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Out of the woods, but still in the weeds: When cancer therapy becomes part of a chronic condition
  1. Kathleen W. Zhang
  1. Cardiovascular Division, Department of Internal Medicine, Washington University in St Louis School of Medicine, St Louis, Missouri, USA
  1. Correspondence to Dr Kathleen W. Zhang, Cardiovascular Division, Department of Internal Medicine, Washington University in St Louis School of Medicine, St Louis, Missouri 63110, USA; kwzhang{at}wustl.edu

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Imatinib was introduced on the cover of TIME magazine in 2001 as ‘the magic bullet’ to cure cancer, ushering in a new era of targeted cancer therapeutics that has transformed the modern landscape of cancer treatment. As the first tyrosine kinase inhibitor (TKI) targeting the Bcr-Abl protein, imatinib revolutionised the treatment of chronic myelogenous leukaemia (CML) by improving 10-year survival from 20% to 90%.1 In patients who achieve complete cytogenetic remission on imatinib, overall survival with CML is now comparable to that of population-based controls.2 Due to this metamorphosis from devastating diagnosis to chronic illness, better understanding of non-cancer-related morbidity and mortality is needed in patients with CML on long-term TKI therapy.

In this issue of Heart, Leong et al 3 examined the incidence of major adverse cardiovascular events (MACE) and cardiovascular mortality in 4238 patients with CML from Ontario, Canada between 1986 and 2017, as compared with an age-matched and sex-matched control group. Separate analyses were performed for patients diagnosed before and after the introduction of TKIs in 2001. MACE was defined as hospitalisation for myocardial infarction, cerebrovascular disease or peripheral arterial disease using administrative codes, while cardiovascular death was determined by the physician certifying the patient’s death.

Among 46 618 patients included in the study, the authors found increased risk of all-cause mortality in the patients with CML that was attenuated post-TKIs, consistent with known improvement in overall survival on TKI therapy. While risks of MACE and cardiovascular mortality were lower in the patients with CML pre-TKIs, there were no differences between the CML and control groups post-TKIs. In fact, the risk of peripheral arterial disease was higher in the patients with CML post-TKIs (HR=1.66 (95% CI 1.15 to 2.39)) while the risk of cerebrovascular event was at least as high and possibly higher (HR=1.35 (95% CI 1.00 to 1.83)). Comparing the pre-TKI and post-TKI time periods, the crude incidence rate of cardiovascular death decreased by 61% in the control group while incidence of MACE decreased by 18%. On the other hand, incidence of cardiovascular death decreased only by 32% in the patients with CML while incidence of MACE increased by 3% between the two time periods.

The authors did not find significant differences in risk of MACE or cardiovascular mortality between imatinib and the newer generation TKIs dasatinib and nilotinib, although this analysis was limited by sample size and follow-up duration.

This study is the first to examine the relevance of TKI therapy for cardiovascular outcomes in a real-world population of patients with CML. To date, cardiovascular risk associated with TKIs has been determined based on clinical trials comparing newer generation TKIs with imatinib. Imatinib and bosutinib have not been associated with significant cardiovascular risk in the clinical trial setting.4 In the Dasatinib Versus Imatinib Study in Treatment-Naive Chronic Myeloid Leukemia Patients (DASISION) study, pulmonary arterial hypertension was reported more frequently on dasatinib than on imatinib (5% vs 0.4%) as were arterial vascular events (5% vs 2%).5 Nilotinib was associated with increased risk of arterial vascular events as compared with imatinib (10% vs 2.1%) in the Evaluating Nilotinib Efficacy and Safety in Clinical Trials-Newly Diagnosed Patients (ENESTnd) study; elevations in serum cholesterol (27%) and glucose (51%) levels were also seen on nilotinib.6 In the Ponatinib Ph(+) ALL and CML Evaluation (PACE) trial of ponatinib versus imatinib, incidence of arterial vascular events on ponatinib was 31% at 5-year follow-up with higher risk seen in patients with ≥2 cardiovascular risk factors.7 Due to these findings, ponatinib was temporarily withdrawn from the market in 2013 and is currently approved only for refractory cases.

