Adverse events associated with nilotinib in chronic myeloid leukemia: mechanisms and management strategies

Zeng, Wang; Jiang, Liyu; Hao, Yan; Xu, Zhifei; Luo, Peihua

doi:10.1080/17512433.2021.1894129

Cited by 14 publications

(7 citation statements)

References 93 publications

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“…While the model accurately predicted TKI trajectories, it also predicted that with administration of higher dose or more effective TKIs, the system may potentially return to the healthy state, Hs ( ). However, the optimal dosage of TKI compatible with the return to health may not be attainable in vivo [ 34 ]. Although the treatment response parameters between TOTO and TKI may not be directly compared, it is interesting that the treatment response effect for TOTO ( ) was higher than that for TKI ( ) suggesting that the suppression of BCR::ABL gene with tetracycline had a greater positive impact on the transcriptome than BCR::ABL protein inhibition by TKI.…”

Section: Discussionmentioning

confidence: 99%

State-transition modeling of blood transcriptome predicts disease evolution and treatment response in chronic myeloid leukemia

Frankhouser,

Rockne,

Uechi

et al. 2024

Leukemia

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Chronic myeloid leukemia (CML) is initiated and maintained by BCR::ABL which is clinically targeted using tyrosine kinase inhibitors (TKIs). TKIs can induce long-term remission but are also not curative. Thus, CML is an ideal system to test our hypothesis that transcriptome-based state-transition models accurately predict cancer evolution and treatment response. We collected time-sequential blood samples from tetracycline-off (Tet-Off) BCR::ABL-inducible transgenic mice and wild-type controls. From the transcriptome, we constructed a CML state-space and a three-well leukemogenic potential landscape. The potential’s stable critical points defined observable disease states. Early states were characterized by anti-CML genes opposing leukemia; late states were characterized by pro-CML genes. Genes with expression patterns shaped similarly to the potential landscape were identified as drivers of disease transition. Re-introduction of tetracycline to silence the BCR::ABL gene returned diseased mice transcriptomes to a near healthy state, without reaching it, suggesting parts of the transition are irreversible. TKI only reverted the transcriptome to an intermediate disease state, without approaching a state of health; disease relapse occurred soon after treatment. Using only the earliest time-point as initial conditions, our state-transition models accurately predicted both disease progression and treatment response, supporting this as a potentially valuable approach to time clinical intervention, before phenotypic changes become detectable.

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Section: Discussionmentioning

confidence: 99%

State-transition modeling of blood transcriptome predicts disease evolution and treatment response in chronic myeloid leukemia

Frankhouser,

Rockne,

Uechi

et al. 2024

Leukemia

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show abstract

“…While the model also accurately predicted TKI trajectories, it also predicted that with administration of higher dose or more effective TKIs, the system may potentially return to the healthy state, Hs ( c & ). However, the optimal dosage of TKI compatible with the return to health may not be attainable in vivo 28 . Although the treatment response parameters between TOTO and TKI may not be directly compared, it is interesting that the treatment response effect for TOTO (𝛾 ( TOTO ) ) was higher than that for TKI (𝛾 ( TKI ) suggesting that the suppression of BCR-ABL gene with tetracycline had a greater positive impact on the transcriptome than BCR/ABL protein inhibition by TKI.…”

Section: Discussionmentioning

confidence: 99%

State-transition Modeling of Blood Transcriptome Predicts Disease Evolution and Treatment Response in Chronic Myeloid Leukemia

Frankhouser,

Rockne,

Uechi

et al. 2023

Preprint

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Chronic myeloid leukemia (CML) is initiated and initially maintained solely by the fusion gene BCR-ABL, encoding a multifaceted chimeric kinase targeted in the clinic with tyrosine kinase inhibitors (TKIs) TKIs are effective in inducing long-term remission, but are also frequently not curative. Thus, CML is an ideal system to test our hypothesis that transcriptome-based state-transition models accurately predict cancer evolution and treatment response. To test our hypothesis, we collected time-sequential blood samples from tetracycline-off (Tet-Off) BCR-ABL-inducible transgenic mice and wild-type controls. Using the time-series bulk RNA-seq analysis to capture a system-wide view of distinct disease states, we identified a single principal component that constructed a CML state-space with a three-well BCR-ABL leukemogenic potential landscape. The potential stable critical points defined observable disease states. Early states were characterized by anti-CML genes opposing leukemic transformation; late states were characterized by pro-CML genes. Genes with expression patterns shaped similarly to the potential landscape were identified as disease transition drivers. Re-introduction of tetracyclines to silence the BCR/ABL gene returned diseased mice transcriptomes to a stable state near to health, without reaching it, suggesting partly irreversible transformation changes. TKI treatment only reverted the diseased mice transcriptomes to an earlier disease state, without approaching health; disease relapse occurred soon after treatment completion. Using only the earliest time-point as initial conditions, our parametrized state-transition models accurately predicted both disease progression and treatment response, supporting this as a potentially valuable approach to time clinical intervention even before phenotypic changes become detectable.

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“…Bosutinib is associated with gastrointestinal (GI) toxicity (diarrhea), and hepatic and renal dysfunction [ 57 , 58 ]. Nilotinib can exacerbate hyperglycemia and cause dyslipidemia [ 59 , 60 ]. After a 10-year follow-up, the incidence of arterio-occlusive events(AOEs) and veno-occlusive events (VOEs) (angina, myocardial infarction, cerebrovascular accidents, transient ischemic cerebral events, peripheral arterial insufficiency) was 24.8% with nilotinib 300 mg BID and 33.4% with nilotinib 400 mg BID [ 24 ].…”

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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Adverse events associated with nilotinib in chronic myeloid leukemia: mechanisms and management strategies

Cited by 14 publications

References 93 publications

State-transition modeling of blood transcriptome predicts disease evolution and treatment response in chronic myeloid leukemia

State-transition modeling of blood transcriptome predicts disease evolution and treatment response in chronic myeloid leukemia

State-transition Modeling of Blood Transcriptome Predicts Disease Evolution and Treatment Response in Chronic Myeloid Leukemia

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

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