RU2693815C1 - Method for managing patients with chronic myeloid leukemia in prescribing tyrosine kinase inhibitors - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: invention refers to medicine, namely to oncology, haematology and cardiology, and can be used for managing patients with chronic myeloid leukaemia in prescribing tyrosine kinase inhibitors (TKI). Cardiovascular system is examined, and a ten-year risk of cardiovascular mortality is assessed by the SCORE scale. Prior to prescribing the treatment, it is necessary to determine presence or absence of ischemic heart disease (IHD) in the patient. If there is no ischemic heart disease with low and medium SCORE risk, the patient is prescribed one of the following preparations: imatinib, dasatinib, nilotinib, bosutinib, ponotinib, after which once in 3 months: the patient is examined by a hematologist, the patient is biochemically analyzed for total cholesterol, a lipid spectrum, glucose, B-type natriuretic peptide, NT-proBNP, troponins, electrocardiography, echocardiography, bicycle ergometry, control of arterial pressure. Dascplerography of the brachiocephalic trunk is performed once in 6 months. If nilotinib is prescribed, the patient is examined by a haematologist and all the above-mentioned studies, except for ultrasonic Doppler sonography of the brachiocephalic trunk, should be performed once a month, and ultrasonic Doppler sonography of the brachiocephalic trunk once in 3 months. If observing no adverse events, the patient is required to be examined by a therapist and cardiologist once every 6 months. If observing the adverse events, the therapist and the cardiologist are examined once a month, reducing frequency to 1 every 6 months with the elimination of the adverse events. If the patient has a high and very high SCORE risk in the absence or presence of IHD, he is prescribed one of the following preparations: imanitib, dasatinib, bozutinib. Thereafter, once a month: a patient is examined by a hematologist, the patient is examined biochemically for total cholesterol, a lipid spectrum, glucose, B-type natriuretic peptide, NT-proBNP, troponins, electrocardiography, echocardiography, bicycle ergometry, control of arterial pressure. Doppler sonography of the brachiocephalic trunk is performed once in 3 months. If observing no adverse events, the patient is examined by a therapist and cardiologist once every 3 months. If observing the undesirable events, the patient is examined by the therapist and cardiologist once a month, reducing the frequency of adverse events by 1 time in 6 months.

EFFECT: method provides preventing the development of IHD in the patients with chronic myeloid leukaemia when prescribing TKI, as a result of the use of a clear scheme of prescribing any TKI, monitoring the occurrence of adverse events, determining the order of examination of the patient in case of adverse events.

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Description

The invention relates to medicine, in particular to internal diseases, cardiology, hematology, and can be used to prevent the development of coronary heart disease (CHD) in patients with chronic myeloid leukemia (CML) when prescribing or changing a tyrosine kinase inhibitor (TKI).

A list of adverse events (AEs) in the use of ITK in patients with CML, as well as recommendations for management and prevention of AEs, is presented in the recommendations of the European LeukemiaNet Society in 2016. Among the AEs, the authors distinguish: coronary artery disease, cerebrovascular disorders, peripheral arterial occlusive disease, cardiac rhythm disturbances, pulmonary arterial hypertension, hyperbilirubinemia, hyperglycemia, hypophosphatemia, and others [1]. One of the most severe AEs is the development of CHD.

The percentage of IHD development according to international studies in the group of patients taking imatinib reaches 2%, taking dasatinib - 4% [2], while taking nilotinib IHD developed in 13.4% of patients [3]. Data on the occurrence of coronary artery disease when taking bozutinib currently not found. With the use of Ponatinib, the development of CHD is noted in 12% of patients [4].

The disadvantage of these recommendations is that they describe only general approaches to the treatment and correction of side effects. First of all, early recognition of AE, which is based on educating the patient by telling him about potential side effects. There are no prognostic risk scales for the development of cardiovascular complications in the recommendations. The result of the approaches to the correction of AE described in the recommendations has not been studied in detail.

The 2017 Russian recommendations noted that it is possible to use the SCORE scale for assessing cardiovascular risk, which allows us to estimate the 10-year risk of death from cardiovascular diseases [5]. These recommendations are taken as prototype.

The disadvantage of these recommendations is the lack of a clear scheme for the appointment of an ITC, control over the occurrence of adverse events, and the procedure for examining a patient when adverse events occur.

The aim of the present invention is to create a method of managing patients with CML in the appointment of ITK to prevent adverse events.

