Impact of TKI Switching, Reduction, and Discontinuation on Cardiovascular Events in cml patients

doi:10.21203/rs.3.rs-3632503/v1

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Impact of TKI Switching, Reduction, and Discontinuation on Cardiovascular Events in cml patients

https://doi.org/10.21203/rs.3.rs-3632503/v1

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The development of tyrosine kinase inhibitors (TKIs) has dramatically improved the treatment outcomes of the chronic myelogenous leukemia-chronic phase (CML-CP). However, cardiovascular events (CVEs), such as hypertension, peripheral arterial occlusive disease, pulmonary arterial hypertension, and cerebral infarction, continue to occur, which highlights the need to develop preventive monitoring and treatment strategy for adverse vascular events. This study retrospectively analyzed the data on CVEs in 63 patients with chronic myeloid leukemia treated with TKIs at our institution. TKI treatments were discontinued in 1 patient and 16 patients owing to serious CVEs and adverse events other than CVEs, respectively. This study showed that male patients tended to experience more abnormal findings on cardiovascular examination and minor CVEs with increasing age than female patients. No prolongation of QT interval was observed. During follow-up, improvements in tricuspid regurgitant pressure gradient and brain natriuretic peptide values and hypertension were observed after reducing the dose of the same TKI, interrupting the TKI treatment, and switching from the second-and third-generation TKIs to imatinib (IM) or bosutinib (BOS). These data suggest the importance of CVE prevention via blood pressure control and cardiovascular examination in CML patients at high risk for CVE. Rapid intervention under the cooperation of a cardiologist is also essential when CVEs develop. The CVE risk may be decreased by switching to IM or BOS or via TKI dose reduction/interruption in patients in whom DMR is achieved. However, further studies with more patients are required.

Adequate TKI switching or dosage adjustment can improve hypertension, TRPG, and BNP levels in CML patients with cardiovascular events.
Male patients tended to experience more abnormal findings on cardiovascular examination and mild CVEs with increasing age than females.

Treatment outcomes of chronic myelogenous leukemia-chronic phase (CML-CP) have improved dramatically with the development of tyrosine kinase inhibitors (TKIs). In Japan, the following TKIs have been indicated for the treatment of CML: imatinib (IM); first-generation TKIs used as a first-line treatment, nilotinib (NIL), dasatinib (DAS), and bosutinib (BOS); second-generation TKIs and ponatinib (PON); and third-generation TKIs. Only PON has been an effective second-line treatment for patients with CML with T315I mutation positivity; however, the prognosis is poor. Several studies have compared the efficacy of IM with that of second-generation TKIs in patients with first CML-CP. The DASISSION trial, which used IM and DAS, showed that the proportion of patients who achieved the 5-year cumulative molecular response (MR) of 4.5 is 33% and 42% in the IM and DAS groups, respectively¹. The ENESTnd, which used IM and NIL, reported that the proportion of patients who achieved the 10-year cumulative MR of 4.5 is 39.2% and 61.0% in the NIL 600mg/day and IM groups, respectively². The BFORE trial, which compared BOS with IM, demonstrated that the proportions of patients who achieved the 12-month cumulative major molecular response (MMR) were 36.9% and 47.2% in the BOS and IM groups, respectively³. These studies have shown the efficacy of second-generation TKIs^3,4. A phase II trial (PACE trial) examined the efficacy of PON in DAS/NIL-resistant or DAS/NIL-intolerant patients or patients with CML and T315I mutation. The results showed a 5-year cumulative MMR of 60%⁵. Results of these studies have proved that second-and third-generation TKIs are highly effective. Thus, second-generation TKIs have been recommended for the treatment of patients deemed to be highly at risk for CML, given their poor Sokal, Hasford, or EUTOS long-term survival (ELTS) scores. The treatment-free remission (TFR) after achieving deep molecular response (DMR) for a long-term period has recently been regarded as a goal of TKI treatment. Factors contributing to TFR achievement include TKI treatment duration, periods from initiating TKI treatment to MMR achievement, and complete molecular response (CMR) duration^6,7. The rate of patients who achieved DMR is higher in those treated with second-generation TKIs than in those treated with IM. Second-generation TKIs provide good effects in early treatment stages and are expected to increase the rate of patients who achieve TFR⁸.

