes in 17%, coronary artery disease in 12%, and valvular heart disease in 5%.

Controls were matched to cases on baseline characteristics, and only those with no pretreatment history of AFib, a pretreatment ECG, and therapeutic ibrutinib dosing (420 mg/day for at least 4 months) were included.

To minimize bias, all ECGs were reviewed by a cardio-oncologist blinded to clinical outcomes.

The findings need prospective validation, as they are limited by the retrospective study design, lack of balance with respect to cardiovascular characteristics among cases and controls, a small number of atrial fibrillation cases, and variable timing of pre-ibrutinib ECG, he said.

Patients should be educated about the signs and symptoms of AFib. “The development of AFib during ibrutinib treatment should not prevent its continuation. These patients should be managed medically,” he added.

Dr. Mato reported having no disclosures.

sworcester@frontlinemedcom.com

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