- Email: [email protected]
substance P antagonist as antipruritic therapy in cutaneous T-cell lymphoma
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Fig 1. The skin crease sign. Four lesions demonstrating a positive skin crease sign; all were histopathologically confirmed pilomatricomas. A, F/7, left cheek. B, F/31, right arm. C, M/40, left elbow. D, F/44, right arm.
Il-Hwan Kim, MD, PhD, and Sang Geun Lee, MD Department of Dermatology, Korea University Ansan Hospital, College of Medicine, Korea University Funding sources: None. Conflicts of interest: None declared. Correspondence to: Il-Hwan Kim, MD, PhD, Department of Dermatology, Korea University Ansan Hospital, No. 516, Gojan-1-dong, Danwon-ku, Ansan, Gyeonggi-do, 425-707, Korea
CASE Aprepitant: A novel neurokinin-1 receptor/substance P antagonist as antipruritic therapy in cutaneous T-cell lymphoma To the Editor: A 66-year old African American man presented with a 3-year history of mycosis fungoides
E-mail: [email protected]
REFERENCES 1. Julian CG, Bowers PW. A clinical review of 209 pilomatricomas. J Am Acad Dermatol 1998;39:191-5. 2. Kleener J. Pilomatrixoma (epithelioma calcificans Malherbe). A clinical and histopathological survey of Danish material from 1954 to 1971. Acta Ophthalmol 1973;51:692-9. 3. Moehlenbeck FW. Pilomatrixoma (calcifying epithelioma). A statistical study. Arch Dermatol 1973;108:532-4. http://dx.doi.org/10.1016/j.jaad.2012.01.035
LETTERS (MF) (T2N1M0B0, stage IIA) and profound pruritus (10 out of 10 on a visual analog scale [VAS]). He previously failed to respond to bexarotene (225-450 mg daily) in combination with methotrexate (10 mg orally weekly) and psoralen plus ultraviolet light
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(PUVA) biweekly, as well as vorinostat (400 mg daily). Furthermore, class I topical steroids and hydroxyzine (25-50 mg every 8 hours) failed to control his pruritus and the addition of doxepin (25 mg nightly) created intolerable drowsiness. The patient was subsequently started on interferon alfa 2b (IFN- 2b) (3 million units subcutaneously [SC] 3 times per week) in combination with PUVA biweekly on alternate days from IFN- . This resulted in a near complete response by 12 weeks, but the patient self-discontinued IFN- secondary to severe nausea and emesis that was not responsive to ondansetron (8 mg every 8 hours). He remained on PUVA biweekly and was restarted on bexarotene (225 mg daily), but suffered a relapse accompanied by severe (10/10 on VAS) pruritus. He was then restarted on a lower dose of IFN- 2b (1.5 million units SC 3 times per week), PUVA biweekly and class I topical steroids with significant clearance of lesions again by 12 weeks. However, he continued to complain of persistent pruritus and refused to try other antihistamines. In addition, nausea and emesis still persisted, despite treatment with ondansetron. A regimen of aprepitant (80 mg/1 hour prior to IFN- injection) in addition to ondansetron (8 mg every 8 hours as needed on the day of IFN- treatment) was initiated, resulting in significant improvement of pruritus, nausea, and emesis. Four months later, he is maintained on this regimen, including PUVA once weekly, and reports well-controlled itch (1/10 on VAS), tolerable nausea, and no emesis. MF is the most common subtype of cutaneous T-cell lymphoma (CTCL) and is frequently associated with debilitating pruritus.1 IFN- is a commonly used, effective therapy for MF and one that is rarely associated with gastrointestinal side effects.2 Our patient, however, demonstrated temporally related nausea and vomiting to IFN- . Aprepitant (Emend) is a neurokinin-1 (NK-1) receptor/substance P (SP) antagonist, which acts by inhibiting binding of the NK-1 receptor with the SP ligand in the skin and central nervous system.3 Elevated SP levels in keratinocytes and the area postrema (vomiting center of the brain) have been associated with pruritus and nausea/emesis, respectively. As compared with antihistamines such as doxepin and hydroxyzine, aprepitant does not act on histaminergic receptors and is not associated with drowsiness.3 Additionally, unlike other antiemetics such as ondansetron, which is primarily a serotonin (5HT3) antagonist, aprepitant is extremely selective for the NK-1 receptor without affinity for serotonin or dopamine receptors.3 In 2003, aprepitant was approved by the Food and Drug Administration for prevention of postoperative