The onset of cardiovascular events (CVEs), such as arterial occlusive events (AOEs)^9–12, pulmonary arterial hypertension, and prolongation of QT interval¹³, has been reported in patients who receive PON, NIL, or DAS. The onset rates of CVEs are 5% and 2% in the DAS and IM groups (DASISSION trial)¹, respectively, and 7.5%, 13.4%, and 2.1% in the NIL 600 mg/day, NIL 800 mg/day, and IM 400 mg/day groups (ENESTnd trial)⁴, respectively. The incidence of CVEs is higher in patients treated with second-generation TKIs and increases in a dose-dependent manner. This study includes 63 patients with CML-CP who received TKIs at our institution. The research clarified real-world data on CVE onset to examine the efficacy of monitoring and prevention approaches for CVE, management strategy for CVE onset, and changes in or dose adjustments of TKIs.

This study included 63 patients with CML who were treated with TKIs between January 1, 2013, and October 31, 2021. The following data were obtained: TKI types, TKI treatment period, presence/absence of TKI interruption, patient characteristics, risk factors (age, sex, blood pressure, glucose level, renal function, and presence/absence of dyslipidemia), electrocardiography (ECG), ultrasound cardiography (UCG), and X-ray. A discontinuation period of TKI treatment at ≥ 1 month was defined as TKI interruption. Abnormal cardiovascular examination findings or mild CVEs were defined as any of the following conditions: abnormal ECG or UCG findings, elevated tricuspid regurgitant pressure gradient (TRPG) (a reference value of ≥ 30 mmHg), elevated brain natriuretic peptide (BNP) (a reference value of ≥ 100 pg/mL), hypertension, increased cardiothoracic ratio (CTR), or pleural effusion (PE) (Table 1-A)^14,15. The onset of ischemic heart disease, cerebral infarction, or myocardial damage that required intervention was defined as a severe CVE. Suita Score¹⁶, SCORE2 Risk Chart¹⁷, and SCORE2-Older Persons (SCORE2-OP) Risk Chart¹⁸ were used to assess the CVE risk. This study was conducted after obtaining approval from the Institutional Review Board of the National Cancer Center in Japan. Data Sharing Statement; For original data, please contact Junichiro Yuda ( [email protected]).

This study included 63 patients with CML-CP treated with TKIs (39 men and 24 women). The median ages at the initial examination, follow-up, and treatment periods were 56 (range, 19–86) years, 72 (range, 6–288) months, and 72 (range, 6–288) months, respectively. IM, NIL, DAS, and BOS were used as first-line treatment in 33 (52%), 15 (24%), 12 (19%), and 3 (5%) patients, respectively. The proportion of second-generation TKIs was higher than first- and third-generation in second-line treatment. Specifically, IM, NIL, DAS, BOS, and PON were used in 4 (11%), 13 (36%), 11 (31%), 7 (19%), and 1 patient, respectively. Regarding TKIs used as a third-line treatment, IM, NIL, DAS, BOS, and PON were used in 6 (40%), 3 (20%), 2 (13%), 3 (20%), and 1 patient, respectively. NIL, DAS, and BOS were administered as a fourth-line treatment to 3 (42%), 2 (29%), and 2 patients (29%), respectively (Table 1-B).

