The effects of dasatinib on IgE receptor–dependent activation and histamine release in human basophils

Kneidinger, Michael; Schmidt, Uwe; Rix, Uwe; Gleixner, Karoline V.; Vales, Anja; Baumgartner, Christian; Lupinek, Christian; Weghofer, Margit; Bennett, Keiryn L.; Herrmann, Harald; Schebesta, Alexandra; Thomas, Wayne R.; Vrtala, Susanne; Valenta, Rudolf; Lee, Francis Y.; Ellmeier, Wilfried; Superti‐Furga, Giulio; Valent, Peter

doi:10.1182/blood-2007-08-104372

Cited by 74 publications

(94 citation statements)

References 57 publications

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“…16,18 An interesting aspect is that dasatinib binds to and blocks major kinases of the immune system including Lyn, Btk, and Src, with consecutive deactivation of immune cells. 11,13,15 At low concentration, however, dasatinib may even trigger the activation of certain immune cells. Likewise, low-dose dasatinib even promotes IgEdependent histamine release in basophils.…”

Section: Resultsmentioning

confidence: 99%

“…Likewise, low-dose dasatinib even promotes IgEdependent histamine release in basophils. 15 Although it has not formally been proven that basophil/mast cell activation and histamine release is involved in serosal inflammation/effusion formation caused by low-dose dasatinib, it seems clear that dose reduction of dasatinib may lower the risk of various side effects but does not eliminate the risk of effusion formation. This may also be true for patients with freshly diagnosed CML.…”

Section: Resultsmentioning

confidence: 99%

“…Furthermore, some stimulating effects of dasatinib on immune cells, such as enhancement of IgE-dependent histamine-liberation from basophils in vitro, are particularily seen at low concentrations of dasatinib. 15 We report on 4 patients with imatinib-resistant CML who were treated with dasatinib at 100 mg or 50 mg per os daily and developed extensive pericardial and/or pleural effusions.…”

Section: Introductionmentioning

confidence: 99%

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Extensive pleural and pericardial effusion in chronic myeloid leukemia during treatment with dasatinib at 100 mg or 50 mg daily

Krauth¹,

Herndlhofer²,

Schmook³

et al. 2010

Haematologica

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Dasatinib is considered an effective drug in imatinib-resistant chronic myeloid leukemia. Although reported to be well-tolerated, severe events such as pleural or pericardial effusion have been reported at 140 mg daily. We examined our chronic myeloid leukemia patients treated with dasatinib at 100 mg or 50 mg daily and identified 4 of 13 patients who developed marked effusion formation. In 2 patients, grade III/IV pleural and/or pericardial effusions were recorded. All 4 patients had received previous anti-leukemia therapy but none had preexisting cardiac or pulmonary diseases. In 3 patients, dasatinib had to be discontinued despite treatment with diuretics and glucocorticosteroids. In conclusion, dasatinib-treated chronic myeloid leukemia patients are at risk for the development of pleural and pericardial effusions even when the drug is administered at 100 mg or 50 mg daily. Therefore, all patients should be examined for pre-existing comorbidity and risk factors before starting dasatinib and all should have repeated chest Xrays during long-term dasatinib therapy.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Extensive pleural and pericardial effusion in chronic myeloid leukemia during treatment with dasatinib at 100 mg or 50 mg daily

Krauth¹,

Herndlhofer²,

Schmook³

et al. 2010

Haematologica

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“…Histamine release experiments were performed on basophils and MC as described previously (31,32). A detailed decription is provided in the Supplement.…”

Section: Histamine Release Experimentsmentioning

confidence: 99%

Target interaction profiling of midostaurin and its metabolites in neoplastic mast cells predicts distinct effects on activation and growth

et al. 2015

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Proteomic-based drug testing is an emerging approach to establish the clinical value and antineoplastic potential of multi-kinase inhibitors. The multikinase inhibitor midostaurin (PKC412) is a promising new agent used to treat patients with advanced systemic mastocytosis (SM). We examined the target interaction-profiles and the mast cell (MC)-targeting effects of two pharmacologically relevant midostaurin metabolites, CGP52421 and CGP62221. All three compounds, midostaurin and the two metabolites, suppressed IgE-dependent histamine secretion in basophils and MC with reasonable IC 50 values. Midostaurin and CGP62221 also produced growth-inhibition and dephosphorylation of KIT in the MC leukemia cell line HMC-1.2, whereas the second metabolite, CGP52421, that accumulates in vivo, showed no substantial effects.Chemical proteomic profiling and drug-competition experiments revealed that midostaurin interacts with KIT and several additional kinase-targets. The key downstream-regulator FES was recognized by midostaurin and CGP62221, but not by CGP52421 in MC lysates, whereas the IgEreceptor-downstream target SYK was recognized by both metabolites. Together, our data show that the clinically relevant midostaurin metabolite CGP52421 inhibits IgE-dependent histamine release, but is a weak inhibitor of MC proliferation which may have clinical implications and may explain why mediator-related symptoms improve in SM patients even when disease progression occurs.

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“…In this regard, it is noteworthy that IgE-mediated histamine release from basophils is augmented by low concentrations of dasatinib. 19 Moreover, therapy with glucocorticosteroids, known to suppress lymphocyte-and basophil function, exerts beneficial effects in these patients. 8,18 From these observations, infections (especially bronchopulmonary infections), autoimmune disorders, and allergic reactions must be taken into account as potentially relevant for the development of effusion-formation in dasatinib-treated patients, and early recognition and management of such comorbidities may be an effective way to prevent effusion-formation.…”

Section: Potential Mechanisms and Treatment Optionsmentioning

confidence: 99%

Second line BCR/ABK TKI-associated severe adverse events:preferential occurrence in patients with comorbidities

Valent¹

2011

Haematologica

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The effects of dasatinib on IgE receptor–dependent activation and histamine release in human basophils

Cited by 74 publications

References 57 publications

Extensive pleural and pericardial effusion in chronic myeloid leukemia during treatment with dasatinib at 100 mg or 50 mg daily

Extensive pleural and pericardial effusion in chronic myeloid leukemia during treatment with dasatinib at 100 mg or 50 mg daily

Target interaction profiling of midostaurin and its metabolites in neoplastic mast cells predicts distinct effects on activation and growth

Second line BCR/ABK TKI-associated severe adverse events:preferential occurrence in patients with comorbidities

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