and chemotherapy-induced nausea and vomiting.3 Recently, aprepitant has also been used as an antipruritic agent in erlotinib-induced pruritus4 and erythrodermic CTCL.5 No previous reports have documented the use of aprepitant for pruritus in non-erythrodermic CTCL. Based on the success of our patient, we suggest aprepitant as adjuvant therapy for CTCL patients with pruritus or gastrointestinal disturbances that are refractory to already established treatments. Barry Ladizinski, MD, Andrea Bazakas, BS, and Elise A. Olsen, MD Dermatopharmacology Study Center, Duke University Medical Center, Durham, North Carolina Funding sources: None. Disclosures: Dr Olsen has served on the advisory board and as an investigator for Merck & Co, Inc. Dr Ladizinski and Andrea Bazakas have no relevant financial disclosures or conflicts of interest. Correspondence to: Barry Ladizinski, MD, Dermatopharmacology Study Center, Duke University Medical Center, Box 3294, Durham, NC 27710. E-mail: [email protected] REFERENCES 1. Olsen EA, Vonderheid E, Pimpinelli N, Willemze R, Kim Y, Knobler R, et al. Revisions to the staging and classification of mycosis fungoides and Sezary syndrome: a proposal of the International Society for Cutaneous Lymphomas (ISCL) and the Cutaneous Lymphoma Study Group of the European Organization of Research and Treatment of Cancer (EORTC). Blood 2007;110:1708-9. 2. Horwitz SM, Olsen EA, Duvic M, Porcu P, Kim YH. Review of the treatment of mycosis fungoides and Sezary syndrome: a stagebased approach. J Natl Compr Canc Netw 2008;6:436-42. 3. Hargreaves R, Ferreira JC, Hughes D, Brands J, Hale J, Mattson B, et al. Development of aprepitant, the first neurokinin-1 receptor antagonist for the prevention of chemotherapyinduced nausea and vomiting. Ann N Y Acad Sci 2011;1222: 40-8. 4. Vincenzi B, Tonini G, Santini D. Aprepitant for erlotinib-induced pruritus. N Engl J Med 2010;363:397-8. 5. Booken N, Heck M, Nicolay JP, Klemke CD, Goerdt S, Utikal J. Oral aprepitant in the therapy of refractory pruritus in erythrodermic cutaneous T-cell lymphoma. Br J Dermatol 2011;164:665-7. http://dx.doi.org/10.1016/j.jaad.2012.02.008
Erlotinib-induced bullous pemphigoid To the Editor: Erlotinib binds to intracellular domain of the epidermal growth factor receptor (EGFR). Its selective action excludes systemic
e198 Letters
NOVEMBER 2012
Fig 1. The skin crease sign. Four lesions demonstrating a positive skin crease sign; all were histopathologically confirmed pilomatricomas. A, F/7, left cheek. B, F/31, right arm. C, M/40, left elbow. D, F/44, right arm.
Il-Hwan Kim, MD, PhD, and Sang Geun Lee, MD Department of Dermatology, Korea University Ansan Hospital, College of Medicine, Korea University Funding sources: None. Conflicts of interest: None declared. Correspondence to: Il-Hwan Kim, MD, PhD, Department of Dermatology, Korea University Ansan Hospital, No. 516, Gojan-1-dong, Danwon-ku, Ansan, Gyeonggi-do, 425-707, Korea
CASE Aprepitant: A novel neurokinin-1 receptor/substance P antagonist as antipruritic therapy in cutaneous T-cell lymphoma To the Editor: A 66-year old African American man presented with a 3-year history of mycosis fungoides
E-mail: [email protected]
REFERENCES 1. Julian CG, Bowers PW. A clinical review of 209 pilomatricomas. J Am Acad Dermatol 1998;39:191-5. 2. Kleener J. Pilomatrixoma (epithelioma calcificans Malherbe). A clinical and histopathological survey of Danish material from 1954 to 1971. Acta Ophthalmol 1973;51:692-9. 3. Moehlenbeck FW. Pilomatrixoma (calcifying epithelioma). A statistical study. Arch Dermatol 1973;108:532-4. http://dx.doi.org/10.1016/j.jaad.2012.01.035
LETTERS (MF) (T2N1M0B0, stage IIA) and profound pruritus (10 out of 10 on a visual analog scale [VAS]). He previously failed to respond to bexarotene (225-450 mg daily) in combination with methotrexate (10 mg orally weekly) and psoralen plus ultraviolet light
J AM ACAD DERMATOL
Letters e199
VOLUME 67, NUMBER 5