The present study demonstrates increased cardiovascular risk associated with TKI therapy for CML in a population-based cohort study. While patients with CML had higher baseline prevalence of cardiovascular risk factors than population-matched controls throughout the study period, the risk of MACE or cardiovascular death was higher in the post-TKI era. Interestingly, the vast majority of patients treated with TKI were on imatinib, which has not shown a strong association with adverse cardiovascular events in the clinical trial setting. Very few patients were on nilotinib and ponatinib, which are associated with the highest cardiovascular risk profile and would likely further increase the incidence of MACE in patients with CML. Importantly, this study highlights a glaring discrepancy that has arisen for our patients with CML in the post-TKI era: worse performance on standard metrics of cardiovascular outcomes as compared with those without CML. Heightened cardiology engagement in the long-term care of patients with CML therefore represents an important frontier in the field. Long-term TKI therapy should be recognised more broadly as a risk factor for cardiovascular disease, particularly arterial vascular events, with aggressive modification of cardiovascular risk factors and proactive evaluation of new cardiovascular symptoms in all patients on chronic TKI treatment.

While these principles of preventative and general cardiology are straightforward, their practical implementation for patients with CML represents a larger challenge. Knowledge about the cardiovascular risk of chronic TKI therapy is largely restricted to oncologists and cardio-oncologists. While oncologists frequently take on broad responsibility for the general internal medicine care of their patients, they are unlikely to manage cardiovascular risk factors with the same intensity as a board-certified cardiologist. Many oncologists may refer patients for cardiology consultation to optimise cardiovascular surveillance. However, despite the recent growth in dedicated cardio-oncology centres, availability of cardio-oncologists remains largely restricted to large, academic medical centres in urban centres. Patients in more rural areas are likely to be referred to general cardiologists, who may not recognise the excess cardiovascular risk of chronic TKI therapy. Frequency of clinical follow-up, intensity of preventative therapies, investigation of cardiovascular symptoms and communication with oncology colleagues may lag due to this knowledge gap.

Certainly this points to a growing need for cardio-oncologists in the community. For trainees, cardio-oncology fellowship training programmes are now available at academic medical centres around the world with emerging standards and metrics for clinical training.8 For those already in clinical practice, dedicated cardio-oncology sessions at major cardiology conferences and stand-alone cardio-oncology meetings and professional societies represent opportunities to gain expertise. The recent proliferation of peer-reviewed cardio-oncology publications and even specialty cardio-oncology journals is rapidly building a foundation for evidence-based clinical practice within this emerging discipline.

To truly optimise cardiovascular care for patients with CML, however, it is likely that engagement of the general cardiology community will be necessary (figure 1). Just as the cardiovascular toxicity profiles of plaquenil and anthracyclines have been included in certification examinations as core principles of general cardiology, long-term cancer therapies with significant cardiovascular toxicities need to be incorporated into the general cardiologist’s knowledge base. Notable examples include increased risk of arterial vascular events on chronic TKI therapy for CML as described above, as well as increased risk of adverse cardiovascular events in men with prostate cancer on androgen axis-targeted therapy, especially gonadotropin releasing hormone agonists.9

Figure 1

Engaging the cardiology community to reduce cardiovascular risk on chronic TKI therapy for CML. Stronger engagement of the cardiology community is necessary to improve cardiovascular outcomes for patients with CML on chronic TKI therapy. Aggressive cardiovascular risk factor modification and prompt investigation of cardiovascular symptoms must be incorporated into routine clinical care. Better education among general cardiologists and cardio-oncologists is also needed to improve awareness of the cardiovascular risks of chronic TKI therapy. CML, chronic myelogenous leukaemia; CV, cardiovascular; TKI, tyrosine kinase inhibitor.

A standardised cardio-oncology curriculum for all general cardiology trainees8 should be implemented parallel to the dedicated cardio-oncology fellowship programmes that are being established. Professional cardiology societies should highlight the cardiovascular toxicities of long-term cancer therapies in educational campaigns targeted towards general cardiologists, and increased attention in forums of Continuing Medical Education are needed. By targeting general cardiologists as part of its educational purview, the cardio-oncology community has the opportunity to greatly amplify its educational reach and thereby optimise the long-term cardiovascular care of patients with cancer on a larger scale.

References

Footnotes

  • Contributors I conceived and designed the work, drafted the article, critically revised the article and provided final approval for publication.

  • Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.

  • Competing interests KWZ reports personal fees from Eidos Therapeutics, outside the submitted work.

  • Patient and public involvement Patients and/or the public were not involved in the design, or conduct, or reporting, or dissemination plans of this research.

  • Patient consent for publication Not required.

  • Provenance and peer review Commissioned; internally peer reviewed.

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