Comparative Analysis of Cardiovascular Disorders in Patients with Chronic Myeloid Leukemia on Tyrosine Kinase Inhibitor Therapy

AUTOIMMUNE THROMBOCYTOPENIA ,

LM Makeeva1, EI Emelina1, AV Bykova2, GE Gendlin1, GA Gusarova2, IG Nikitin1, EYu Chelysheva2, OYu Vinogradova1,3,4, IE Lazarev3, EG Arshanskaya3, AG Turkina2

1 NI Pirogov Russian National Research Medical University, 1 Ostrovityanova str., Moscow, Russian Federation, 117997

2 National Research Center for Hematology, 4 Novyi Zykovskii pr-d, Moscow, Russian Federation, 125167

3 SP Botkin Municipal Clinical Hospital, 5 2-i Botkinskii pr-d, Moscow, Russian Federation, 125284

4 Dmitry Rogachev National Research Center of Pediatric Hematology, Oncology and Immunology, 1 Samory Mashela str., Moscow, Russian Federation, 117997

For correspondence: Prof. Gennadii Efimovich Gendlin, MD, PhD, 1 Ostrovityanova str., Moscow, Russian Federation, 117997; e-mail: rgmugt2@mail.ru

For citation: Makeeva LM, Emelina EI, Bykova AV, et al. Comparative Analysis of Cardiovascular Disorders in Patients with Chronic Myeloid Leukemia on Tyrosine Kinase Inhibitor Therapy. Clinical oncohematology. 2020;13(1):104–111 (In Russ).

DOI: 10.21320/2500-2139-2020-13-1-104-111

ABSTRACT

Aim. To analyze adverse cardiovascular events in chronic myeloid leukemia (CML) patients who received various tyrosine kinase inhibitors (TKI).

Materials & Methods. The trial included 97 CML patients with nilotinib, dasatinib or imatinib indications. By the time of examination the patients had undergone TKI therapy for 1–138 months. The three of them were sequentially treated with 2 drugs over the monitoring period. All CML patients were aged 22–79 years (median 53.5 years): 55 women were aged 22–71 years (median 53.5 years) and 42 men were aged 24–79 years (median 53 years).

Results. The comparative analysis demonstrated significantly higher impact of nilotinib on QTc duration compared with other TKIs. The patients who received nilotinib (n = 15) throughout 38 months had QTc of 0.47 s (interquartile range [IQR] 0.46–0.47 s), in imatinib group (n = 17) QTc was 0.43 s (IQR 0.43–0.44 s), and in dasatinib group (n = 4) QTc was 0.43 s (IQR 0.42–0.44 s) (p = 0.0008). Among all patients treated with nilotinib there were 62 % (31/50) with QTc > 0.46 s, in imatinib (6/41) and dasatinib (2/18) groups it was detected in 14.6 % and 11.1 % of patients, respectively (p = 0.0008). Five patients had QTc > 0.48 s, which is the criterion for discontinuation of treatment or dose reduction. In two patients the identified changes of QTc duration required TKI temporary suspension. After nilotinib dose reduction or discontinuation QTc duration normalized in all cases within 2 weeks. Decreased ankle-brachial index (ABI) < 0.9 without pronounced clinical symptoms was identified in two patients who received nilotinib. Afterwards they showed peripheral occlusive disease of lower extremities, and nilotinib treatment was discontinued. In patients treated with other TKIs no occlusive vascular lesions were observed. A case of chronic heart failure with reduced left ventricular ejection fraction developing on nilotinib therapy was revealed and described.

Conclusion. Despite high specificity for BCR-ABL tyrosine kinase, new TKIs can, although rarely, induce cardiovascular adverse events. Prior to TKI treatment assignment CML patients should be examined with ECG and EchoCG with systolic function evaluation, and the measurement of pulmonary artery pressure as well as ABI. The examination should be repeated in the end of the 1st year TKI treatment if there is no reason for extra examinations. It is recommended to hold 24-hour ECG monitoring with QTc max measurement prior to nilotinib assignment, then once a year within 2 years of nilotinib treatment, and once in 6 months after 3 years of therapy.

Keywords: imatinib, dasatinib, nilotinib, chronic myeloid leukemia, QTc prolongation, sudden cardiac death, peripheral occlusive disease of lower extremities, chronic heart failure, cardiomyopathy, pulmonary arterial hypertension.

Received: September 8, 2019

Accepted: December 21, 2019

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