SKIN January 2023 Volume 7 Issue 1 (c) 2022 THE AUTHORS. Published by the National Society for Cutaneous Medicine. 625 BRIEF ARTICLE A Case of Dasatinib-Induced Keratosis Pilaris Olivia Arriaza, BS1, Frank Winsett, MD2, Janice Wilson, MD2, Brent Kelly, MD2 1John Sealy School of Medicine, The University of Texas Medical Branch, Galveston, TX 2Department of Dermatology, The University of Texas Medical Branch, Galveston, TX Dasatinib is a second-generation tyrosine kinase inhibitor (TKI) that is indicated for treatment of chronic myeloid leukemia (CML). Mechanistically, it targets several proteins specific to cancer pathogenesis as they are involved in differentiation, proliferation, and survival. The main proteins targeted are Bcr-Abl, Src, c-kit and PDGFR.1 Dasatinib is structurally similar to the first-generation kinase, imatinib, but has a 325-fold greater potency and is effective against most imatinib-resistant kinase domain mutations.1 Although, dasatinib has a high safety profile and is generally well tolerated, Drucker et al found a 23.3% incidence of all-grade rashes and 1.1% incidence of high-grade rashes associated with dasatinib.2,3 Clinical presentation of rashes from this study were described as pruritic, keratosis pilaris-like eruptions.2 Cutaneous reactions are a well- documented side effect of first and second- generation TKIs, however, there are limited reports of dasatinib induced rash.4,5 Further, the mechanism of rashes due to TKIs are theorized to be pharmacologic rather than immunologic as symptoms are generally dose-dependent and resolve upon cessation of dosing.6 Unfortunately, it is not always possible to discontinue TKI treatment and therefore cutaneous side effects may be treated pharmacologically. As of now, evidence-based guidelines have not been established for management of dasatinib induced cutaneous side effects, but eruptions that are suggestive of inflammatory processes can be managed with topical corticosteroids.2,7 We report a case of persistent keratosis pilaris occurring in a young male that was ABSTRACT Dasatinib is a second-generation tyrosine kinase inhibitor (TKI) indicated for treatment of chronic myeloid leukemia (CML). Dasatinib targets several proteins specific to cancer pathogenesis such as Bcr-Abl, Src, c-kit and PDGFRb. Cutaneous reactions are a well- documented side effect of many TKIs, however, there are limited reports and characterization of dasatinib induced rash. We report a case of keratosis pilaris and follicular epithelial thinning in a 19-year-old patient one month after beginning dasatinib for treatment of CML. This report suggests a possible role of dasatinib in the induction of epithelial follicular instability via reduced Src activity and subsequent down regulation of EGFR. INTRODUCTION CASE REPORT SKIN January 2023 Volume 7 Issue 1 (c) 2022 THE AUTHORS. Published by the National Society for Cutaneous Medicine. 626 exacerbated upon beginning treatment of CML with dasatinib. A 19-year-old-male was diagnosed in August 2017 with CML that was confirmed through bone marrow biopsy resulting in BCR/ABL fusion in 91% of the nuclei. At that time, he was started on chemotherapy consisting of imatinib 400 mg daily. The patient was switched from imatinib to dasatinib because of lack of documented cytogenic/molecular remission after 2.8 years on imatinib. Throughout the duration of imatinib treatment, the patient experienced an intermittent mild, pruritic papular rash over his upper extremities that spread to his abdomen and chest. Once the patient switched to dasatinib, the severity of the rash worsened significantly. The patient described it as extremely pruritic and exacerbated by heat. The patient briefly took himself off the medication for an entire month (February 2021) without resolution of the rash and has since restarted dasatinib. The patient presented to dermatology in May 2021, with abundant uniform spiky follicular papules covering the trunk, arms, thighs, back and face (Figure 1). Clinically, our patient’s rash was consistent with keratosis