This goal is achieved by the fact that before the appointment of treatment it is necessary to determine the presence or absence of the patient's ischemic heart disease; in the absence of coronary artery disease, at low and medium risk on the SCORE scale, the patient is prescribed one of the following drugs: imatinib, dasatinib, nilotinib, bozutinib, ponatinib; then 1 time in 3 months: a hematologist examines a patient, a biochemical blood test is performed for total cholesterol, lipid spectrum, glucose, B-type natriuretic peptide, NT-proBNP, troponins, electrocardiography, echocardiography, bicycle ergometry, blood pressure control; Once every 6 months ultrasound dopplerography of the brachiocephalic trunk is performed; in the case of nilotinib, a patient’s examination by a hematologist and all of the above studies, except for ultrasound Doppler imaging of the brachiocephalic trunk, should be performed once a month, and Doppler ultrasound of the brachiocephalic trunk 1 time in 3 months; in the absence of adverse events, examination of the patient by a general practitioner and a cardiologist is necessary 1 time in 6 months; in case of occurrence of adverse events, examination by a therapist and a cardiologist is carried out 1 time per month, reducing its frequency to 1 time in 6 months when arresting adverse events; if the patient has a high and very high risk on the SCORE scale, the presence of IHD is prescribed one of the following drugs: imatinib, dasatinib, bozutinib; then once a month: a hematologist examines a patient, a biochemical blood test for total cholesterol, lipid spectrum, glucose, B-type natriuretic peptide, NT-proBNP, troponins are performed by the patient, electrocardiography, echocardiography, bicycle ergometry, blood pressure control are performed; Once every 3 months ultrasound dopplerography of the brachiocephalic trunk is performed; in the absence of adverse events, the patient and the cardiologist will examine the patient once every 3 months; in case of adverse events, the patient and the cardiologist examine the patient once a month, reducing its frequency when the adverse event is stopped up to 1 time in 6 months.

For three years (2015–2017), we monitored 57 patients with newly diagnosed CML who received ITC as a therapy, analyzed the data obtained during the study of the cardiovascular system. Separation by sex and age did not produce. A history of CHD was available in 24 patients (42.1%). Due to the fact that in the Samara region imatinib, dasatinib and nilotinib are available the patients were divided into groups: the first group included 21 patients who were prescribed imatinib at a dose of 400 mg / day, the second group of 19 patients - dasatinib 100 mg / day., in the third group of 17 patients who were prescribed nilotinib at a dose of 400 mg 2 times a day. Patients who had IHD were divided into three groups evenly - 8 people each. Each patient was identified 10-year risk of death from cardiovascular diseases according to the SCORE scale. Patients assigned to the low and medium risk groups on the SCORE scale in the first group consisted of 7 people, in the second - 5, in the third -5. Patients assigned to the high and very high risk groups on the SCORE scale in the first group consisted of 6 people, in the second - 6, in the third - 4. Patients were examined monthly for 1 year: examination by a hematologist, biochemical blood test for total cholesterol, lipid spectrum, glucose, B-type natriuretic peptide, NT-proBNP, troponins, electrocardiography, echocardiography, bicycle ergometry, blood pressure control; Before treatment, and every 3 months, an ultrasound dopplerography of the brachiocephalic trunk was performed, and the therapist and cardiologist were examined.

When using imatinib and dasatinib in patients assigned to the group with low and medium risk on the SCORE scale, after 3 months a significant increase in total cholesterol, glucose, NT-proBNP, troponins was observed. In 4 patients, a prolongation of the QT interval was observed, in 6 patients an increase in blood pressure was noted above 140 and 90 mm Hg. In 1 patient, a decrease in the left ventricular ejection fraction of less than 55% was noted, the ST interval was elevated on the electrocardiogram when performing bicycle ergometry, after 6 months a statistically significant significant increase in the thickness of the intima-media complex was observed in Doppler ultrasound of the brachiocephalic trunk compared with the study conducted before the appointment of ITK. YA were assessed as mild to moderate (1, 2 degrees) according to the recommendations of LeukemiaNet [1]. Bosutinib is not available for use in the Samara Region, however, the literature indicates insignificant differences in the incidence of cardiovascular complications when using Bosutinib and Imatinib [6, 7]. Therefore, these drugs are advisable to use in patients belonging to the group of low and medium risk on the SCORE scale, and it is advisable to carry out studies within the specified time frame: examination of a hematologist, performing a biochemical blood test for the indicated markers, electrocardiography, echocardiography, bicycle ergometry, blood pressure monitoring 1 time in 3 months; Once every 6 months ultrasound dopplerography of the brachiocephalic trunk is performed. In the absence of adverse events, it is advisable that the physician and cardiologist inspect the patient once every 6 months; in case of occurrence of adverse events - once a month, reducing its multiplicity to 1 time in 6 months when arresting adverse events.