The following data on 63 patients are shown in Tables 2 and 3-A-1: comorbidity; concomitant drugs (anticoagulant drugs, antiplatelet agents, lipid-lowering drugs, antihypertensive drugs, and hypoglycemic drugs); CVE risk evaluation based on SCORE2 Risk Chart, SCORE2-OP Risk Chart, or Suita Score; and the presence or absence of CVE onset. Of 30 patients with CVE risk factors, such as cardiovascular diseases (cerebral infarction, hypertension, aortic stenosis, bradycardia–tachycardia syndrome, and myocardial infarction [MI]), type 2 diabetes, or dyslipidemia, 17 received interventions for lifestyle-related diseases. Specifically, anticoagulant drugs, antiplatelet agents, lipid-lowering drugs, antihypertensive drugs, and hypoglycemic drugs were administered to 1, 4, 5, 14, and 5 patients, respectively (Table 2). The following symbols were used to represent the patient status: ◆, patients who required TKI switching because of CVE onset; ▼, patients with reduced TKI dose because of CVEs; ●, patients who experienced CVE that required intervention but continued the same TKI at the same dosage; ○, patients who experienced a CVE that did not require intervention and continued the same TKI at the same dosage; and ■, patients in whom the TKI treatment was discontinued after CVE onset. Elevated BNP (≥ 100 pg/mL), elevated TRPG (≥ 30 mmHg), and increased CTR on chest X-ray (≥ 50%) were observed in 8 (13%), 10 (16%), and 19 (30%) patients, respectively; however, TKIs were continued at the same dose in all the patients. PE occurred in 10 (16%) patients. Owing to this adverse event, a TKI was switched in 6 patients, a TKI was not switched, but its dose was reduced in 2 patients unique patient number (UPN): 22 and 48), and no intervention was performed, and the same TKI and dose were continued in 2 patients (UPN: 7 and 14). Abnormal findings on UCG were observed in 15 patients, and one of them (UPN: 1) required TKI discontinuation because of depressed left/right ventricular systolic function, right heart strain, pericardial effusion, and PE. Abnormal ECG findings were observed in 30 patients, and one of them (UPN:1) required TKI discontinuation because of T-wave inversion attributed to myocardial damage. Hypertension classified as Grade 2 (i.e., systolic blood pressure, sBP ≥ 140 mmHg; diastolic blood pressure, dBP ≥ 90 mmHg) occurred in 32/63 patients (51%) after TKI initiation or switching. Of these, 11 patients (17%) required hypotensive therapy (Table 2). Nine patients (UPN: 1, 5, 23, 26, 30, 31, 39, 41, and 42) experienced ischemic heart disease (angina pectoris [AP] and MI) or cerebral infarction. Specifically, 2 patients (UPN: 1 and 41) had PE, 4 (UPN: 1, 26, 41 and 42) had elevated TRPG, 5 (UPN: 1, 23, 31, 39, and 41) showed abnormal findings on UCG, 5 (UPN: 1, 5, 23, 41, and 42) had an increased CTR, and 8 (UPN: 1, 5, 23, 26, 31, 39, 41, and 42) showed abnormal ECG findings. TKI switching (9 patients), reduction (3 patients), and discontinuation (1 patient) because of CVEs, as well as CVE treatment (14 patients), were required. The risk assessment of CVE onset based on the SCORE2 Risk Chart and SCORE2-OP Risk Chart showed that 21, 31, and 11 patients were classified into low-, moderate-, and high-risk groups, respectively (Tables 2 and 3-A-1). The risk assessment of CVE onset based on the Suita Score indicated that 30, 22, and 11 patients were classified into low-, moderate-, and high-risk groups, respectively. Of the 9 patients who experienced serious CVEs (AP, cerebral infarction, and MI) that required intervention, 8 (89%) patients were categorized as a moderate- or high-risk group (unique patient number [UPN]: 5, 23, 26, 30, 31, 39, 41, and 42) and the other patient (UPN: 1) was categorized to the low-risk group based on the SCORE2 Risk Chart, SCORE2-OP Risk Chart, and Suita Score. Before the initial TKI treatment, 22 patients had abnormal findings on cardiovascular examination and mild CVEs. During the TKI treatment, abnormal findings on cardiovascular examination and mild CVEs were observed. Specifically, Grade 2 hypertension (sBP, ≥ 140 mmHg, dBP, ≥ 90 mmHg), elevated BNP, increased CTR on plain chest X-ray (≥ 50%), abnormal findings on ECG, elevated TRPG, and abnormal findings on UCG occurred in 32 (51%), 8 (13%), 19 (30%), 30 (48%), 10 (16%) and 15 (24%) patients, respectively. Prolongation of QT interval (≥ 500 ms), an adverse event associated with NIL, did not occur (Table 3-B). Non-cardiogenic PE developed in 10/63 patients (16%). The median age at the initial examination was compared among the following three groups: patients with abnormal findings on cardiovascular examination and mild CVEs (mild CVEs group), those with serious CVEs (serious CVEs group), and those without serious CVEs (non-CVEs group). The median age was 58 (range, 19–85), 66 (range, 27–78), and 38 (range, 28–70) years for men in mild CVEs group, serious CVEs group, and non-CVEs group, respectively, and 58 (range, 40–75), 63, and 64 (range, 32–72) years for women in mild CVEs group, serious CVEs group, and non-CVEs group, respectively. Male patients tended to experience more abnormal findings on cardiovascular examination and mild CVEs ith increasing age (Table 3-C), whereas female patiens did not show such a tendency. Abnormal findings on cardiovascular examination was freqyenth of seved in CML patients under TKI treatment; however, blood pressure control and periodical cardiovascular examination allowed prevention or early detection of CVEs, which enabled the safe continuation of TKIs.