pilaris. A punch biopsy was taken. Histopathological analysis revealed follicular epithelial thinning affecting mainly the upper portion of the hair follicle, leading to free hair shafts with a mild associated reactive inflammatory infiltrate. The overlying follicular ostia contained parakeratotic debris with mild associated perifollicular acanthosis (Figure 2). The patient was started on triamcinolone 0.1% cream twice daily, applied to affected areas and over the counter ammonium lactate lotion applied all over, every day. It is well known that one of the most common non-hematologic adverse effects of TKIs cutaneous reactions, however, there is little evidence of cutaneous side effects associated with dasatinib.8 Although, keratosis pilaris-like eruptions are the most common adverse cutaneous effects reported from dasatinib treatment, they have not been well characterized as morphologies are varied.2,5,9 Bergman, et al. describes a case of neutrophilic dermatosis associated with dasatinib that presented as recurrent erythematous plaques on the face, neck, chest, arms and back. Biopsies showed a variably cellular, superficial, and deep perivascular and interstitial predominantly neutrophilic infiltrate without evidence of vasculitis.9 In our case, biopsy remarkably revealed destabilization of follicular epithelium characterized by follicular epithelial thinning leading to follicular rupture on histopathology. The typical epidermal hyperkeratosis, hypergranulosis and plugging of individual hair follicles of regular keratosis pilaris was not observed, despite our patient’s clinical presentation being consistent with keratosis pilaris. Differential diagnosis of keratosis pilaris includes other follicular disorders such as follicular hyperkeratotic spicules, trichodysplasia spinulosa, disseminate and recurrent infundibular folliculitis, disseminated spiked hyperkeratosis and multiple digitate hyperkeratosis. Characteristics of these diseases in respect to clinical manifestations, histopathological findings and their associated conditions are summarized in Table 1. Follicular destabilization is thought to underlie the common acneiform rash that can be seen with TKI therapy, especially those DISCUSSION SKIN January 2023 Volume 7 Issue 1 (c) 2022 THE AUTHORS. Published by the National Society for Cutaneous Medicine. 627 Figure 1. Uniform spiky follicular papules covering the chest, abdomen, arms, and back SKIN January 2023 Volume 7 Issue 1 (c) 2022 THE AUTHORS. Published by the National Society for Cutaneous Medicine. 628 Figure 2. follicular epithelial thinning affecting mainly the upper portion of the hair follicle, leading to free hair shafts with a mild associated reactive inflammatory infiltrate. The overlying follicular ostia contained parakeratotic debris with mild associated perifollicular acanthosis SKIN January 2023 Volume 7 Issue 1 (c) 2022 THE AUTHORS. Published by the National Society for Cutaneous Medicine. 629 Table 1. Clinical findings, histopathology, and associations of the differential diagnosis for keratosis pilaris Diseases Clinical Findings Histopathology Associations Follicular hyperkeratotic spicules Tiny hyperkeratotic spicules in follicular distribution and predominantly on the face Infundibular hyperkeratosis, focal parakeratosis, and mild acanthosis with evidence of follicular plugging Multiple myeloma Trichodysplasia spinulosa Numerous keratotic spicules on follicular erythematous papules, disproportionately affects the face Follicular hyperkeratosis and multiple vellus hairs enveloped by a keratotic sheath within a dilated hair follicle Viral associations in immunocompromised hosts Disseminate and recurrent infundibular folliculitis Hundreds of uniform, skin-colored papules likened to “goose bumps”. Presents on the trunk, neck, and upper extremities Mild inflammation of the follicular infundibulum Primarily seen in adults with darkly pigmented skin Disseminated spiked hyperkeratosis Widely disseminated small spikes of keratin that are unrelated to hair follicles Digitate orthokeratosis with moderate epidermal cell hyperplasia and a normal underlying dermis Familial, early adulthood Multiple digitate hyperkeratosis Fine filiform hyperkeratotic lesions. Predominately affects the trunk and extremities Nonfollicular, focal columns of orthokeratosic hyperkeratosis emerging from a raised epidermis with significant stratum granulosum Familial, sporadic, post-inflammation, paraneoplastic SKIN January 2023 Volume 7 Issue 1 (c) 2022 THE AUTHORS. Published by the National Society for Cutaneous Medicine. 