Vascular adverse events in chronic myeloid leukaemia patients during tyrosine kinase inhibitor therapy in daily clinical practice – analysis from the INFINITY database
Authors:
P. Čičátková 1; D. Žáčková 1; T. Horňák 1; H. Klamová 2; P. Bělohlávková 3; L. Stejskal 4; Z. Křístková 5; J. Baranová 5; A. Kvetková 1; L. Semerád 1; J. Procházková 1; J. Mayer 1,6
Authors‘ workplace:
Interní hematologická a onkologická klinika LF MU a FN Brno
1; Ústav hematologie a krevní transfuze Praha
2; IV. interní hematologická klinika LF UK a FN Hradec Králové
3; Klinika hematoonkologie LF OU a FN Ostrava
4; Institut bio statistiky a analýz, s. r. o., Brno
5; Středoevropský technologický institut – MU, Brno
6
Published in:
Transfuze Hematol. dnes,29, 2023, No. 1, p. 29-37.
Category:
Original Papers
doi:
https://doi.org/10.48095/cctahd202329
Overview
The introduction of the first tyrosine kinase inhibitor imatinib into clinical practice has been associated with dramatical change in chronic myeloid leukaemia treatment over the past 20 years. It represents one of the biggest achievements in haematology and oncology per se. Imatinib was followed by second- and third generation tyrosine kinase inhibitors (nilotinib, dasatinib, bosutinib and ponatinib) resulting in newly diagnosed chronic myeloid leukaemia patients having almost the same life expectancy as the general population. Nevertheless, this often-lifelong treatment can be associated with side effects, which in extraordinary cases may be life threatening. Vascular adverse events are also included among such serious adverse events and their incidence varies over a wide range from 0.32–47.8%, most frequently in association with nilotinib or ponatinib treatment. Their incidence in daily clinical practice in the Czech Republic was evaluated in a retrospective analysis of the INFINITY database. From January 2005 to August 2020, chronic myeloid leukaemia was diagnosed in 1029 patients, with 1007 having valid records for analysis. Of these, 964 patients were in chronic phase. At least one vascular adverse event occurred in 82 patients (8.5%) in chronic phase during tyrosine kinase inhibitors therapy, most frequently in patients receiving nilotinib (10.8%) and ponatinib (8.3%). During first-line tyrosine kinase inhibitor treatment, 60 patients (6.3%) experienced at least one vascular adverse event. In direct comparison of first line imatinib and nilotinib therapy, we found a significantly higher incidence of cardiovascular (2.6 vs. 7.2%; P = 0.013), cerebrovascular (1.4 vs. 4.8%; P = 0.019), and peripheral vascular adverse events (0.2 vs. 4.0%; P = 0.001) in nilotinib treated patients, respectively. This paper offers a more detailed overview of vascular adverse event incidence in patients with chronic myeloid leukaemia treated with tyrosine kinase inhibitors in clinical practice in the Czech Republic and its comparison with available literature.
Keywords:
chronic myeloid leukaemia – Tyrosine kinase inhibitors – nilotinib – ponatinib – vascular adverse events – INFINITY
Sources
1. Nowel PC. A minute chromosome (Ph1) in human chronic granulocytic leukaemia. Blut. 1962; 8: 65–66.
2. Shtivelman E, Lifshitz B, Gale RP, Canaani E. Fused transccript of abl and bcr genes in chronic myelogenous leukaemia. Nature. 1985; 315 (6020): 550–554.
3. Bower H, Björkholm M, Dickman PW et al. Life expectancy of patients with chronic myeloid leukemia approaches the life expectancy of the general population. J Clin Oncol. 2016; 34 (24): 2851–2857.
4. Hochhaus A, Baccarani M, Silver RT, et al. European LeukemiaNet 2020 recommendation for treating chronic myeloid leukemia. Leukemia. 2020; 34 (4): 966–984.
5. Hochhaus A, Saussele S, Rosti G, et al. Chronic myeloid leukaemia: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2017; 28 (suppl_4): iv41–iv51.