Figure 1 shows the presence or absence of TKI treatment and CVE status over time. TKIs were discontinued in 1 patient (UPN: 1) because of serious CVE. After achieving a deep molecular response, other patients (UPN: 2–8). The TKIs were discontinued in 1 patient (UPN: 1) and 16 (UPN: 9–24) patients owing to serious CVEs and adverse events other than CVEs, respectively, and were interrupted in 7 patients after achieving DMR. Furthermore, TKIs were discontinued in 16 patients (UPN: 9–24) because of adverse events other than CVEs. Other patients were able to continue TKIs (UPN: 25–63). The clinical course of these patients was shown as follows also examined. In June 2014, 4 years after initiating DAS as a second-line treatment, UNP: 1 (Fig. 3-A) experienced pleural effusion; thus, DAS was switched to NIL. In July 2014, the NIL was discontinued because of abnormal findings on UCG and T-wave inversion on ECG owing to myocardial damage. The patient achieved MR 4.5 at the time of the discontinuation. DMR has been maintained for 75 months since the discontinuation; therefore, TKI re-administration is not required. Among the 7 patients (i.e., [UPN: 2–8] who maintained long-term DMR and in whom TKIs were discontinued to achieve TFR), 4 (UPN: 2–5) had an IM treatment history of ≥ 10 years, 2 (UNP: 6 and 7) had a DAS treatment history of ≥ 2 years, and 1 (UPN: 8) had a NIL treatment history of ≥ 2 years. Of the 8 (UPN: 1–8) patients, 3 (UPN: 2, 5, and 6) patients lost MR 3.0, and the same TKI (i.e., the same TKI was used in these patients before and after the discontinuation) was readministered. DMR was maintained in the other 5 patients, and no TKI was administered. TKIs were discontinued in a total of 16 patients because of adverse events other than CVEs. Specifically, hyperbilirubinemia, cytopenia, and other adverse events (e.g., rash [UPN: 10], colitis [UPN: 24], gastrointestinal symptoms [UPN: 12 and 14], fever [UPN: 13], and herpes zoster [UNP: 21]) occurred in 5 (UPN: 15, 18, 19, 20, and 23), 5 (UPN: 9, 11, 14, 16, and 17), and 6 patients, respectively.

