LETTERS AND COMMUNICATIONS
References 1. Allende I, Truchuelo MT, Alcantara J, Boixeda P. Carbon dioxide-laser treatment of trichoepitheliomas in Brooke-Spiegler syndrome [in Spanish]. Actas Dermosifiliogr 2011;102:76–7. 2. Retamar RA, Stengel F, Saadi ME, Kien MC, et al. Brooke-Spiegler syndrome—report of four families: treatment with CO2 laser. Int J Dermatol 2007;46:583–6. 3. Patrocinio LG, Damasceno PG, Patrocinio TG, Patrocinio JA. Solitary nasal trichoepithelioma. Braz J Otorhinolaryngol 2008;74: 637. 4. Dvir E. Solitary trichoepithelioma in a 70-year-old man. Arch Dermatol 1981;117:455–6.
Angeline Anning Yong, MBBS, MRCP (UK) MRCS (Edin), Dip Derm (RCPSG), FRCP (Edin) FAMS (Derm) Chee-Leok Goh, MBBS, MD, MMed (Int Med) MRCP (UK), FRCP (Edin), FAMS (Derm) National Skin Centre, Singapore Singapore The authors have indicated no significant interest with commercial supporters.
Catastrophic Eruptive Keratoacanthomas and Squamous Cell Cancers After Treatment With an FLT3 Inhibitor Quizartinib (AC220)
Quizartinib (AC220) is a receptor tyrosine kinase inhibitor (RTKI) currently in Phase III clinical studies for FLT3-positive acute myeloid leukemia (AML). Quizartinib is not only analogous to other RTKIs such as vemurafenib and sorafenib but also targets the kinase FLT3. FLT3 mutation is associated with aggressive AML and is thought to act like a “power switch” causing leukemic recurrence and spread after chemotherapy; quizartinib inhibits that “switch.” Current trials are exploring its use as a single agent and in combination with chemotherapy, stem cell, or bone marrow transplant.1 A 68-year-old white man with history of AML was treated with hematopoietic stem cell transplant after melphalan/cyclophosphamide conditioning and hydroxyurea. After relapse, his AML was found to harbor FLT3 mutation and he was subsequently treated with an experimental FLT3 inhibitor, quizartinib. Six months after initiation of quizartinib, he developed lichenoid Graft-versus-host disease (GVHD) in a sun-exposed distribution, followed by numerous cutaneous keratoacanthomas (KAs) and squamous cell cancers (SCCs) just weeks later (Figures 1 and 2). The GVHD resolved with topical steroids, a short course of oral tacrolimus and mycophenolate mofetil along with photoprotection only. The AML continued to be in remission on quizartinib, and no additional treatments were required. Treatment of the skin cancers,
530
which numbered up to 30 at the same time, included topical 5-fluorouracil, imiquimod, surgical excisions, photodynamic therapy, and radiation therapy. Despite discontinuation of quizartinib, he continued to develop disfiguring and life-threatening SCCs and died 4 years later of necrotizing myopathy. Quizartinib is a new Class III RTK inhibitor, which has shown promising results in AML treatment.2 Analogous to other RTKIs such as B-RAF inhibitor sorafenib, it modulates enzymatic pathways and controls cell proliferation and differentiation. Modulation of these enzymatic pathways not only induces apoptosis in leukemic cells but also promotes development of other neoplasms. Thus, numerous side effects have been demonstrated with the therapy of RTKIs,
Figure 1. Extensive hyperkeratotic SCCs on sun-exposed skin. The right forearm shows a large advanced squamous proliferation.
DERMATOLOGIC SURGERY
© 2015 by the American Society for Dermatologic Surgery, Inc. Published by Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
LETTERS AND COMMUNICATIONS
keratinocytes. Quizartinib, which targets the same pathway, could potentially trigger a “second hit,” facilitating the development of cutaneous malignancy. Paradoxical activation of the MAP Kinase pathway has been associated with several RTKIs, causing the development of SCCs and KAs. The effects of quizartinib seem permanent, given the progression of SCCs despite the discontinuation of the drug.