6. Hochhaus A, Larson RA, Guilhot F, et al. Long-term outcomes of imatinib treatment for chronic myeloid leukemia. Engl J Med. 2017; 376 (10): 917–927.
7. Kantarjian HM, Huges TP, Larson RA, et al. Long-term outcomes with frontline nilotinib versus imatinib in newly diagnosed chronic myeloid leukemia in chronic phase: ENESTnd 10-year analysis. Leukemia. 2021; 35: 440–453.
8. Kantarjian HM, Giles F, Gattermann N, et al. Nilotinib (formerly AMN107), a highly selective BCR-ABL tyrosine kinase inhibitor, is effective in patients with Philadelphia chromosome-positive chronic myelogenous leukemia in chronic phase following imatinib resistance and intolerance. Blood. 2007; 110 (10): 3540–3546.
9. Cortes JE, Saglio G, Kantarjian HM, et al. Final 5-year study results of DASISION: The dasatinib versus imatinib study in treatment-naïve chronic myeloid leukemia patients trial. J Clin Oncol. 2016; 34 (20): 2333–2340.
10. Saglio G, Kim DW, Issaragrisil S, et al. Nilotinib versus imatinib for newly diagnosed chronic myeloid leukemia. N Engl J Med. 2010; 362 (24): 2251–2259.
11. Kantarjian H, Shah NP, Hochchaus A, et al. Dasatinib versus imatinib in newly diagnosed chronic-phase chronic myeloid leukemia. N Engl J Med. 2010; 362: 2260–2270.
12. Hochhaus A, Kantarjian HM, Baccarani M, et al. Dasatinib induces notable hematologic and cytogenetic response in chronic-phase chronic myeloid leukemia after failure of imatinib therapy. Blood. 2007; 109 (6): 2303–2230.
13. Cortes JE, Gabacorti-Passerini C, Deininger MW, et al. Bosutinib versus imatinib for newly diagnosed chronic myeloid leukemia: results from the randomized BFORE trial. J Clin Oncol. 2018; 36 (3): 231–239.
14. Cortes JE, Kantarjian HM, Brümmendorf TH, et al. Safety and efficacy of bosutinib (SKI-606) in chronic phase Philadelphia chromosome-positive chronic myeloid leukemia patients with resistance or intolerance to imatinib. Blood. 2011; 118 (17): 4567–4576.
15. Cortes JE, Kim DW, Pinila-Ibraz J, et al. Ponatinib efficacy and safety in Philadelphia chromosome-positive leukemia: final 5-year results of the phase 2 PACE trial. Blood. 2018; 132 (4): 393–404.
16. Lipton JH, Chuah Ch, Guerci-Bresler A, et al. Ponatinib versus imatinib for newly diagnosed chronic myeloid leukaemia: an international, randomised, open-label, phase 3 trial. Lancet Oncol. 2016; 17: 612–621.
17. Quintás-Cardama A, Kantarjian H, Cortes J. Nilotinib-associated vascular events. Clin Lymphoma Myeloma Leuk. 2012; 12 (5): 337–340.
18. Giles FJ, Mauro MJ, Hong F, et al. Rates of peripheral arterial occlusive disease in patients with chronic myeloid leukemia in the chronic phase treated with imatinib, nilotinib, or non-tyrosine kinase therapy: a retrospective cohort analysis. Leukemia. 2013; 27: 1310–1315.
19. Cortes JE, Kantarjian HM, Mauro MJ, et al. Long-term cardiac, vascular, hypertension, and effusion safety of bosutinib in patients with Philadelphia chromosome-positive leukemia resistent or intolerant to prior therapy. Eur J Haematol. 2021; 106 (6): 808–820.
20. Jain P, Kantarjian H, Boddu PC, et al. Analysis of cardiovascular and arteriothrombotic adverse events in chronic-phase CML patients after frontline TKIs. Blood Adv. 2019; 3 (6) 851–861.
21. Gugliotta G, Castagnetti F, Breccia M, et al. Long-term outcomes of a phase 2 trial with nilotinib 400 mg twice daily in first-line treatment of chronic myeloid leukemia. Haematologica. 2015; 100 (9): 1146–1150.
