5-year study of the effect of cardiac monitoring on the overall survival of patients with chronic lymphocytic leukemia receiving targeted therapy with ibrutinib

Aim      To evaluate the effect of cardiac monitoring on overall survival of patients with chronic lymphoid leukosis (CLL) on targeted therapy with ibrutinib.

Material and methods  Survival of oncological patients depends not only on the efficacy of the antitumor therapy. Cardiovascular comorbidities and emerging cardiotoxicity of the antitumor treatment can considerably impair the quality and duration of patients’ life. The problem of the need for regular cardiological monitoring of oncological patients remains unsolved. A prospective 5-year study was performed that included cardiological monitoring of patients with CLL on chronic targeted therapy with ibrutinib, the side effects of which include atrial fibrillation (AF) and arterial hypertension (AH). The study included 217 patients aged 66.0 [32.0; 910.] years; 144 of them were men aged 66.0 [32.0; 91.0] years and 83 were women aged 65.0 [39.0; 83.0] years. Electrocardiography and echocardiography, evaluation of comorbidity with the Charlson’s index, and evaluation of frailty with the Geriatric 8 questionnaire and the Groningen Frailty Index were performed repeatedly for all patients. In the active cardiac monitoring group (n=89), besides the standard evaluation, active medical monitoring of symptoms and general well-being, blood pressure (BP) and pulse rate, monitoring of cardioprotective drug intake and correction, if necessary, and calling patients for examination and additional evaluation were performed every week. The remaining 128 patients were evaluated repeatedly but did not maintain the remote monitoring with messengers; they constituted a standard follow-up group.

Results This was a study of overall survival of patients with CLL on targeted therapy with ibrutinib depending on the cardiac monitoring program. The age of patients did not differ in the active cardiac monitoring group and the standard follow-up group (66.0 [60.0; 70.0] and 66.0 [59.0; 74.0] years, respectively). The active cardiac monitoring group contained somewhat more men than the standard follow-up group (68.8 and 53.9 %, respectively; р=0.026). At baseline, the groups did not differ in the number of pretreatment lines, frailty test results (Geriatric 8 questionnaire, Groningen Frailty Index), comorbidity (Charlson’s index), and echocardiographic data. The active cardiac monitoring group contained more patients with AH (р<0.0001), with AF (р<0.0001), patients receiving anticoagulants (р<0.0001), and a comparable number of patients with ischemic heart disease. In the active cardiac monitoring group, 70 (90.9%) of 77 patients with CLL and AH achieved goal BP whereas in the standard follow-up group, 26 (39.9 %) of 66 (р<0.0001) patients achieved the BP goal, regardless of whether their elevated BP developed before or during the ibrutinib treatment. This group contained significantly more patients who required cardiac surgical intervention (coronary stenting, pacemaker implantation), 12 vs. 0 in the standard follow-up group (р=0.0004). The overall 5-year survival was significantly higher for patients of the active cardiac monitoring group, both for men (р<0.0001) and women (р<0.0001) with CLL, including patients older than 70 years (р=0.0004), CLL patients with a median pretreatment line number of 1 (р<0.0001), patients with a median chemotherapy line number of 4 (р<0.0001), and patients with genetic abnormalities (р=0.004) pretreated with fludarabine and/or anthracyclines (р<0.0001). The Cox regression analysis showed that the strongest predictor of survival was the achievement of stable goal BP in CLL patients with AH during the continuous cardiac monitoring. Despite more pronounced cardiac comorbidity, CLL patients on the active cardiac monitoring group showed a longer survival than patients on the standard follow-up. Thus, mean survival time of deceased CLL patients who had been on the cardiac monitoring was 36.1 months vs. 17.5 months (р<0.0001) for patients who had been on the standard follow-up.

Conclusion      The study has demonstrated the prognostic significance of continuous participation of a cardiologist in managing onco-hematological patients. CLL patients on the active cardiac monitoring, the regular pattern of which was provided by the remote control, had a significantly higher overall survival compared to patients who visited a cardiologist periodically. A significant predomination of patients with CLL and AH who achieved stable goal BP, continuous monitoring of anticoagulant dosing in patients with AF in that group, and early detection and correction of cardiovascular complications can explain the highly significant difference in the 5-year survival between CLL patients on chronic targeted ibrutinib treatment with different cardiac monitoring programs (р<0.0001). The active cardiac monitoring with remote control allows achievement of a higher 5-year overall survival of CLL patients receiving ibrutinib (p<0.0001).