Figure 2. Hematoxylin–eosin stain of the specimen shows SCC with endophytic dermal invasion of squamous cells (original magnification ·10).
most notably the induction of KAs and SCCs.3 RAF inhibitors affect the MAP Kinase pathway, and more than any other class of RTKIs have been associated with the development of malignant cutaneous lesions secondary to paradoxical activation of the pathway. Quizartinib decreases MAP Kinase pathway activation but might similarly to RAF inhibitors lead to a paradoxical increase in signaling.2 Thus far, reported common adverse effects of quizartinib include GI symptoms, fatigue, and QTc prolongation.2 Neutrophilic dermatoses, presenting as painful subcutaneous nodules, have been reported in very few cases but no other skin manifestations including skin cancer.4 Chronic cutaneous GVHD and its prolonged systemic therapy have been associated with an increased risk for SCC.5 The short duration of GVHD and the sudden eruption of squamous neoplasms argue against GVHD as a confounding factor. The photo-distributed presentation of squamous proliferations and GVHD in the patient suggests antecedent actinic damage as a contributing factor. Ultraviolet radiation has been shown to cause activating mutations in the MAP Kinase pathway in
The authors believe that quizartinib should be added to the list of RTKIs capable of inducing cutaneous SCCs. Physicians need to be aware of this side effect to provide close monitoring and appropriate treatment. References 1. Ambit Biosciences Corporation. Quizartinib (AC220). Available from: http://www.ambitbio.com/quizartinib. Accessed May 25, 2014. 2. Kampa-Schittenhelm KM, Heinrich MC, Akmut F, et al. Quizartinib (AC220) is a potent second generation class III tyrosine kinase inhibitor that displays a distinct inhibition profile against mutant-FLT3, -PDGFRA, and -KIT isoforms. Mol Cancer 2013;12:19. 3. Arnault JP, Mateus C, Escudier B, Tomasic G, et al. Skin tumors induced by sorafenib; paradoxic RAS-RAF pathway activation and oncogenic mutations of HRAS, TP53, and TGFBR1. Clin Cancer Res 2012;18:263–72. 4. Fathi AT, Le L, Hasserjian RP, Sadrzadeh H, et al. FLT3 inhibitorinduced neutrophilic dermatosis. Blood 2013;122:239–42. 5. Curtis RE, Metayer C, Rizzo JD, Socie G, et al. Impact of chronic GVHD therapy on the development of squamous-cell cancer after hematopoietic stem-cell transplantation: an international case-control study. Blood 2005;105:3802–11.
Kirstin Altman, MD Department of Dermatology University of Wisconsin–Madison Hospital and Clinics, Madison, Wisconsin Harry Sharata, MD, PhD Department of Dermatology University of Wisconsin–Madison Hospital and Clinics, Madison, Wisconsin Madison Skin & Research Inc., Madison, Wisconsin The authors have indicated no significant interest with commercial supporters.
41:4:APRIL 2015
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© 2015 by the American Society for Dermatologic Surgery, Inc. Published by Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
References 1. Allende I, Truchuelo MT, Alcantara J, Boixeda P. Carbon dioxide-laser treatment of trichoepitheliomas in Brooke-Spiegler syndrome [in Spanish]. Actas Dermosifiliogr 2011;102:76–7. 2. Retamar RA, Stengel F, Saadi ME, Kien MC, et al. Brooke-Spiegler syndrome—report of four families: treatment with CO2 laser. Int J Dermatol 2007;46:583–6. 3. Patrocinio LG, Damasceno PG, Patrocinio TG, Patrocinio JA. Solitary nasal trichoepithelioma. Braz J Otorhinolaryngol 2008;74: 637. 4. Dvir E. Solitary trichoepithelioma in a 70-year-old man. Arch Dermatol 1981;117:455–6.
Angeline Anning Yong, MBBS, MRCP (UK) MRCS (Edin), Dip Derm (RCPSG), FRCP (Edin) FAMS (Derm) Chee-Leok Goh, MBBS, MD, MMed (Int Med) MRCP (UK), FRCP (Edin), FAMS (Derm) National Skin Centre, Singapore Singapore The authors have indicated no significant interest with commercial supporters.