22. le Coutre PD, Hughes TP, Mahon FX, et al. Low incidence of peripheral arterial disease in patients receiving dasatinib in clinical trials. Leukemia. 2016; 30: 1593–1596.
23. Lang K, McGarry LJ, Huang H, et al. Mortality and vascular events among elderly patients with chronic myeloid leukemia: a retrospective analysis of linked SEER-Medicare data. Clin Lymphoma Myeloma Leuk. 2016; 16 (5): 275–285.
24. Aichberg KJ, Herndlhofer S, Schernthaner GH, et al. Progressive peripheral arterial occlusive and other vascular events during nilotnib therapy in CML. Am J Hematol. 2011; 86: 533–539.
25. Dahlén T, Edgren G, Lambe M, et al. Cardiovascular events associated with use of tyrosine kinase inhibitors in chronic myeloid leukemia. Ann Intern Med. 2016; 165: 161-166.
26. Gora-Tybor J, Medras E, Calbecka M, et al. Real-life comparison of severe vascular events and other non-hematological complications in patients with chronic myeloid leukemia undergoing second-line nilotinib or dasatinib treatment. Leuk Lymphoma. 2015; 56 (8): 2309–2314.
27. Caocci G, Mulas O, Abruzzese E, et al. Incidence and evaluation of predisposition to cardiovascular toxicity in chronic myeloid leukemia patients treated with bosutinib in the real-life practice. Ann Hematol. 2019; 98: 1885–1890.
28. Shacham-Abulafia A, Raanani O, Lavie D, et al. Real-life experience with ponatinib in chronic myeloid leukemia: a multicenter observational study. Clin Lymphoma Myeloma Leuk. 2018; 18 (7): e295–e301.
29. Caocci G, Mulas O, Bonifacio M, et al. Recurrent arterial occlusive events in patients with chronic myeloid leukemia treated with second- and third-generation tyrosine kinase inhibitors and role of secondary prevention. Int J Cardiol. 2019; 288: 124–127.
30. Huguet F, Cayuela JM, Cambier N, et al. Nilotinib efficacy, safety, adherence and impact on quality of life in newly diagnosed patients with chronic myeloid laukaemia in chronic phase: a prospective observational study in daily clinical practice. Br J Haematol. 2019; 187: 615–626.
31. Caocci G, Mulas O, Abruzzese E, et al. Arterial occlusive events in chronic myeloid leukemia patients treated with ponatinib in the real-life practice are predicted by the Systematic Risk Evaluation (SCORE) chart. Hematol Oncol. 2019; 37: 296–302.
32. Breccia M, Abruzzese E, Castagnetti F, et al. Ponatinib as second-line treatment chronic phase chronic myeloid leukemia patients in real-life practice. Ann Hematol. 2018; 97: 1577–1580.
33. Heiblig M, Rea D, Chrétien ML, et al. Ponatinib evaluation and safety in real-life chronick myelogenous leukemia patients failing more than two tyrosine kinase inhibitors: the PEARL observational study. Experiment Hematol. 2018; 67: 41–48.
34. Hadzijusufovic E, Albrecht-Schgoer K, Huber K, et al. Nilotinib-induced vasculopathy: identificationof vascular endothelial cells as a primary target site. Leukemia. 2017; 31 (11): 2388–2397.
35. Haguet H, Bouvy C, Delvigne AS, et al. The risk of arterial thrombosis in patients with chronic myeloid leukemia treated with second and third generation BCR-ABL tyrosine kinase inhibitors may be explained by their impact on endotelial cells: an in-vitro study. Front Farmacol. 2020; 11: 1–11.
36. Hieschbuehl K, Rank A, Pfeiffer T, et al. Large vessel vasculitis as a possible mechanism of vascular side effects of ponatinib: a cacse report. J Hematol. 2019; 8 (2): 83–85.
37. Gover-Proaktor A, Granot G, Pasmanik-Chor M, et al. Bosutinib, dasatinib, imatinib, nilotinib and ponatinib differentially affect vascular, molecular pathways and functionality of human endothelial cells. Leuk Lymphoma. 2019; 60 (1): 189–199.
