Subscribe to RSS
DOI: 10.1055/a-1941-7438
Chronisch myeloische Leukämie
Current management and new treatment strategies of chronic myeloid leukemia![](https://www.thieme-connect.de/media/dmw/202312/lookinside/thumbnails/dmw-19417438_10-1055-a-1941-7438-1.jpg)
Was ist neu?
Therapieentscheidung Neben der Wirksamkeit spielen individuelle Therapieziele, Komorbiditäten, Komedikationen und auch Compliance-Themen eine zunehmende Rolle bei der Auswahl des individuell zu präferierenden Tyrosinkinase-Inhibitors (TKI).
Nebenwirkungen Hier gilt es, die sog. Klasseneffekte (ein Effekt, der unter allen TKIs bei einer bestimmten Klasse von TKIs auftreten kann) von den substanzspezifischen Nebenwirkungen der einzelnen TKIs zu unterscheiden.
Was tun bei Nebenwirkungen und Unverträglichkeit? In Studien konnte gezeigt werden, dass durch Anpassung der Dosis des TKIs (ggf. auch mit zeitlich begrenzter Therapiepause) und/oder Änderung der Begleitmedikation eine Verbesserung der Therapietreue (Adhärenz) in den meisten Fällen erreicht werden konnte.
Wie können TKI-Nebenwirkungen vermieden werden? Zur Evaluation der Belastungen und Einschränkungen ist eine gute Arzt-Patienten-Interaktion entscheidend. Hiermit wird das Therapieziel einer guten Wirksamkeit und Adhärenz am ehesten erreicht.
Abstract
The introduction of orally available tyrosine kinase inhibitors (TKI) into the treatment of chronic myeloid leukemia (CML) 25 years ago has substantially improved the clinical outcome of affected patients and resulted in a near-normal life expectancy in chronic phase (CP). Despite of a significant fraction of currently about one third of newly diagnosed CP patients eventually reaching treatment-free remission, the majority of patients still remain on life-long treatment with TKIs. Therefore, a profound knowledge of TKI-related side effects including an increased sensitivity for organ systems predominantly involved, grading, kinetics, duration and reversibility, class-effects versus compound-relatedness as well as a better understanding of how particularly long-lasting, chronic, sometimes formally low-grade toxicities can actually significantly impair patient’s self-assessed quality of life is of utmost importance for an adequate patient/doctor relationship. Given that nowadays, severity and degree of preexisting comorbidities might predict long-term survival of individual patients more significantly than the underlying CML itself, it becomes most important to properly and thoroughly select the TKI of choice on this basis as well as on the individually required co-medications. Given the variety of 2nd, 3rd and now allosteric TKIs available for the molecular targeting of the disease-driving BCR-ABL oncogene in addition to the “class-defining” Imatinib, personalization of CML therapy should now be further extended towards a better appreciation of comorbidities and co-medications before selection of an individual’s TKI treatment complemented by a long-term oriented, patient-centered management and prevention of (sometimes irreversible) TKI side effects.
Schlüsselwörter
Leukämie - CML - Cytochrom P450 (CYP450) - Tyrosinkinaseinhibitor - TKI-WechselwirkungenPublication History
Article published online:
31 May 2023
© 2023. Thieme. All rights reserved.
Georg Thieme Verlag KG
Rüdigerstraße 14, 70469 Stuttgart, Germany
-
Literatur
- 1 Holyoake TL, Vetrie D. The chronic myeloid leukemia stem cell: stemming the tide of persistence Blood. 2017; 129 (12) 1595-1606 DOI: 10.1182/blood-2016-09-696013. (PMID: 28159740)
- 2 Hochhaus A, Larson RA, Guilhot F. et al. Long-Term Outcomes of Imatinib Treatment for Chronic Myeloid Leukemia. N Engl J Med 2017; 376 (10) 917-927 DOI: 10.1056/NEJMoa1609324. (PMID: 28273028)
- 3 Hochhaus A, Rosti G, Cross NC. et al. Frontline nilotinib in patients with chronic myeloid leukemia in chronic phase: results from the European ENEST1st study. Leukemia 2016; 30 (01) 57-64 DOI: 10.1038/leu.2015.270.
- 4 Brümmendorf TH, Cortes JE, Milojkovic D. et al. Bosutinib versus imatinib for newly diagnosed chronic phase chronic myeloid leukemia: final results from the BFORE trial Leukemia. 2022; 36 (07) 1825-1833 DOI: 10.1038/s41375-022-01589-y.
- 5 Kantarjian HM, Shah NP, Cortes JE. et al. Dasatinib or imatinib in newly diagnosed chronic-phase chronic myeloid leukemia: 2-year follow-up from a randomized phase 3 trial (DASISION). Blood 2012; 119 (05) 1123-1129 DOI: 10.1182/blood-2011-08-376087. (PMID: 22160483)
- 6 Balabanov S, Braig M, Brümmendorf TH. Current aspects in resistance against tyrosine kinase inhibitors in chronic myelogenous leukemia. Drug Discov Today Technol 2014; 11: 89-99 DOI: 10.1016/j.ddtec.2014.03.003. (PMID: 24847658)
- 7 Efficace F, Vignetti M, Sparano F. et al. Optimizing health-related quality of life in patients with chronic myeloid leukemia treated with tyrosine kinase inhibitors. Expert Rev Hematol 2021; 14 (03) 293-302 DOI: 10.1080/17474086.2021.1886918.