Catastrophic Eruptive Keratoacanthomas and Squamous Cell Cancers After Treatment With an FLT3 Inhibitor Quizartinib (AC220)
Quizartinib (AC220) is a receptor tyrosine kinase inhibitor (RTKI) currently in Phase III clinical studies for FLT3-positive acute myeloid leukemia (AML). Quizartinib is not only analogous to other RTKIs such as vemurafenib and sorafenib but also targets the kinase FLT3. FLT3 mutation is associated with aggressive AML and is thought to act like a “power switch” causing leukemic recurrence and spread after chemotherapy; quizartinib inhibits that “switch.” Current trials are exploring its use as a single agent and in combination with chemotherapy, stem cell, or bone marrow transplant.1 A 68-year-old white man with history of AML was treated with hematopoietic stem cell transplant after melphalan/cyclophosphamide conditioning and hydroxyurea. After relapse, his AML was found to harbor FLT3 mutation and he was subsequently treated with an experimental FLT3 inhibitor, quizartinib. Six months after initiation of quizartinib, he developed lichenoid Graft-versus-host disease (GVHD) in a sun-exposed distribution, followed by numerous cutaneous keratoacanthomas (KAs) and squamous cell cancers (SCCs) just weeks later (Figures 1 and 2). The GVHD resolved with topical steroids, a short course of oral tacrolimus and mycophenolate mofetil along with photoprotection only. The AML continued to be in remission on quizartinib, and no additional treatments were required. Treatment of the skin cancers,
530
which numbered up to 30 at the same time, included topical 5-fluorouracil, imiquimod, surgical excisions, photodynamic therapy, and radiation therapy. Despite discontinuation of quizartinib, he continued to develop disfiguring and life-threatening SCCs and died 4 years later of necrotizing myopathy. Quizartinib is a new Class III RTK inhibitor, which has shown promising results in AML treatment.2 Analogous to other RTKIs such as B-RAF inhibitor sorafenib, it modulates enzymatic pathways and controls cell proliferation and differentiation. Modulation of these enzymatic pathways not only induces apoptosis in leukemic cells but also promotes development of other neoplasms. Thus, numerous side effects have been demonstrated with the therapy of RTKIs,
Figure 1. Extensive hyperkeratotic SCCs on sun-exposed skin. The right forearm shows a large advanced squamous proliferation.
DERMATOLOGIC SURGERY
© 2015 by the American Society for Dermatologic Surgery, Inc. Published by Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
LETTERS AND COMMUNICATIONS
keratinocytes. Quizartinib, which targets the same pathway, could potentially trigger a “second hit,” facilitating the development of cutaneous malignancy. Paradoxical activation of the MAP Kinase pathway has been associated with several RTKIs, causing the development of SCCs and KAs. The effects of quizartinib seem permanent, given the progression of SCCs despite the discontinuation of the drug.
Figure 2. Hematoxylin–eosin stain of the specimen shows SCC with endophytic dermal invasion of squamous cells (original magnification ·10).
most notably the induction of KAs and SCCs.3 RAF inhibitors affect the MAP Kinase pathway, and more than any other class of RTKIs have been associated with the development of malignant cutaneous lesions secondary to paradoxical activation of the pathway. Quizartinib decreases MAP Kinase pathway activation but might similarly to RAF inhibitors lead to a paradoxical increase in signaling.2 Thus far, reported common adverse effects of quizartinib include GI symptoms, fatigue, and QTc prolongation.2 Neutrophilic dermatoses, presenting as painful subcutaneous nodules, have been reported in very few cases but no other skin manifestations including skin cancer.4 Chronic cutaneous GVHD and its prolonged systemic therapy have been associated with an increased risk for SCC.5 The short duration of GVHD and the sudden eruption of squamous neoplasms argue against GVHD as a confounding factor. The photo-distributed presentation of squamous proliferations and GVHD in the patient suggests antecedent actinic damage as a contributing factor. Ultraviolet radiation has been shown to cause activating mutations in the MAP Kinase pathway in
The authors believe that quizartinib should be added to the list of RTKIs capable of inducing cutaneous SCCs. Physicians need to be aware of this side effect to provide close monitoring and appropriate treatment. References 1. Ambit Biosciences Corporation. Quizartinib (AC220). Available from: http://www.ambitbio.com/quizartinib. Accessed May 25, 2014. 2. Kampa-Schittenhelm KM, Heinrich MC, Akmut F, et al. Quizartinib (AC220) is a potent second generation class III tyrosine kinase inhibitor that displays a distinct inhibition profile against mutant-FLT3, -PDGFRA, and -KIT isoforms. Mol Cancer 2013;12:19. 3. Arnault JP, Mateus C, Escudier B, Tomasic G, et al. Skin tumors induced by sorafenib; paradoxic RAS-RAF pathway activation and oncogenic mutations of HRAS, TP53, and TGFBR1. Clin Cancer Res 2012;18:263–72. 4. Fathi AT, Le L, Hasserjian RP, Sadrzadeh H, et al. FLT3 inhibitorinduced neutrophilic dermatosis. Blood 2013;122:239–42. 5. Curtis RE, Metayer C, Rizzo JD, Socie G, et al. Impact of chronic GVHD therapy on the development of squamous-cell cancer after hematopoietic stem-cell transplantation: an international case-control study. Blood 2005;105:3802–11.
Kirstin Altman, MD Department of Dermatology University of Wisconsin–Madison Hospital and Clinics, Madison, Wisconsin Harry Sharata, MD, PhD Department of Dermatology University of Wisconsin–Madison Hospital and Clinics, Madison, Wisconsin Madison Skin & Research Inc., Madison, Wisconsin The authors have indicated no significant interest with commercial supporters.
41:4:APRIL 2015
531
© 2015 by the American Society for Dermatologic Surgery, Inc. Published by Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
