Long-term safety review of tyrosine kinase inhibitors in chronic myeloid leukemia - What to look for when treatment-free remission is not an option

Lipton, Jeffrey H.; Brümmendorf, Tim H.; Gambacorti‐Passerini, Carlo; García‐Gutiérrez, Valentín; Deininger, Michael W.; Cortés, Jorge E.

doi:10.1016/j.blre.2022.100968

Cited by 29 publications

(22 citation statements)

References 193 publications

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“…35,36 Although quantitative evaluation of differences in CV event risk is limited by the heterogeneity of CV event reporting in the relevant clinical trials, additional monitoring has been recommended for bosutinib, dasatinib, nilotinib and ponatinib. 35,36 Of note, recently published ESC guidelines recommend baseline echocardiography screening for patients commencing dasatinib. 37 Although the majority of panellists did not recommend this, there was a difference of opinion between cardiologists and haematologists, with cardiologists supporting this additional testing.…”

Section: Discussionmentioning

confidence: 99%

Cardiovascular risk in chronic myeloid leukaemia: A multidisciplinary consensus on screening and management

Milojković

Lyon

Mehta³

et al. 2023

European J of Haematology

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Introduction Tyrosine kinase inhibitors (TKIs) have become the mainstay of treatment for chronic myeloid leukaemia (CML), but cardiovascular (CV) risk and exacerbation of underlying risk factors associated with TKIs have become widely debated. Real‐world evidence reveals little application of CV risk factor screening or continued monitoring within UK CML management. This consensus paper presents practical recommendations to assist healthcare professionals in conducting CV screening/comorbidity management for patients receiving TKIs. Methods We conducted a multidisciplinary panel meeting and two iterative surveys involving 10 CML specialists: five haematologists, two cardio‐oncologists, one vascular surgeon, one haemato‐oncology pharmacist and one specialist nurse practitioner. Results The panel recommended that patients commencing second‐/third‐generation TKIs undergo formal CV risk assessment at baseline, with additional investigations and involvement of cardiologists/vascular surgeons for those with high CV risk. During treatment, patients should undergo CV monitoring, with the nature and frequency of testing dependent on TKI and baseline CV risk. For patients who develop CV adverse events, decision‐making around TKI interruption, cessation or change should be multidisciplinary and balance CV and haematological risk. Conclusion The panel anticipates these recommendations will support healthcare professionals in implementing CV risk screening and monitoring, broadly and consistently, and thereby help optimise TKI treatment for CML.

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Section: Discussionmentioning

confidence: 99%

Cardiovascular risk in chronic myeloid leukaemia: A multidisciplinary consensus on screening and management

Milojković

Lyon

Mehta³

et al. 2023

European J of Haematology

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“…The known adverse events during TKI development include leukopenia, thrombocytopenia, anemia, neutropenia, hypertension, abnormal liver function, oral mucosal inflammation, fatigue, sensory nerve abnormalities, thyroid dysfunction, hypopigmentation, proteinuria, and gastrointestinal symptoms. 248 Many new TKIs have been improved in terms of enhancing targeted delivery, prolonging circulation time, improving targeted delivery efficiency, and reducing normal tissue damage to improve their effects. 249 The main focus of CMGC histone kinase drugs is the CDK, MAPK, and GSK3 families.…”

Section: Discussionmentioning

confidence: 99%

Role of protein phosphorylation in cell signaling, disease, and the intervention therapy