In the group of patients taking nilotinib, belonging to the low and medium risk group on the SCORE scale, a statistically significant increase (p <0.05) in total cholesterol, glucose, B-type natriuretic peptide was observed after 1 month from the start of administration; Heart rate and ST interval elevation on ECG during bicycle ergometry, decrease in ejection fraction during echocardiography, after 1 month, a statistically significant increase (p <0.05) of NT-proBNP, troponin, PQ interval on electrocardiogram, increase in C values was observed metropolitan and diastolic pressures when measuring blood pressure, after 3 months there was a statistically significant significant increase in the thickness of the intima-media complex with ultrasound dopplerography of the brachiocephalic trunk compared with the study conducted before the appointment of ITC. YA were assessed as mild and moderate severity (1-3 degrees) according to the recommendations of LeukemiaNet [1]. Therefore, it is advisable to use this drug in patients belonging to the group of low and medium risk on the SCORE scale, and it is advisable to carry out studies within the specified time frame: examination of a hematologist, performing a biochemical blood test on the indicated markers, electrocardiography, echocardiography, bicycle ergometry, blood pressure monitoring 1 time per month; 1 time in 3 months doppler sonography of a brachiocephalic trunk is carried out. In the absence of adverse events, it is advisable that the physician and cardiologist inspect the patient once every 6 months; in case of occurrence of adverse events - once a month, reducing its multiplicity to 1 time in 6 months when arresting adverse events.

In the group of patients using imatinib and dasatinib, assigned to the group with high and very high risk on the SCORE scale, with IHD after 1 month from the start of administration, a statistically insignificant increase (p> 0.05) in total cholesterol, glucose, natriuretic peptide B was observed -type, persistent increase in heart rate and ST interval elevation on electrocardiogram when performing ergometry, decrease in ejection fraction during echocardiography, after 1 month a statistically significant increase in (p <0.05) NT-proBNP, troponin, PQ interval was observed, an increase in systolic and diastolic pressure during blood pressure measurement, after 3 months, a statistically significant significant increase in the thickness of the intima-media complex was observed with ultrasound Doppler imaging of the brachiocephalic trunk compared with the study conducted before the prescription of ITC. Bosutinib is not available for use in the Samara Region, however, the literature indicates insignificant differences in the incidence of cardiovascular complications when using Bosutinib and Imatinib [6, 7]. YA were assessed as mild and moderate severity (1-3 degrees) according to the recommendations of LeukemiaNet [1]. Therefore, these drugs should be used in patients belonging to the group of high and very high risk on the SCORE scale with IHD, and it is advisable to carry out studies within the specified time frame: examination by a hematologist, performing a biochemical blood test for the indicated markers, electrocardiography, echocardiography, bicycle ergometry, control blood pressure 1 time per month; Once every 3 months ultrasound dopplerography of the brachiocephalic trunk is performed. In the absence of adverse events, it is advisable that the physician and cardiologist examine the patient once every 3 months; in case of adverse events, the patient and the cardiologist examine the patient once a month, reducing its frequency when the adverse event is stopped up to 1 time in 6 months.

In the group of patients taking nilotinib, belonging to the high and very high risk groups on the SCORE scale, who have IHD after 1 month from the start of administration, a statistically significant increase (p <0.05) in total cholesterol, glucose, B-type natriuretic peptide was observed , persistent increase in heart rate and ST interval elevation on electrocardiogram when performing ergometry, decrease in ejection fraction during echocardiography, after 1 month a statistically significant increase in (p <0.05) NT-proBNP, troponin, PQ interval, increase values of systolic and diastolic blood pressures at blood pressure measurement, after 3 months was statistically significant significant increase in the thickness of intima-media complex at ultrasonic Doppler brachiocephalic trunk, compared with the investigation conducted by the CTI to the destination. YAN were regarded as serious adverse events (3, 4 degrees) according to the recommendations of LeukemiaNet [1], difficult to correct, requiring a change in ITK. Ponatinib is not registered in the Russian Federation, literature data indicate a high incidence of cardiovascular complications (in particular, the development of coronary artery disease) when it is taken [4]. Therefore, it is impractical to assign nilotinib and ponatinib to patients with a high / very high risk group on the SCORE scale in patients with coronary artery disease.