Figure 2 shows the data on TRPG (reference value ≦ 30 mmHg), BNP (reference value < 100 mmHg) status, and sBP/dBP changes before and after TKI (switching/reduction/discontinuation) in 63 patients. TRPG data of 19 patients were also provided. Of these, elevated TRPG returned to normal in the following 3 (16%) patients: BOS was switched to IM as a second-line treatment in 1 patient (UPN: 41, TRPG decreased from 45 to 28 mmHg); NIL was changed to BOS as a fourth-line treatment (5%) (UPN: 40, TRPG decreased from 31 to 24 mmHg) and DAS as a first-line treatment was reduced from 100 to 20 mg (5%) (UPN: 12, TRPG decreased from 30 to 24 mmHg). TRPG was increased from the reference to high values in the following 4 patients (21%): DAS as a first-line treatment (UPN: 7, TRPG increased from 24 to 34 mmHg); NIL switched to PON as a fourth-line treatment (UPN: 26, TRPG increased from 12 to 33 mmHg); NIL reduced from 800 to 400 mg as the second-line treatment (UPN: 40, TRPG increased from 21 to 31 mmHg); and BOS as a second-line treatment after NIL (UPN: 18, TRPG increased from 22 to 30 mmHg) (Fig. 2-A). Data on BNP before and after TKI discontinuation were available for 19 patients with elevated BNP ( ≧ 100 pg/ml), which returned to normal in 5 (26%) patients; TKI was discontinued after completing the first-line treatment using NIL in 1 patient (UPN: 41, BNP decreased from 238 to 28 pg/ml); BOS was switched to IM as a third-line treatment in 1 patient (UPN: 41, BNP decreased from 209 to 49 pg/ml); NIL was switched to BOS as the third-line treatment in 1 patient (UPN: 48, BNP decreased from 155 pg/ml to 33 pg/ml); DAS as a first-line treatment was reduced from 70 to 20 mg in 1 patient (UPN: 7, BNP decreased from 123 to 57 pg/ml); DAS was changed to BOS as a second-line treatment in 1 patient (UPN: 12, BNP decreased from 105 to 56 pg/ml); and BNP increased from the reference value to ≥ 100 pg/ml in 3 patients (16%). Specifically, NIL was reduced from 400 mg to 150 mg in 2 patients (11%) (UPN: 41 and UPN: 48, BNP increased from 20 pg/ml to 238 pg/ml in the former and from 57 to 155 pg/ml in the latter). NIL was discontinued because of PE, and BOS was initiated as a second-line treatment in 1 patient (UNP: 41, BNP increased from 28 to 209 pg/ml) (Fig. 2-B). Elevated TRPG and BNP levels were observed after switching from the second-and third-generation TKIs to BOS or after IM and TKI discontinuation; however, such abnormal findings improved. Nevertheless, BNP increased after TKI reduction in 2 patients (UPN: 41 and 48) who had received NIL, a second-generation TKI, for > 2 years. Before and after TKI switching, data on blood pressure were available in 27 patients. Of these, Grade 2 hypertension (sBP, ≥ 140 mmHg; dBP, ≥ 90 mmHg) developed in the following 3 patients (11%): (UPN: 26) who received PON as a fourth-line treatment after receiving IM as a first-line treatment, (UPN: 8) who initiated NIL as a first-line treatment, and (UPN: 48) in whom NIL was reduced from 200 to 150 mg (Fig. 2-C). Grade 2 or higher hypertension became normal in the following 5 patients (18%): (UPN: 28) in whom NIL used as a fourth-line treatment was reduced from 600 to 400 mg (UPN: 12,13), in whom DAS was switched to BOS (UPN: 7), in whom DAS used as a first-line treatment was discontinued (UPN: 31), and in whom PON used as a second-line treatment was discontinued. These results showed that TKI reduction, switching from the second-and third-generation TKIs to BOS or IM, and TKI discontinuation were associated with normalized TRPG, BNP, and blood pressure. Such positive findings were observed in 12/14 patients (86%). Conversely, TKI reduction was not associated with TRPG and BNP improvement in the remaining 2 patients (14%) (UPN: 40 and 41) who received NIL for > 6 years.

PE and heart failure developed in UPN 7 during the treatment with second-generation TKIs; however, the patient’s condition improved after TKI discontinuation (Fig. 3-B). The severity of cardiotoxicity improved after switching from the second-generation TKI to BOS in UPN 12 (Fig. 3-C). UPN 7 was diagnosed with CML in April 2016. DAS 100 mg/day was administered, and the patient achieved MR 4.5 in January 2017. However, PE and elevated BNP were observed; thus, it was reduced to 20 mg/day (Fig. 3-B). However, DAS was discontinued in July 2019 because BNP increased from 123 to 163 pg/ml. Subsequently, BNP decreased to 74.2 pg/ml. The patient maintained an MR4.5 without cardiotoxicity (Fig. 3-B). UPN 12 was diagnosed with CML in January 2012. DAS 100 mg/day was initiated (Fig. 3-C). The patient maintained an MR of 4.5 for > 2 years, but BNP increased, and DAS decreased to 20 mg/day in April 2017. However, the patient failed to achieve an MR of 4.0 in January 2018. DAS was increased to 100 mg/day, achieving an MR of 4.5. However, BNP increased to 232 pg/ml, and DAS was switched to BOS 100 mg/day in April 2019. BOS was increased to 300 mg/day while monitoring the patient’s tolerability. The patient maintained an MR of 4.0 without worsening CVEs (Fig. 3-C).

