Cardiovascular events leading to ischemic heart disease (IHD), ischemic cerebrovascular events (ICVE), or peripheral artery occlusive disease (PAOD) are an emerging type of toxicity in CML patients treated with nilotinib or ponatinib. The incidence of PAOD ranges between 1.2 and 16.7 % with a potential increase frequency over time. When ankle-brachial index (ABI) has been used prospectively to screen for asymptomatic PAOD (and Doppler US for confirmation), an incidence of >10 % of asymptomatic arterial disease was found [4, 5] (significantly higher with nilotinib as compared to imatinib). Besides PAOD, other reports revealed an increase incidence of IHD and ICVE with nilotinib (rep. in six). The ENESTnd at 72 months revealed an incidence of 12.9 % for all cardiovascular events and of 5.8 %, 2.3 %, and 3.8 % for IHD, ICVE, and PAOD, respectively [7].

Similarly, ponatinib employed in second-line treatment (45 mg OAD) is associated with an increased risk for vascular events (arterial and venous): the latest update (at 3 years) showed a 22 % rate for all cardiovascular events [8]. With ponatinib, the importance of dose intensity is evident [9]. In contrast, there are no data suggesting a higher risk of cardiovascular events in patients treated with imatinib, bosutinib, or dasatinib [10–15]. All these data suggest that arterial events are not a class effect of all the TKIs employed to treat CML (any line of treatment) but specific toxicities related to nilotinib and ponatinib. Both in nilotinib and ponatinib trials, patients developing vascular complications mostly had preexisting CV risk factors [6]. So far, nilotinib (and ponatinib) seemingly determines an increase risk of arterial events exacerbating a preexisting atherosclerotic condition (however, there are reports even in patients without CV risk factor baseline). Early [16, 17] and later [7] trials showed the capacity of nilotinib to promote an increase in fasting blood glucose. Hypercholesterolemia, a well-recognized risk factor for atherosclerosis, has also been observed, even if not constantly, with nilotinib [4] possibly secondary to hyperglycemia. Other possible mechanisms include a pro-inflammatory condition under nilotinib and genetic predisposition [18], direct pro-atherogenic and anti-angiogenic effects on vascular endothelial cells, and the induction of hyperhomocysteinemia. The proper screening of patient candidate to receive nilotinib (and ponatinib) is pivotal, including either ABI or duplex ultrasonography in all newly diagnosed patients with CML and cardiovascular risk factors or positive claudication questionnaire. Moreover, the chemistry profile (baseline and every 4–6 months) should include fasting glucose, HbA1c, lipids (cholesterol, LDL, HDL, and triglycerides), C-reactive protein, and creatinine. Moreover, the calculation of the CV risk score should be done for any new CML patient based on national or international guidelines.

The risk of effusions exists with all the TKIs currently indicated for CML in first line but is much most commonly seen with dasatinib. In second-line treatment with dasatinib, the median time of appearance is 5–11 months [19, 20], but it could be delayed until 2 years. In first-line treatment, time to pleural effusion was 10 months, and most effusions (89 %) occurred more than 8 weeks into treatment [21]. The overall cumulative incidence in first and second line treatment can reach 25–30 % of all the patients treated with dasatinib 100 mg OAD. Although the risk diminished with time, PE can occur along all the treatment. In second-line treatment, previous or concomitant cardiac disease and hypertension seem to be the more common predisposing conditions [22, 23]. Also, BID schedule [22], advanced phases, hypercholesterolemia, a previous history of autoimmune disorders, and skin rashes experienced during imatinib therapy have been identified as risk factors [23]. Older age is also associated with PE [19], and in patients older than 60 years, the presence of concomitant pulmonary disease, initial daily dose of dasatinib (140 mg vs 100 mg), and higher comorbidity index were associated with PE. Apart from knowing the conditions which could increase the risk of PE, patients and doctors must be vigilant on the presence of cough, dyspnea, or chest pain. Physical exam must include auscultation, and it is prudent but not mandatory to order an X-ray exam every year.

However, to the scope of this brief commentary, it is more relevant to look to the future as far as the burden of adverse events, not severe by definition but central to determine compliance of the patients and QOL. In fact, the evaluation of the response for many years (all the past decade) attracted of course the attention of researchers; on the other hand, while collection of the incidence and rate of biochemical and laboratory abnormalities, recorded objectively, continued to determine the overall safety profile of different TKIs, providing useful instruments of management, the incidence of other, and clinical side effects (the majority of AEs referred by the patients) continued to be based on CTC grading system. This way to collect symptoms is, once more, useful to indicate the generic level of toxicity and consequent TKI treatment optimization but not ideal to understand to what extent the patients QOL is affected. This aspect is of particular interest, in general and because QOL perception affects, in turn, compliance and adherence: a lower than ideal adherence may easily jeopardize treatment results, inducing refractoriness to the treatment itself [24]. All available TKIs for first-line therapy, that is, imatinib (i.e., first-generation TKIs) and dasatinib or nilotinib (i.e., second-generation TKIs), have side effects that should be considered when deciding which therapy is best for the individual patient. Imatinib was, since 2001, and remains the golden standard for many patients with CML. While survival of patients who respond to imatinib is not different from that of the general population, it is important to consider that these patients require lifelong therapy that affects their health-related quality of life [25, 26]. The most frequently reported long-term, chronic adverse effects of imatinib therapy include edema, nausea, muscle cramps, and musculoskeletal pain. More recently, “second-generation” tyrosine kinase inhibitors (i.e., dasatinib and nilotinib) have been approved for first-line use in CML patients, based on results from two large randomized trials. This makes the choice of tyrosine kinase inhibitor to be used as first-line therapy a major challenge. While imatinib, dasatinib, and nilotinib have different toxicity profiles, they have been reported to produce similar outcomes in terms of progression-free survival and overall survival. In most studies, recording and assessing the type, the intensity, and the duration of the side effects are not planned, apart from formal reference to some internationally recognized scoring systems (e.g., NCI, SWOG). The data obtained with this methodology can be very different, even in company-sponsored, registrative studies. For example, the incidence of any grade fatigue, muscle pain, and joint/bone pain with imatinib varied in published experience (only RCTs considered) between 8 and 54 %, 34 and 95 %, 0 and 28 %, respectively [27]. It has, therefore, been suggested that, regardless of which drug is used as first-line therapy, timely management of side effects, changing the tyrosine kinase inhibitor when required, is a critical factor for optimal management of patients. In this scenario, close monitoring of relevant symptoms experienced by patients is pivotal to facilitate a timely switch to other available tyrosine kinase inhibitors. Instrumental to the physician’s ability to consider alternative treatment strategies, however, is an accurate estimation of symptom severity and overall health status of their patients. Experience in solid tumors has shown that physicians tend to rate symptoms as being less severe than their patients do. Also, patients’ self-reported symptoms have been shown to reflect daily health status better than physician-reported symptoms do. Following these considerations, the National Cancer Institute sponsored initiative to create a version of the Institute’s Common Terminology Criteria for Adverse Events (PRO-CTCAE) that can be completed by patients themselves [28–30], providing direct feedback from patients on their symptom experience during treatment. These instruments will be of particular value in observational studies and randomized clinical trials (RCTs). Another important area of application of PRO instruments would be their implementation in routine practice, facilitating the discussion of health problems between patients and physicians and supporting the early identification of those CML patients for whom a given therapy is particularly burdensome.