The method of management of patients with chronic myeloid leukemia when prescribing tyrosine kinase inhibitors is implemented as follows: before prescribing treatment, it is necessary to determine the presence or absence of IHD in a patient; in the absence of coronary artery disease, at low and medium risk on the SCORE scale, the patient is prescribed one of the following drugs: imatinib, dasatinib, nilotinib, bozutinib, ponatinib; then 1 time in 3 months: a hematologist examines a patient, a biochemical blood test is performed for total cholesterol, lipid spectrum, glucose, B-type natriuretic peptide, NT-proBNP, troponins, electrocardiography, echocardiography, bicycle ergometry, blood pressure control; Once every 6 months ultrasound dopplerography of the brachiocephalic trunk is performed; in the case of nilotinib, a patient’s examination by a hematologist and all of the above studies, except for ultrasound Doppler imaging of the brachiocephalic trunk, should be performed once a month, and Doppler ultrasound of the brachiocephalic trunk 1 time in 3 months; in the absence of adverse events, examination of the patient by a general practitioner and a cardiologist is necessary 1 time in 6 months; in case of occurrence of adverse events, examination by a therapist and a cardiologist is carried out 1 time per month, reducing its frequency to 1 time in 6 months when arresting adverse events; if the patient has a high and very high risk on the SCORE scale, the presence of IHD is prescribed one of the following drugs: imatinib, dasatinib, bozutinib; then once a month: a hematologist examines a patient, a biochemical blood test for total cholesterol, lipid spectrum, glucose, B-type natriuretic peptide, NT-proBNP, troponins are performed by the patient, electrocardiography, echocardiography, bicycle ergometry, blood pressure control are performed; Once every 3 months ultrasound dopplerography of the brachiocephalic trunk is performed; in the absence of adverse events, the patient and the cardiologist will examine the patient once every 3 months; in case of adverse events, the patient and the cardiologist examine the patient once a month, reducing its frequency when the adverse event is stopped up to 1 time in 6 months.

The method is illustrated by the following examples.

1. Patient N., 42 years old. Diagnosis: chronic myeloid leukemia, Ph-positive, chronic phase. Low risk on the SCORE scale, the patient has no CHD. Thus, one of the following drugs can be prescribed as first-line therapy: imatinib, nilotinib, dasatinib, bozutinib, ponatinib. The patient was prescribed imatinib at a dose of 400 mg per day. 1 time in 3 months the patient underwent a hematologist examination, the examinations indicated in the developed method, no adverse events were detected, therefore 1 time in 6 months the patient was consulted by a general practitioner and a cardiologist. Within two years, the patient was treated with the specified ITC, adverse events did not occur.

2. Patient M., 49 years old. Diagnosis: chronic myeloid leukemia, Ph-positive, chronic phase. The average risk on the SCORE scale, the patient has no coronary artery disease. Thus, one of the following drugs can be prescribed as first-line therapy: imatinib, nilotinib, dasatinib, bozutinib, ponatinib. The patient was prescribed nilotinib at a dose of 400 mg 2 times a day. Once a month the patient underwent a hematologist's examination, examinations indicated in the developed method, undesirable phenomena in the form of thickening of the intima-media complex up to 1.3 mm when performing ultrasound dopplerography of the brachiocephalic trunk were detected 3 months after the start of the drug, therefore the frequency of examination by the therapist and a cardiologist made 1 time per month, prescribed therapy for correction. In the course of further prescription, adverse events did not occur, the frequency of examinations by the therapist and cardiologist was reduced to 1 time in 6 months. Within two years, the patient was treated with the specified ITC, adverse events did not occur.

3. Patient L., 47 years old. Diagnosis: chronic myeloid leukemia, Ph-positive, chronic phase. High risk on the SCORE scale, the patient has no coronary artery disease. Thus, one of the drugs can be prescribed as the first line of therapy: imatinib, dasatinib, and bosutinib. The patient was prescribed dasatinib at a dose of 100 mg per day. Once a month, the patient underwent a hematologist's examination, examinations indicated in the developed method. Adverse events in the form of reducing the ejection fraction to 55% during echocardiography were detected after 1 month from the start of the drug, so the patient was consulted by a general practitioner and cardiologist once a month, and therapy was prescribed for correction. In the course of further prescription, adverse events did not occur, the frequency of examinations by the therapist and cardiologist was reduced to 1 time in 6 months. Within two years, the patient was treated with the specified ITC, adverse events did not occur.

