Australasian haematologists and cardio-oncologists outline evidence-based strategies to minimise cardiotoxicity without compromising disease control.
Australian and New Zealand haematologists have released the first regional consensus statement on cardiovascular management in patients with chronic lymphocytic leukaemia treated with Bruton’s tyrosine kinase inhibitors, recognising the growing need for guidance tailored to local practice.
The position paper, published in the Internal Medicine Journal and endorsed by the Haematology Society of Australia and New Zealand, reflects the outcome of a multidisciplinary roundtable held in August 2023 and provides detailed recommendations for risk assessment, monitoring and management of cardiotoxicities associated with this class of drugs.
Bruton’s tyrosine kinase inhibitors, particularly ibrutinib, have revolutionised the management of chronic lymphocytic leukaemia, offering significant improvements in progression-free and overall survival compared with chemoimmunotherapy.
However, their clinical benefit has been offset by concerns around cardiovascular safety, the authors of the paper wrote.
Hypertension, atrial fibrillation, ventricular arrhythmias, bleeding and, more rarely, sudden cardiac death have emerged as important toxicities, with real-world studies reporting a higher incidence than that seen in clinical trials.
Hypertension has been shown to develop or worsen in more than three quarters of patients taking ibrutinib over two to three years, with those affected experiencing more than a two-fold increase in major cardiac events.
Atrial fibrillation has been observed in 10–20% of patients on ibrutinib within the first year of therapy, while bleeding episodes, mostly low-grade but occasionally severe, affect more than half of patients.
Although the development of second-generation BTKi such as acalabrutinib and zanubrutinib has reduced the incidence of some toxicities, particularly atrial fibrillation, concerns remain, particularly for patients with underlying cardiovascular disease.
The consensus statement, which involved a panel of six haematologists and two cardio-oncologists from Australia and New Zealand and US blood cancer specialist Professor Farrukh Awan, emphasised the importance of conducting a thorough baseline cardiovascular risk assessment before initiating therapy.
All patients should have a documented history, blood pressure and pulse measurements, and a 12-lead ECG, with additional investigations and cardiology input guided by the level of risk.
The recommendations are pragmatic in recognising that treatment should not be unduly delayed except in those with very high cardiovascular risk or significant pre-existing disease, in which case multidisciplinary team discussion was required to balance safety with the imperative of controlling the leukaemia.
For most patients, achieving and maintaining a target blood pressure of less than 140/90 mmHg was considered sufficient, though this threshold should be reduced to 130/80 mmHg in those with higher cardiovascular risk or established disease.
The panel advised that management strategies during BTKi therapy should be tailored to individual risk profiles.
Patients deemed low risk could proceed with therapy and standard monitoring, whereas those at medium risk required closer follow-up and, in some cases, referral to cardiology or cardio-oncology services.
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Patients categorised as high or very high risk, including those with heart failure, prior arterial vascular events, cardiomyopathy or persistent uncontrolled hypertension, should be referred to a cardiologist where possible.
Where access was limited, the patient should be referred to other medical specialists such as general physicians to provide interim support.
Second-generation BTKi were generally preferred in patients with significant cardiovascular comorbidities, and in certain cases alternative therapies should be considered.
Throughout treatment, vigilance for new or worsening cardiovascular symptoms was critical, the authors said.
Hypertension was the most common adverse event and required close surveillance, with referral to a hypertension specialist or cardiologist if blood pressure could not be controlled with multiple agents.
Atrial fibrillation presented a particular management challenge, as it increased stroke risk while coexisting with a bleeding tendency associated with BTKi.
Oral anticoagulation is usually recommended in men with a CHA2DS2-VASc score of two or more and in women with a score of three or more, but the panel said this must be weighed against bleeding risk, which may be mitigated through the use of the HAS-BLED score.
Management of atrial fibrillation ranged from rate control with beta blockers to cardioversion or switching to a second-generation BTKi, with decisions best made in consultation with cardiology specialists.
Ventricular arrhythmias and sudden cardiac death, though less frequent, represented some of the most serious complications. In patients with a history of ventricular tachycardia or ventricular arrhythmias, BTKi use was generally contraindicated.
Should new symptoms such as palpitations, syncope or light-headedness occur, urgent cardiology assessment was advised, the panel recommended.
The paper also highlighted special considerations for groups such as patients with Waldenström’s macroglobulinaemia, who may require screening for cardiac amyloidosis, and those with mantle cell lymphoma who may have received prior anthracyclines or transplants and were therefore at high cardiovascular risk.
It recognised the challenges of delivering cardio-oncology care in regional and rural Australia and New Zealand, where cardiology services may be limited and primary care access variable.
The authors advocated for early referral where possible, engagement of general practitioners in blood pressure and cardiovascular risk management, and increased use of telehealth to support patients outside major centres.
They also drew attention to Indigenous populations, who experience a disproportionately high burden of cardiovascular disease and face additional barriers to accessing care.
Collaboration with Aboriginal Medical Services and Māori health providers was encouraged to ensure equitable delivery of BTKi therapy.
While the consensus statement provides practical and regionally relevant recommendations, the authors noted that further research was required.
The risk of ventricular arrhythmias and sudden death in patients on BTKi remained poorly defined, and there was a need to validate screening tools, identify predictors of cardiotoxicity and evaluate potential strategies such as cardioprotective medications or dose reductions.
There was also an ongoing need for better communication between haematology and cardiology teams to optimise outcomes for patients requiring long-term therapy.
“Managing BTKi-associated CV issues in CLL patients is paramount, given an increased risk of major CV events and potential negative consequences on patient outcomes,” the authors concluded.
“RCTs and real-world studies demonstrate an increased risk of AF, bleeding and hypertension with BTKi. Off-target effects likely contribute to these CV toxicities as head-to-head studies with a second-generation BTKi, acalabrutinib and zanubrutinib, show a lower incidence of AF versus ibrutinib, and less hypertension was reported in a study of acalabrutinib versus ibrutinib.
“Baseline CV risk assessment with a 12-lead ECG is recommended in all CLL patients considered for BTKi therapy. The management approach and monitoring requirements should reflect the patient’s risk status. A multidisciplinary strategy and shared decision-making between CV and oncology teams are needed for optimal use of BTKi therapies in patients with medium to high/very high CV risk.
“Further studies, however, are required to validate CV screening tools, better assess predictors of CV toxicity and evaluate the effectiveness of these consensus recommendations. Future research should be directed at alternate strategies to reduce cardiotoxicity, such as administering a cardioprotective agent or reducing the BTKi dose in patients with pre-existing CVD or de novo cardiotoxicity.
“Further data are also required to better elucidate the risk of VA and sudden death in patients on a BTKi. Finally, greater effort to improve multi-disciplinary communication to optimise patient outcomes in CLL is warranted.”