38. Gover-Proaktor A, Granot G, Shapira S, et al. Ponatinib reduces viability, migration, and functionality of human endotelial cells. Leuk Lymphoma. 2017; 58: 1455–1467.
39. Horňák R, Semerád L, Žáčková D, et al. Analysis of serum lipids, cardiovascular risk, and indication for statin use during nilotinib and imatinib therapy in de novo CML patients – results from real-life prospective study. Leuk Lymphoma. 2020; 61 (2): 494–496.
40. Rea D, Mirault T, Cluzeau T et al. Early onset hypercholesterolemia induced by the 2nd-generation tyrosine kinase inhibitor nilotinib in patients with chronic myeloid leukemia. Haematologica. 2014; 99 (7): 1197–1203.
41. Racil Z, Razga F, Drapalova J, et al. Mechanism of impaired glucose metabolism durong nilotinib therapy in patients with chronic myelogenous leukemia. Hematologica. 2013; 98 (10): e124–e126.
42. Valent P, Hadzijusufovic E, Schernthaner GH, et al. Vascular safety issues in CML patients treated with BCR/ABL1 kinase inhibitors. Blood. 2015; 125 (6): 901–905.
43. P, Valent. Severe adverse events associated with the use of second-line BCR/ABL tyrosine kinase inhibitors: preferential occurence in patients with comorbities. Haematologica. 2011; 96 (10): 1395–1397.
44. Steegmann JL, Baccarani M, Breccia M, et al. European LeukemiaNet recommendations for the management and avoidance of adverse events of treatment in chronic myeloid leukaemia. Leukemia. 2016; 30: 1648–1671.
45. Žáčková D, Čičátková P, Kvetková A, et al. Jaké dávky inhibitorů tyrozinkináz jsou v léčbě pacientů s chronickou myeloidní leukemií optimální? Transfuze Hematol Dnes. 2021; 27 (1): 28–41.
46. Čičátková P, Kvetková A, Horňák T, et al. Úskalí léčby chronické myeloidní leukemie dasatinibem – plicní arteriální hypertenze jako vzácná komplikace. Transfuze Hematol Dnes. 2021; 27 (2): 166–171.
47. Townsend N, Wilson L, Bhatnagar P, at al. Cardiovascular disease in Europe: epidemiological update 2016. Eur Heart J. 2016; (42): 3232–3245.
48. Huguet F, Cayuela JM, Cambier N, et al. Nilotinib efficacy, safety, adherence and impact on quality of life in newly diagnosed patients with chronic myeloid laukaemia in chronic phase: a prospective observational study in daily clinical practice. Br J Haematol. 2019; 187: 615–626.
49. Saussele S, Haverkamp W, Lang F, et al. Ponatinib in the treatment of chronic myeloid leukemia and Philadelphia chromosome-positive acute leukemia: recommendations of a German expert consensus panel with focus on cardiovascular management. Acta Hematol. 2020; 143: 217-231.
50. Aghel N, Delgado DH, Lipton JH. Cardiovascular toxicities of BCR-ABL tyrosine kinase inhibitors in chronic myeloid leukemia: preventive strategies and cardiovascular surveillance. Vasc Health Risk Manag. 2017; 13: 293–303.
51. Žáčková D, Faber E, Stejskal L, et al. HALF: A prospective multi-centre phase II clinical trial evaluating the efficacy and safety of tyrosine kinase inhibitors‘ discontinuation after two-step dose reduction in patients with chronic myeloid leukemia in deep molecular remission. Blood. 2021; 138: 3606.
Labels
Haematology Internal medicine Clinical oncologyArticle was published in
Transfusion and Haematology Today
2023 Issue 1
Most read in this issue
- Recommendations of the Czech Society of Haematology for the diagnosis and treatment of immune thrombocytopenia in adults
- Recommendations for thrombotic risk stratification and targeted thromboprophylaxis in women during assisted reproduction
- Rare and unfavorable course of chronic myeloid leukemia – a case report and review of the literature
- Blast phase of chronic myeloid leukaemia