- 8 Bütow M, Testaquadra FJ, Baumeister J. et al. Targeting cytokine-induced leukemic stem cell persistence in chronic myeloid leukemia by IKK2-inhibition. Haematologica 2022; 108 (04) 1179-1185 DOI: 10.3324/haematol.2022.280922. (PMID: 36453102)
- 9 Lipton JH, Brümmendorf TH, Gambacorti-Passerini C. et al. Long-term safety review of tyrosine kinase inhibitors in chronic myeloid leukemia – What to look for when treatment-free remission is not an option. Blood Rev 2022; 56: 100968 DOI: 10.1016/j.blre.2022.100968.
- 10 Kantarjian HM, Hughes 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 (02) 440-453 DOI: 10.1038/s41375-020-01111-2.
- 11 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 DOI: 10.1200/JCO.2015.64.8899. (PMID: 27217448)
- 12 Hochhaus A, Saglio G, Hughes TP. et al. Long-term benefits and risks of frontline nilotinib vs imatinib for chronic myeloid leukemia in chronic phase: 5-year update of the randomized ENESTnd trial. Leukemia 2016; 30 (05) 1044-1054 DOI: 10.1038/leu.2016.5. (PMID: 26837842)
- 13 Kumar V, Singh P, Gupta SK. et al. Transport and metabolism of tyrosine kinase inhibitors associated with chronic myeloid leukemia therapy: a review. Mol Cell Biochem 2022; 477 (04) 1261-1279 DOI: 10.1007/s11010-022-04376-6.
- 14 Wang CL, Wu VC, Lee CH. et al. Effectiveness and safety of non-vitamin-K antagonist oral anticoagulants versus warfarin in atrial fibrillation patients with thrombocytopenia. J Thromb Thrombolysis 2019; 47: 512-519
- 15 Saussele S, Krauss MP, Hehlmann R. et al. Impact of comorbidities on overall survival in patients with chronic myeloid leukemia: results of the randomized CML study IV. Blood 2015; 126 (01) 42-49 DOI: 10.1182/blood-2015-01-617993.
- 16 Manley PW, Barys L, Cowan-Jacob SW. The specificity of asciminib, a potential treatment for chronic myeloid leukemia, as a myristate-pocket binding ABL inhibitor and analysis of its interactions with mutant forms of BCR-ABL1 kinase. Leuk Res 2020; 98: 106458 DOI: 10.1016/j.leukres.2020.106458. (PMID: 33096322)
- 17 Hochhaus A, Réa D, Boquimpani C. et al. Asciminib vs bosutinib in chronic-phase chronic myeloid leukemia previously treated with at least two tyrosine kinase inhibitors: longer-term follow-up of ASCEMBL. Leukemia 2023; 37 (03) 617-626 DOI: 10.1038/s41375-023-01829-9.
- 18 Takahashi N, Cortes JE, Sakaida E. et al. Safety profile of bosutinib in Japanese versus non-Japanese patients with chronic myeloid leukemia: a pooled analysis. Int J Hematol 2022; 115 (06) 838-851 DOI: 10.1007/s12185-022-03314-y.
- 19 Yuda J, Doki N, Matsuoka H. et al. Asciminib vs bosutinib in CML patients pretreated with ≥2 tyrosine kinase inhibitors: Results from the Japanese subgroup analysis of ASCEMBL study. Cancer Med 2023; 12 (03) 2990-2998 DOI: 10.1002/cam4.5212.
- 20 Brümmendorf TH, Cortes JE, Deininger MW. The effect of BMI on Efficacy and Safety of Bosutinib and Imatinib in Patients with newly diagnosed CML. ASCO Abstract book 2021. Poster 7037. https://ascopubs.org/doi/abs/10.1200/JCO.2021.39.15_suppl.7037
- 21 Isfort S, Wolf D, Crysandt M. et al. ASH 2021: #3608. 2021; 138 (Suppl. 01) 3608 DOI: 10.1182/blood-2021-151240.
- 22 Mita A, Abumiya M, Miura M. et al. Correlation of plasma concentration and adverse effects of bosutinib: standard dose or dose-escalation regimens of bosutinib treatment for patients with chronic myeloid leukemia. Exp Hematol Oncol 2018; 7: 9 DOI: 10.1186/s40164-018-0101-1. (PMID: 29682402)
- 23 Cortes J, Apperley J, Lomaia E. et al. Ponatinib dose-ranging study in chronic-phase chronic myeloid leukemia: a randomized, open-label phase 2 clinical trial. Blood 2021; 138 (21) 2042-2050 DOI: 10.1182/blood.2021012082.. (PMID: 34407543)
- 24 La Rosée P, Martiat P, Leitner A. et al. Improved tolerability by a modified intermittent treatment schedule of dasatinib for patients with chronic myeloid leukemia resistant or intolerant to imatinib. Ann Hematol 2013; 92 (10) 1345-50 DOI: 10.1007/s00277-013-1769-2. (PMID: 23625298)
- 25 Sharf G, Marin C, Bradley JA. et al. Treatment-free remission in chronic myeloid leukemia: the patient perspective and areas of unmet needs. Leukemia 2020; 34 (08) 2102-2112 DOI: 10.1038/s41375-020-0867-0. (PMID: 32457354)