(PUVA) biweekly, as well as vorinostat (400 mg daily). Furthermore, class I topical steroids and hydroxyzine (25-50 mg every 8 hours) failed to control his pruritus and the addition of doxepin (25 mg nightly) created intolerable drowsiness. The patient was subsequently started on interferon alfa 2b (IFN- 2b) (3 million units subcutaneously [SC] 3 times per week) in combination with PUVA biweekly on alternate days from IFN- . This resulted in a near complete response by 12 weeks, but the patient self-discontinued IFN- secondary to severe nausea and emesis that was not responsive to ondansetron (8 mg every 8 hours). He remained on PUVA biweekly and was restarted on bexarotene (225 mg daily), but suffered a relapse accompanied by severe (10/10 on VAS) pruritus. He was then restarted on a lower dose of IFN- 2b (1.5 million units SC 3 times per week), PUVA biweekly and class I topical steroids with significant clearance of lesions again by 12 weeks. However, he continued to complain of persistent pruritus and refused to try other antihistamines. In addition, nausea and emesis still persisted, despite treatment with ondansetron. A regimen of aprepitant (80 mg/1 hour prior to IFN- injection) in addition to ondansetron (8 mg every 8 hours as needed on the day of IFN- treatment) was initiated, resulting in significant improvement of pruritus, nausea, and emesis. Four months later, he is maintained on this regimen, including PUVA once weekly, and reports well-controlled itch (1/10 on VAS), tolerable nausea, and no emesis. MF is the most common subtype of cutaneous T-cell lymphoma (CTCL) and is frequently associated with debilitating pruritus.1 IFN- is a commonly used, effective therapy for MF and one that is rarely associated with gastrointestinal side effects.2 Our patient, however, demonstrated temporally related nausea and vomiting to IFN- . Aprepitant (Emend) is a neurokinin-1 (NK-1) receptor/substance P (SP) antagonist, which acts by inhibiting binding of the NK-1 receptor with the SP ligand in the skin and central nervous system.3 Elevated SP levels in keratinocytes and the area postrema (vomiting center of the brain) have been associated with pruritus and nausea/emesis, respectively. As compared with antihistamines such as doxepin and hydroxyzine, aprepitant does not act on histaminergic receptors and is not associated with drowsiness.3 Additionally, unlike other antiemetics such as ondansetron, which is primarily a serotonin (5HT3) antagonist, aprepitant is extremely selective for the NK-1 receptor without affinity for serotonin or dopamine receptors.3 In 2003, aprepitant was approved by the Food and Drug Administration for prevention of postoperative
and chemotherapy-induced nausea and vomiting.3 Recently, aprepitant has also been used as an antipruritic agent in erlotinib-induced pruritus4 and erythrodermic CTCL.5 No previous reports have documented the use of aprepitant for pruritus in non-erythrodermic CTCL. Based on the success of our patient, we suggest aprepitant as adjuvant therapy for CTCL patients with pruritus or gastrointestinal disturbances that are refractory to already established treatments. Barry Ladizinski, MD, Andrea Bazakas, BS, and Elise A. Olsen, MD Dermatopharmacology Study Center, Duke University Medical Center, Durham, North Carolina Funding sources: None. Disclosures: Dr Olsen has served on the advisory board and as an investigator for Merck & Co, Inc. Dr Ladizinski and Andrea Bazakas have no relevant financial disclosures or conflicts of interest. Correspondence to: Barry Ladizinski, MD, Dermatopharmacology Study Center, Duke University Medical Center, Box 3294, Durham, NC 27710. E-mail: [email protected] REFERENCES 1. Olsen EA, Vonderheid E, Pimpinelli N, Willemze R, Kim Y, Knobler R, et al. Revisions to the staging and classification of mycosis fungoides and Sezary syndrome: a proposal of the International Society for Cutaneous Lymphomas (ISCL) and the Cutaneous Lymphoma Study Group of the European Organization of Research and Treatment of Cancer (EORTC). Blood 2007;110:1708-9. 2. Horwitz SM, Olsen EA, Duvic M, Porcu P, Kim YH. Review of the treatment of mycosis fungoides and Sezary syndrome: a stagebased approach. J Natl Compr Canc Netw 2008;6:436-42. 3. Hargreaves R, Ferreira JC, Hughes D, Brands J, Hale J, Mattson B, et al. Development of aprepitant, the first neurokinin-1 receptor antagonist for the prevention of chemotherapyinduced nausea and vomiting. Ann N Y Acad Sci 2011;1222: 40-8. 4. Vincenzi B, Tonini G, Santini D. Aprepitant for erlotinib-induced pruritus. N Engl J Med 2010;363:397-8. 5. Booken N, Heck M, Nicolay JP, Klemke CD, Goerdt S, Utikal J. Oral aprepitant in the therapy of refractory pruritus in erythrodermic cutaneous T-cell lymphoma. Br J Dermatol 2011;164:665-7. http://dx.doi.org/10.1016/j.jaad.2012.02.008
Erlotinib-induced bullous pemphigoid To the Editor: Erlotinib binds to intracellular domain of the epidermal growth factor receptor (EGFR). Its selective action excludes systemic