1. Eloranta S, Smedby KE, Dickman PW, Andersson TM. Cancer survival statistics for patients and healthcare professionals – a tutorial of real‐world data analysis. Journal of Internal Medicine. 2021;289(1):12–28. DOI: 10.1111/joim.13139

2. Emelina E.I., Gendlin G.E., Nikitin I.G. Cardio-oncology and Oncohematology: Examination Algorithms, Prophylactic and Treatment of Cardiotoxicity, Trends in Rehabilitation. Clinical oncohematology. 2021;14(2):239–61. DOI: 10.21320/2500-2139-2021-14-2-239-261

3. Gribben JG, Bosch F, Cymbalista F, Geisler CH, Ghia P, Hillmen P et al. Optimising outcomes for patients with chronic lymphocytic leukaemia on ibrutinib therapy: European recommendations for clinical practice. British Journal of Haematology. 2018;180(5):666–79. DOI: 10.1111/bjh.15080

4. Curigliano G, Lenihan D, Fradley M, Ganatra S, Barac A, Blaes A et al. Management of cardiac disease in cancer patients throughout oncological treatment: ESMO consensus recommendations. Annals of Oncology. 2020;31(2):171–90. DOI: 10.1016/j.annonc.2019.10.023

5. Lee C-S, Rattu MA, Kim SS. A review of a novel, Bruton’s tyrosine kinase inhibitor, ibrutinib. Journal of Oncology Pharmacy Practice. 2016;22(1):92–104. DOI: 10.1177/1078155214561281

6. Tang CPS, McMullen J, Tam C. Cardiac side effects of bruton tyrosine kinase (BTK) inhibitors. Leukemia & Lymphoma. 2018;59(7):1554–64. DOI: 10.1080/10428194.2017.1375110

7. Lyon AR, Dent S, Stanway S, Earl H, Brezden‐Masley C, Cohen‐Solal A et al. Baseline cardiovascular risk assessment in cancer patients scheduled to receive cardiotoxic cancer therapies: a position statement and new risk assessment tools from the Cardio-Oncology Study Group of the Heart Failure Association of the European Society of Cardiology in collaboration with the International Cardio-Oncology Society. European Journal of Heart Failure. 2020;22(11):1945–60. DOI: 10.1002/ejhf.1920

8. Xiao L, Salem J-E, Clauss S, Hanley A, Bapat A, Hulsmans M et al. Ibrutinib-Mediated Atrial Fibrillation Attributable to Inhibition of CTerminal Src Kinase. Circulation. 2020;142(25):2443–55. DOI: 10.1161/CIRCULATIONAHA.120.049210

9. Dickerson T, Wiczer T, Waller A, Philippon J, Porter K, Haddad D et al. Hypertension and incident cardiovascular events following ibrutinib initiation. Blood. 2019;134(22):1919–28. DOI: 10.1182/blood.2019000840

10. Emelina E.I., Gendlin G.E., Nikitin I.G., Dmitrieva E.A., Nikitin E.A., Ptushkin V.V. Rhythm and Conduction Disorders in Patients Receiving Ibrutinib. Clinical oncohematology. 2019;12(2):120–30. DOI: 10.21320/2500-2139-2019-12-2-220-230

11. Lampson BL, Yu L, Glynn RJ, Barrientos JC, Jacobsen ED, Banerji V et al. Ventricular arrhythmias and sudden death in patients taking ibrutinib. Blood. 2017;129(18):2581–4. DOI: 10.1182/blood-2016-10-742437

12. Brown JR. How I treat CLL patients with ibrutinib. Blood. 2018;131(4):379–86. DOI: 10.1182/blood-2017-08-764712

13. Salem J-E, Manouchehri A, Bretagne M, Lebrun-Vignes B, Groarke JD, Johnson DB et al. Cardiovascular Toxicities Associated With Ibrutinib. Journal of the American College of Cardiology. 2019;74(13):1667–78. DOI: 10.1016/j.jacc.2019.07.056

14. Emelina E.I., Gendlin G.E., Nikitin I.G. Antithrombotic Therapy in Patients with Malignant Lymphoproliferative Disorders Treated with Ibrutinib. Clinical oncohematology. 2019;12(4):449–60. DOI: 10.21320/2500-2139-2019-12-4-449-460

15. Yun S, Vincelette ND, Acharya U, Abraham I. Risk of Atrial Fibrillation and Bleeding Diathesis Associated With Ibrutinib Treatment: A Systematic Review and Pooled Analysis of Four Randomized Controlled Trials. Clinical Lymphoma, Myeloma & Leukemia. 2017;17(1):31-37.e13. DOI: 10.1016/j.clml.2016.09.010

16. Stadnik E.A., Timofeeva N.S., Strugov V.V., Zaritskey A.Yu. Ibrutinib in the Treatment of Relapsed Chronic Lymphocytic Leukemia. Clinical oncohematology. 2018;11(1):42–9. DOI: 10.21320/2500-2139-2018-11-1-42-49

17. Mehta LS, Watson KE, Barac A, Beckie TM, Bittner V, Cruz-Flores S et al. Cardiovascular Disease and Breast Cancer: Where These Entities Intersect: A Scientific Statement From the American Heart Association. Circulation. 2018;137(8):e30–66. DOI: 10.1161/CIR.0000000000000556

18. Plummer C, Driessen C, Szabo Z, Mateos M-V. Management of cardiovascular risk in patients with multiple myeloma. Blood Cancer Journal. 2019;9(3):26. DOI: 10.1038/s41408-019-0183-y

19. Sukhanov M.S., Karakulova Yu.V., Prokhorov K.V., Spasenkov G.N., Koryagina N.A. Experience of remote monitoring of patients with cardiovascular diseases in the Perm Krai. Cardiovascular Therapy and Prevention. 2021;20(3):87–90. DOI: 10.15829/1728-8800-2021-2838