Treatment outcomes of CML-CP have dramatically improved after TKI development. The efficacies of the second-and third-generation TKIs for the treatment of this disease are higher than that of the first-generation TKIs ^3,5,6. Haguet et al. investigated patients with CML, and a meta-analysis was performed using the results of the early-phase TKI treatment. The results showed that the odds ratio for CVE onset is higher in the second-and third-generation TKI groups than in the IM group (i.e., 3.89, 2.68, and 1.61 in the NIL, DAS, and BOS groups, respectively)¹⁹. Cirmi et al. analyzed the adverse events during the TKI treatment in patients with CML using the FDA Adverse Event Reporting System. The results showed that the onset rates of CVEs in clinical practice are 59% (NIL), 21.2% (DAS), 14.4% (PON), 4.4% (IM), and 1.0% (BOS), indicating that it is higher in second-generation TKIs²⁰. The onset rate of AOEs associated with IM is 0.6%, which is similar to that of age- and sex-matched general populations¹⁴. The onset rate of CVEs in the BEFORE trial, which compared BOS with IM, is similar between the two groups³. These results suggest that CVE incidence is lower in patients who receive IM or BOS than in those who receive second-and third-generation TKIs^21–24. In clinical practice, patients with CML-CP are at high risk for lifestyle-related diseases and cardiovascular complications and have received TKIs for an extended period; moreover, their age is relatively high. Given such characteristics, treatment effects and adverse event profiles should be considered; thus, TKIs should be carefully selected. Furthermore, CVE monitoring via ECG, UCG, and BNP assessment is essential to continue the treatment in patients with CML-CP safely.

A study showed a significant prolongation of QT interval immediately after IM in a first-generation TKI at pre-and-post-TKI treatment²⁵. The onset rate of QT interval prolongation is 25% in patients with IM-resistant CML-CP who receive NIL²⁶. Care should be taken in prolonging QT interval regardless of TKI generations. However, QTc of ≥ 500 mc was not observed in this study. Furthermore, the incidence of QT interval prolongation was lower in this study than in previous studies^25,26. This observation may be partially explained by the fact that TKIs were reduced in patients who positively responded to treatment. In patients who experienced AP, cerebral infarction, and MI (UPN: 5, 39, 41, and 42), abnormal findings on ECG were seen 2–18 months before the onset of these diseases; therefore, ECG should be performed every 3–6 months²² or when subjective symptoms occur.

In addition to diabetes, dyslipidemia, and smoking, hypertension is the main risk factor for coronary artery disease. A meta-analysis of essential hypertension showed that antihypertensive drugs decrease the sBP (10 mmHg) and dBP (5 mmHg), resulting in an approximately 20% reduction of coronary artery disease onset^27–29. Blood pressure control is essential to prevent CVEs^29–31. In this study, serious CVEs occurred in 9 patients, with 7 (UPN: 5, 23, 26, 30, 31, 39, and 41) of them having hypertension. Of the 7 patients, 3 (UPN: 30, 39, and 41) received antihypertensive drugs and blood pressure monitoring. Hence, TKIs were continued in these patients without dose modifications. A reduced TKI dose with antihypertensive drug treatment was continued in 1 patient (UPN: 26). The TKIs had to be changed in the other 3 patients because of serious CVEs (AP [UPN: 5 and 23] and cerebral infarction [UPN: 31]). It has been reported that PON is more likely to cause hypertension than IM or DAS because of its stronger VEGFR inhibition³². However, hypertension developed in patients who received TKIs other than PON in this study. Blood pressure control is essential for patients who receive a TKI regardless of its type. In this study, the incidence of serious CVEs was higher in patients classified into the moderate- or severe-risk group based on the criteria of SCORE2 Risk Chart, SCORE2-OP Risk Chart, and Suita Score. Regular blood pressure monitoring is essential as a preventive approach for lifestyle-related diseases.

