Dermatological Toxicities of Bruton’s Tyrosine Kinase Inhibitors

Sibaud, V.; Beylot‐Barry, M.; Protin, Caroline; Vigarios, Émmanuelle; Récher, Christian; Ysebaert, Loïc

doi:10.1007/s40257-020-00535-x

Cited by 68 publications

(93 citation statements)

References 64 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Dermatological toxicities are among the most common AEs of ibrutinib with mostly mild to moderate intensity. Their incidence is highest during the first year of treatment (Sibaud et al, 2020). This also means that in the clinical trials with long follow up, dermatological side-effects are scarce.…”

Section: Mechanisms Underlying Rashmentioning

confidence: 99%

“…These include bruising and ecchymoses, panniculitis, human herpesvirus infections, cellulitis, and skin rash. As summarized in a recent review on dermatological side effects, rash occurs in 13-27% (0-3% grade 3) of patients treated with ibrutinib, as compared to 15-18% and 13-18% in patients receiving acalabrutinib or zanubrutinib, respectively (Sibaud et al, 2020). As presented in Table 3, 11-33% (0% ≥ grade 3) of zanubrutinib, 6-33% (0-< 2% ≥ grade 3) of acalabrutinib and 11-44% (0-6% ≥ grade 3) of tirabrutinib treated patients experience rash.…”

Section: Mechanisms Underlying Rashmentioning

confidence: 99%

“…Suppression of BRK is associated with an increase in apoptosis of proliferating cells (Basile et al, 2019). Inhibition of BRK has been reported for ibrutinib (IC50: 3.3 nM) (Honigberg et al, 2010) and zanubrutinib (IC50: 33 nM) (Guo et al, 2019), however, no cases of stomatitis/mucositis have been reported in acalabrutinibor zanubrutinib-treated patients (Sibaud et al, 2020). While it is always difficult to estimate an inhibitory effect on kinases not carrying a cysteine in the catalytic cleft, zanubrutinib binds to BRK with a higher IC50 than ibrutinib (Guo et al, 2019).…”

Section: Mechanisms Underlying Diarrhoeamentioning

confidence: 99%

See 2 more Smart Citations

Comparative Analysis of BTK Inhibitors and Mechanisms Underlying Adverse Effects

Estupiñán

Berglöf

Zain

et al. 2021

Front. Cell Dev. Biol.

154

171

View full text Add to dashboard Cite

The cytoplasmic protein-tyrosine kinase BTK plays an essential role for differentiation and survival of B-lineage cells and, hence, represents a suitable drug target. The number of BTK inhibitors (BTKis) in the clinic has increased considerably and currently amounts to at least 22. First-in-class was ibrutinib, an irreversible binder forming a covalent bond to a cysteine in the catalytic region of the kinase, for which we have identified 228 active trials listed at ClinicalTrials.gov. Next-generation inhibitors, acalabrutinib and zanubrutinib, are approved both in the United States and in Europe, and zanubrutinib also in China, while tirabrutinib is currently only registered in Japan. In most cases, these compounds have been used for the treatment of B-lymphocyte tumors. However, an increasing number of trials instead addresses autoimmunity and inflammation in multiple sclerosis, rheumatoid arthritis, pemphigus and systemic lupus erythematosus with the use of either irreversibly binding inhibitors, e.g., evobrutinib and tolebrutinib, or reversibly binding inhibitors, like fenebrutinib. Adverse effects (AEs) have predominantly implicated inhibition of other kinases with a BTKi-binding cysteine in their catalytic domain. Analysis of the reported AEs suggests that ibrutinib-associated atrial fibrillation is caused by binding to ERBB2/HER2 and ERBB4/HER4. However, the binding pattern of BTKis to various additional kinases does not correlate with the common assumption that skin manifestations and diarrhoeas are off-target effects related to EGF receptor inhibition. Moreover, dermatological toxicities, diarrhoea, bleedings and invasive fungal infections often develop early after BTKi treatment initiation and subsequently subside. Conversely, cardiovascular AEs, like hypertension and various forms of heart disease, often persist.

show abstract

Section: Mechanisms Underlying Rashmentioning

confidence: 99%

Section: Mechanisms Underlying Rashmentioning

confidence: 99%

Section: Mechanisms Underlying Diarrhoeamentioning

confidence: 99%

See 1 more Smart Citation

Comparative Analysis of BTK Inhibitors and Mechanisms Underlying Adverse Effects

Estupiñán

Berglöf

Zain

et al. 2021

Front. Cell Dev. Biol.

154

171

View full text Add to dashboard Cite

show abstract

“…Increased capillary permeability through elevated VEGF signalling induced by HGF/MET inhibition 43 BCR-Abl: 44 imatinib, dasatinib, nilotinib bosutinib, ponatinib -increased capillary permeability through endothelial Abl kinases inhibition 45 and by off-target inhibition of PDGFRβ and Src kinases 46,47 -decreased hydrostatic interstitial pressure through PDGFRβ inhibition 46,48 -heart failure (imatinib) 4 BTK: ibrutinib 49 Unknown PI3K/AKT: idelalisib, 50 alpelisib 51 Lymphedema 52 through PI3K/AKT inhibition that prevents VEGFR-3/VEGFC-dependant lymphangiogenesis 53 VEGF: sunitinib 32,54 -off-target inhibition of PDGFRβ 55,56 increases capillary permeability and decreases hydrostatic interstitial pressure 46,48 -proteinuria 57 -heart failure 4…”

Section: Ceritinib Crizotinibmentioning

confidence: 99%

Drug‐induced peripheral oedema: An aetiology‐based review

Largeau

Cracowski

Lengelle

et al. 2021

Brit J Clinical Pharma

View full text Add to dashboard Cite

show abstract

“…A recent proteomic study showed that ibrutinib could also covalently react with non-kinase proteins in cells [ 35 ]. To overcome ibrutinib off-target side effects (i.e., skin and dermatological problems [ 36 ], bleeding, infection [ 37 ], headache and atrial fibrillation) and the emerging resistances [ 24 , 38 , 39 ], some selective second-generation BtkIs were developed.…”

Section: Btk Inhibitorsmentioning

confidence: 99%

Btk Inhibitors: A Medicinal Chemistry and Drug Delivery Perspective

Brullo

Villa

Tasso

et al. 2021

IJMS

View full text Add to dashboard Cite

In the past few years, Bruton’s tyrosine Kinase (Btk) has emerged as new target in medicinal chemistry. Since approval of ibrutinib in 2013 for treatment of different hematological cancers (as leukemias and lymphomas), two other irreversible Btk inhibitors have been launched on the market. In the attempt to overcome irreversible Btk inhibitor limitations, reversible compounds have been developed and are currently under evaluation. In recent years, many Btk inhibitors have been patented and reported in the literature. In this review, we summarized the (ir)reversible Btk inhibitors recently developed and studied clinical trials and preclinical investigations for malignancies, chronic inflammation conditions and SARS-CoV-2 infection, covering advances in the field of medicinal chemistry. Furthermore, the nanoformulations studied to increase ibrutinib bioavailability are reported.

show abstract

Dermatological Toxicities of Bruton’s Tyrosine Kinase Inhibitors

Cited by 68 publications

References 64 publications

Comparative Analysis of BTK Inhibitors and Mechanisms Underlying Adverse Effects

Comparative Analysis of BTK Inhibitors and Mechanisms Underlying Adverse Effects

Drug‐induced peripheral oedema: An aetiology‐based review

Btk Inhibitors: A Medicinal Chemistry and Drug Delivery Perspective

Contact Info

Product

Resources

About