630 that modulate the epidermal growth factor receptor (EGFR) pathway, as EGFR signaling is important in hair follicle homeostasis.7,10,11 Although dasatinib does not result in direct inhibition of EGFR, targeted activity against Src down-regulates EGFR activity.10,12 This suggests a possible role of dasatinib in the induction of follicular instability via reduced EGFR activity, leading to a phenomenon similar to that seen in patients on EGFR inhibitors. We report a case of keratosis pilaris induced by dasatinib treatment that histologically revealed evidence of follicular destabilization, characterized by follicular epithelial thinning, leading to follicular rupture. This specific characterization has not yet been reported and proposes further questioning of the relationship between reduced Src and EGFR down regulation. Conflict of Interest Disclosures: None Funding: None Corresponding Author: Olivia Arriaza, BS John Sealy School of Medicine The University of Texas Medical Branch 1605 Market St, Galveston, TX 77550 Phone: (817) 470-1651 Email: ocarriaz@utmb.edu References: 1. Hořínková J, Šíma M, Slanař O. Pharmacokinetics of Dasatinib. Prague Med Rep. 2019;120(2-3):52-63. doi:10.14712/23362936.2019.10 2. Drucker AM, Wu S, Busam KJ, Berman E, Amitay-Laish I, Lacouture ME. Rash with the multitargeted kinase inhibitors nilotinib and dasatinib: Meta-analysis and clinical characterization. Eur J Haematol. 2013;90(2):142-150. doi:10.1111/ejh.12052 3. Gambacorti-Passerini C, Aroldi A, Cordani N, Piazza R. Chronic myeloid leukemia: Second-line drugs of choice. Am J Hematol. 2016;91(1):67-75. doi:10.1002/ajh.24247 4. Cortes JE, Jones D, O’Brien S, et al. Results of dasatinib therapy in patients with early chronic-phase chronic myeloid leukemia. J Clin Oncol. 2010;28(3):389-404. doi:10.1200/JCO.2009.25.4920 5. Patel AB, Solomon AR, Mauro MJ, Ehst BD. Unique Cutaneous Reaction to Second- and Third-Generation Tyrosine Kinase Inhibitors for Chronic Myeloid Leukemia. Dermatology. 2016;232(1):122-125. doi:10.1159/000437383 6. Amitay-Laish I, Stemmer SM, Lacouture ME. Adverse cutaneous reactions secondary to tyrosine kinase inhibitors including imatinib mesylate, nilotinib, and dasatinib. Dermatol Ther. 2011;24(4):386-395. doi:10.1111/j.1529-8019.2011.01431.x 7. Huang X, Patel S, Ahmed N, Seiter K, Liu D. Severe toxicity of skin rash, fever and diarrhea associated with imatinib: Case report and review of skin toxicities associated with tyrosine kinase inhibitors. Drug Des Devel Ther. 2008;(2):215-219. doi:10.2147/dddt.s3843 8. Tarantini F, Anelli L, Ingravallo G, et al. Skin lesions in chronic myeloid leukemia patients during dasatinib treatment. Cancer Manag Res. 2019;11:7991-7996. doi:10.2147/CMAR.S217872 9. Bergman JC, Ly TY, Keating MM, Hull PR. Recurrent and fixed neutrophilic dermatosis associated with dasatinib. J Cutan Med Surg. 2018;22(6):621-623. doi:10.1177/1203475418775663 10. Lin YC, Wu MH, Wei TT, et al. Degradation of epidermal growth factor receptor mediates dasatinib-induced apoptosis in head and neck squamous cell carcinoma cells. Neoplasia (United States). 2012;14(6):463- 475. doi:10.1596/neo.12300 11. Ensslin CJ, Rosen AC, Wu S, Lacouture ME. Pruritus in patients treated with targeted cancer therapies: Systematic review and meta-analysis. J Am Acad Dermatol. 2013;69(5):708-720. doi:10.1016/j.jaad.2013.06.038 12. Chen Z, Oh D, Dubey AK, et al. EGFR family and Src family kinase interactions: mechanics matters? Curr Opin Cell Biol. 2018;51:97-102. doi:10.1016/j.ceb.2017.12.003 CONCLUSION