4. Patient V., 56 years old. Diagnosis: chronic myeloid leukemia, Ph-positive, chronic phase. The average risk on the SCORE scale, the patient has coronary artery disease. Thus, one of the drugs can be prescribed as the first line of therapy: imatinib, dasatinib, and bosutinib. The patient was prescribed imatinib at a dose of 400 mg per day. Once a month the patient underwent a hematologist's examination, the examinations indicated in the developed method did not show any undesirable effects, and once a month the patient was consulted by a general practitioner and a cardiologist. In the course of further prescription, adverse events did not occur, the frequency of examinations by the therapist and cardiologist was reduced to 1 time in 6 months. Within two years, the patient was treated with the specified ITC, adverse events did not occur.

The method can be applied in hematological, chemotherapeutic, therapeutic departments in patients with CML, receiving ITC.

Information sources

1. Steegmann JL, Baccarani M, Breccia M, et al. European LeukemiaNet recommendations for myeloid leukaemia. Leukemia. 2016; 30 (8): 1648-1671. doi: 10.1038 / leu.2016.104

chronic myeloid leukemia patients trial. Journal of clinical oncology. 2016;34(20): 2333-23402. Cortes JE, Saglio G, Kantarjian HM et al. Final 5-Year study results of DASISION: the dasatinib versus imatinib study in

chronic myeloid leukemia patients trial. Journal of clinical oncology. 2016; 34 (20): 2333-2340

3. Hochhaus A, G Saglio G, Hughes TP, et al. For example, a list of the most recent and most recent cases in the global health system. Leukemia. 2016; 30: 1044-1054

4. Cortes JE, Kim DW, Pinilla-Ibarz J, et al. A phase 2 trial of ponatinib in Philadelphia chromosome-positive leukemias. N Engl J Med 2013; 369: 1783-1796

5. Turkina A.G., Zaritsky A.Yu., Shuvaev V.A. Clinical guidelines for the diagnosis and treatment of chronic myeloid leukemia. Clinical oncohematology. 2017; 10 (3): 294-316. doi: 10.21320 / 2500-2139-2017-10-3-294-316

6. Gambacorti-Passerini C, Cortes JE, Lipton JH, et al. BELA trial of a newly diagnosed chronic phase chronic myeloid leukemia. American Journal of Hematology. 2014; 89 (10): 947-953.doi: 10.1002 / ajh.23788;

7. Cortes JE, Gambacorti-Passerini C, Deininger MW, et al. Bosutinib Versus Imatinib for Newly Diagnosed Myeloid Leukemia: Results From the Randomized BFORE Trial. American Society of Clinical Oncology. 2018; 36 (3): 231-239.

Claims (1)

The method of management of patients with chronic myeloid leukemia in the appointment of tyrosine kinase inhibitors, including research of the cardiovascular system, assessment of the ten-year risk of cardiovascular mortality on the SCORE scale, characterized in that before the appointment of treatment, it is necessary to determine the presence or absence of IHD in the patient; in the absence of IHD with low and medium risk on the SCORE scale, the patient is prescribed one of the following drugs: imatinib, dasatinib, nilotinib, bozutinib, ponatinib; then 1 time in 3 months: a hematologist examines a patient, a biochemical blood test is performed for total cholesterol, lipid spectrum, glucose, B-type natriuretic peptide, NT-proBNP, troponins, electrocardiography, echocardiography, bicycle ergometry, blood pressure control; Once every 6 months ultrasound dopplerography of the brachiocephalic trunk is performed; in the case of nilotinib, a patient’s examination by a hematologist and all of the above studies, except for ultrasound Doppler imaging of the brachiocephalic trunk, should be performed once a month, and Doppler ultrasound of the brachiocephalic trunk 1 time in 3 months; in the absence of adverse events, examination of the patient by a general practitioner and a cardiologist is necessary 1 time in 6 months; in case of occurrence of adverse events, examination by a therapist and a cardiologist is carried out 1 time per month, reducing its frequency to 1 time in 6 months when arresting adverse events; if the patient has a high and very high risk on the SCORE scale in the absence or presence of IHD, he is prescribed one of the following drugs: imatinib, dasatinib, bosutinib; then once a month: a hematologist examines a patient, a biochemical blood test for total cholesterol, lipid spectrum, glucose, B-type natriuretic peptide, NT-proBNP, troponins are performed by the patient, electrocardiography, echocardiography, bicycle ergometry, blood pressure control are performed; Once every 3 months ultrasound dopplerography of the brachiocephalic trunk is performed; in the absence of adverse events, the patient and the cardiologist will examine the patient once every 3 months; in case of adverse events, the patient and the cardiologist examine the patient once a month, reducing its frequency when the adverse event is stopped up to 1 time in 6 months.