The CVE incidence rates are 2% and 5% in the IM and DAS groups, respectively, (DASISSION trial¹); 2.1% and 7.5% in the IM 400 mg/day and NIL 600 mg/day groups, respectively (ENTETnd trial); and 16% in the PON group (PACE trial), thus showing a higher CVE incidence of the second-and third-generation TKIs¹³. Conversely, the incidence of IM-associated AOEs is 0.6%, which is similar to that of age- and sex-matched general populations¹⁴. The CVE incidence is similar between the BOS and IM in the BEFORE trial³, and tends to be lower in IM and BOS than in the second-and third-generation TKIs^{14, 20–23}. Results of a meta-analysis performed by Jonathan Douxfils et al. showed that the onset rates of CVEs are 1.04% and 5.88% in the IM and second-and third-generation TKI groups, respectively, thereby indicating a significant high onset rate in the latter group¹³. In the ENESTnd trial, the CVE onset was associated with NIL decrease in a dose-dependent manner⁴. The risk factors for PAH in patients who receive DAS are age and treatment duration^{13, 33–34}. In this study, the median age of patients with abnormal findings on cardiovascular examination who experienced mild CVEs was higher than that of those who experienced severe CVEs at the initial examination. Such adverse events were improved after reducing the TKI dose; however, it was not associated with a decreased BNP in 2 patients (UPN: 40, 41) who used the second-generation TKI for an extended period. Careful monitoring of CVE onset is required for older adults and patients receiving second-generation TKIs for an extended period (Fig. 1; Tables B,C). Taken together, reduction of the same TKI, TKI discontinuation, and switching the second-and third-generation TKIs to IM or BOS are recommended for patients who have a CVE history and those who experience CVEs during TKI treatment.

In the STIM trial, TKIs were successfully discontinued in 40% of patients who maintained CMR for > 2 years. In the Destiny trial by Richard et al., TKIs were discontinued after being administered at half of the standard dose level for 12 months. With such a strategy, TFR is achieved in 36% of patients administered with TKIs for > 3 years and maintained MR 3.0 for 12 months. Selection of the first-line TKI, which is associated with the early achievement of DMR, is essential to achieve TFR. Furthermore, TKI switching and DMR duration are essential factors to achieve TFR in patients who fail to achieve DMR¹³. The use of second-generation TKIs is expected when aiming at achieving and maintaining DMR earlier and longer. To prevent treatment interruption because of CVEs, regular monitoring via cardiovascular examination (e.g., chest X-ray, ECG, UCG, and BNP evaluation) is essential.

We retrospectively analyzed the frequency of CVE onset and efficacy of cardiac function monitoring in 63 patients with CML-CP administered with TKIs at our institution. Regular monitoring, such as BNP assessment, UCG, and blood pressure, was associated with early CVE detection, which allowed early intervention and safe and continuous CML treatment. This study asserts the usefulness of BOS or IM in patients with a history of CVEs and TKI switching to BOS or IM or TKI reduction in patients who experience CVEs during TKI treatment. Furthermore, TKI discontinuation reduces the risk of CVE onset if patients achieve sufficient treatment effects with TKIs.

Acknowledgments: The authors thank the medical and nursing staff working on National Cancer Center Hospital East for patients’ care and providing clinical information. We also thank Maki Miwa, Hiroko Hashimoto, Fumiko Goto, Aya and Nihei, the data manager. We thank ulatus for their English language editing services.

Contribution: designed the research and wrote the paper; N.S. and J.Y. collected the data and analyzed the data.; N.S., J.Y., Y.G., N.Y., H.N., S.U., K.K.,C.S., A.N., Y.M., and T.K. provided variable discussion.

Conflict-of-interest disclosure: The author declares no competing financial interests.

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Tables 1-3 is available in the Supplementary Files section.

No competing interests reported.

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Impact of TKI Switching, Reduction, and Discontinuation on Cardiovascular Events in cml patients

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