RASopathic Skin Eruptions during Vemurafenib Therapy

Jeannine D. Rinderknecht, Simone M. Goldinger, Sima Rozati, Jivko Kamarashev, Katrin Kerl, Lars E. French, Reinhard Dummer, Benedetta Belloni

Research output: Contribution to journalArticle

Abstract

Purpose: Vemurafenib is a potent inhibitor of V600 mutant BRAF with significant impact on progression-free and overall survival in advanced melanoma. Cutaneous side effects are frequent. This single-center observational study investigates clinical and histological features of these class-specific cutaneous adverse reactions. Patients and Methods: Patients were all treated with Vemurafenib 960 mg b.i.d. within local ethic committees approved clinical trials. All skin reactions were collected and documented prospectively. Cutaneous reactions were classified by reaction pattern as phototoxic and inflammatory, hair and nail changes, keratinocytic proliferations and melanocytic disorders. Results: Vemurafenib was well tolerated, only in two patients the dose had to be reduced to 720 mg due to arthralgia. 26/28 patients (93%) experienced cutaneous side effects. Observed side effects included UVA dependent photosensitivity (n = 16), maculopapular exanthema (n = 14), pruritus (n = 8), folliculitis (n = 5), burning feet (n = 3), hair thinning (mild alopecia) (n = 8), curly hair (n = 2) and nail changes (n = 2). Keratosis pilaris and acanthopapilloma were common skin reactions (n = 12/n = 13), as well as plantar hyperkeratosis (n = 4), keratoacanthoma (n = 5) and invasive squamous cell carcinoma (n = 4). One patient developed a second primary melanoma after more than 4 months of therapy (BRAF and RAS wild type). Conclusion: Vemurafenib has a broad and peculiar cutaneous side effect profile involving epidermis and adnexa overlapping with the cutaneous manifestations of genetic diseases characterized by activating germ line mutations of RAS (RASopathy). They must be distinguished from allergic drug reaction. Regular skin examination and management by experienced dermatologists as well as continuous prophylactic photo protection including an UVA optimized sun screen is mandatory.

Original languageEnglish (US)
Article numbere58721
JournalPLoS One
Volume8
Issue number3
DOIs
StatePublished - Mar 14 2013
Externally publishedYes

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skin (animal)
Skin
nails (integument)
Nails
therapeutics
adverse effects
hairs
hyperkeratosis
melanoma
Hair
Sun hoods
exanthema
Photosensitivity
Therapeutics
pruritus
alopecia
photostability
epidermis (animal)
squamous cell carcinoma
ethics

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)

Cite this

Rinderknecht, J. D., Goldinger, S. M., Rozati, S., Kamarashev, J., Kerl, K., French, L. E., ... Belloni, B. (2013). RASopathic Skin Eruptions during Vemurafenib Therapy. PLoS One, 8(3), [e58721]. https://doi.org/10.1371/journal.pone.0058721

RASopathic Skin Eruptions during Vemurafenib Therapy. / Rinderknecht, Jeannine D.; Goldinger, Simone M.; Rozati, Sima; Kamarashev, Jivko; Kerl, Katrin; French, Lars E.; Dummer, Reinhard; Belloni, Benedetta.

In: PLoS One, Vol. 8, No. 3, e58721, 14.03.2013.

Research output: Contribution to journalArticle

Rinderknecht, JD, Goldinger, SM, Rozati, S, Kamarashev, J, Kerl, K, French, LE, Dummer, R & Belloni, B 2013, 'RASopathic Skin Eruptions during Vemurafenib Therapy', PLoS One, vol. 8, no. 3, e58721. https://doi.org/10.1371/journal.pone.0058721
Rinderknecht JD, Goldinger SM, Rozati S, Kamarashev J, Kerl K, French LE et al. RASopathic Skin Eruptions during Vemurafenib Therapy. PLoS One. 2013 Mar 14;8(3). e58721. https://doi.org/10.1371/journal.pone.0058721
Rinderknecht, Jeannine D. ; Goldinger, Simone M. ; Rozati, Sima ; Kamarashev, Jivko ; Kerl, Katrin ; French, Lars E. ; Dummer, Reinhard ; Belloni, Benedetta. / RASopathic Skin Eruptions during Vemurafenib Therapy. In: PLoS One. 2013 ; Vol. 8, No. 3.
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abstract = "Purpose: Vemurafenib is a potent inhibitor of V600 mutant BRAF with significant impact on progression-free and overall survival in advanced melanoma. Cutaneous side effects are frequent. This single-center observational study investigates clinical and histological features of these class-specific cutaneous adverse reactions. Patients and Methods: Patients were all treated with Vemurafenib 960 mg b.i.d. within local ethic committees approved clinical trials. All skin reactions were collected and documented prospectively. Cutaneous reactions were classified by reaction pattern as phototoxic and inflammatory, hair and nail changes, keratinocytic proliferations and melanocytic disorders. Results: Vemurafenib was well tolerated, only in two patients the dose had to be reduced to 720 mg due to arthralgia. 26/28 patients (93{\%}) experienced cutaneous side effects. Observed side effects included UVA dependent photosensitivity (n = 16), maculopapular exanthema (n = 14), pruritus (n = 8), folliculitis (n = 5), burning feet (n = 3), hair thinning (mild alopecia) (n = 8), curly hair (n = 2) and nail changes (n = 2). Keratosis pilaris and acanthopapilloma were common skin reactions (n = 12/n = 13), as well as plantar hyperkeratosis (n = 4), keratoacanthoma (n = 5) and invasive squamous cell carcinoma (n = 4). One patient developed a second primary melanoma after more than 4 months of therapy (BRAF and RAS wild type). Conclusion: Vemurafenib has a broad and peculiar cutaneous side effect profile involving epidermis and adnexa overlapping with the cutaneous manifestations of genetic diseases characterized by activating germ line mutations of RAS (RASopathy). They must be distinguished from allergic drug reaction. Regular skin examination and management by experienced dermatologists as well as continuous prophylactic photo protection including an UVA optimized sun screen is mandatory.",
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