Pang

Wang

Qin

et al. 2022

MedComm

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Protein phosphorylation is an important post‐transcriptional modification involving an extremely wide range of intracellular signaling transduction pathways, making it an important therapeutic target for disease intervention. At present, numerous drugs targeting protein phosphorylation have been developed for the treatment of various diseases including malignant tumors, neurological diseases, infectious diseases, and immune diseases. In this review article, we analyzed 303 small‐molecule protein phosphorylation kinase inhibitors (PKIs) registered and participated in clinical research obtained in a database named Protein Kinase Inhibitor Database (PKIDB), including 68 drugs approved by the Food and Drug Administration of the United States. Based on previous classifications of kinases, we divided these human protein phosphorylation kinases into eight groups and nearly 50 families, and delineated their main regulatory pathways, upstream and downstream targets. These groups include: protein kinase A, G, and C (AGC) and receptor guanylate cyclase (RGC) group, calmodulin‐dependent protein kinase (CaMK) group, CMGC [Cyclin‐dependent kinases (CDKs), Mitogen‐activated protein kinases (MAPKs), Glycogen synthase kinases (GSKs), and C dc2‐like kinases (CLKs)] group, sterile (STE)‐MAPKs group, tyrosine kinases (TK) group, tyrosine kinase‐like (TKL) group, atypical group, and other groups. Different groups and families of inhibitors stimulate or inhibit others, forming an intricate molecular signaling regulatory network. This review takes newly developed new PKIs as breakthrough point, aiming to clarify the regulatory network and relationship of each pathway, as well as their roles in disease intervention, and provide a direction for future drug development.

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“…Some toxicities are highly TKI-specific ( Table 1 ) [ 55 ]. Common side-effects with imatinib therapy include fluid retention, periorbital edema, bone and muscle aches, and, less commonly, weight gain.…”

Section: Management Of CML Post-tki Toxicitiesmentioning

confidence: 99%

“…Knowing the common side effects of a TKI can help in the selection of the drug based on patient co-morbidities, as discussed earlier (under the choice of frontline therapy) [ 69 ]. While we once assumed that these toxicities were particular to certain TKIs, recent data showed a higher-than-expected rate of TKI cross-intolerances [ 55 , 68 , 70 , 71 ]. In a registry analysis from Canada, the reason for treatment failure post frontline TKI therapy was about 57% due to intolerance and 43% due to resistance.…”

Section: Management Of CML Post-tki Toxicitiesmentioning

confidence: 99%

Management of chronic myeloid leukemia in 2023 – common ground and common sense

et al. 2023

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With the improving knowledge of CML and its management, the goals of therapy need to be revisited to ensure an optimal use of the BCR::ABL1 TKIs in the frontline and later-line therapy of CML. In the frontline therapy of CML in the chronic phase (CML-CP), imatinib and the three second-generation TKIs (bosutinib, dasatinib and nilotinib) are associated with comparable survival results. The second-generation TKIs may produce earlier deep molecular responses, hence reducing the time to reaching a treatment-free remission (TFR). The choice of the second-generation TKI versus imatinib in frontline therapy is based on the treatment aims (survival, TFR), the CML risk, the drug cost, and the toxicity profile with respect to the patient’s comorbidities. The TKI dosing is more flexible than has been described in the registration trials, and dose adjustments can be considered both in the frontline and later-line settings (e.g., dasatinib 50 mg frontline therapy; dose adjusted schedules of bosutinib and ponatinib), as well as during an ongoing TKI therapy to manage toxicities, before considering changing the TKI. In patients who are not candidates for TFR, BCR::ABL1 (International Scale) transcripts levels <1% are acceptable, result in virtually similar survival as with deeper molecular remissions, and need not warrant a change of TKI. For patients with true resistance to second-generation TKIs or with the T315I gatekeeper mutation, the third-generation TKIs are preferred. Ponatinib should be considered first because of the cumulative experience and results in the CML subsets, including in T315I-mutated CML. A response-based dosing of ponatinib is safe and leads to high TKI compliance. Asciminib is a third-generation TKI with possibly a better toxicity profile, but lesser activity in T315I-mutated CML. Olverembatinib is another potent third-generation TKI with early promising results.

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Long-term safety review of tyrosine kinase inhibitors in chronic myeloid leukemia - What to look for when treatment-free remission is not an option

Cited by 29 publications

References 193 publications

Cardiovascular risk in chronic myeloid leukaemia: A multidisciplinary consensus on screening and management

Cardiovascular risk in chronic myeloid leukaemia: A multidisciplinary consensus on screening and management

Role of protein phosphorylation in cell signaling, disease, and the intervention therapy

Management of chronic myeloid leukemia in 2023 – common ground and common sense

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