Imatinib mesylate (Gleevec [STI-571]; Novartis Pharmaceuticals. Imatinib Mesylate Causes Hypopigmentation in the Skin

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1 2483 Imatinib Mesylate Causes Hypopigmentation in the Skin Anne S. Tsao, M.D. 1 Hagop Kantarjian, M.D. 2 Jorge Cortes, M.D. 2 Susan O Brien, M.D. 2 Moshe Talpaz, M.D. 3 1 Medical Oncology Fellowship Program, University of Texas M. D. Anderson Cancer Center, Houston, Texas. 2 Department of Leukemia, University of Texas M. D. Anderson Cancer Center, Houston, Texas 3 Department of Bioimmunotherapy, University of Texas M. D. Anderson Cancer Center, Houston, Texas BACKGROUND. Imatinib mesylate is a tyrosine kinase inhibitor that targets the BCR-ABL protein in CML, c-kit (KIT) and platelet-derived growth factor receptors. In clinical trials with imatinib mesylate, common side effects of nausea, emesis, diarrhea, periorbital edema, fluid retention, and myelosuppression have been documented. METHODS. In this case series, the authors describe unique clinical findings of skin hypopigmentation in six patients with CML who were treated with imatinib mesylate. RESULTS. Most patients developed onset of skin hypopigmentation within the first month of treatment and all of the patients experienced additional drug toxicity. Despite patient susceptibility to toxicity, the presence of hypopigmentation did not appear to predict leukemic cell response or clinical outcome. All six patients established a hematologic response but only two patients had a complete cytogenetic response. Imatinib mesylate induced hypopigmentation also appeared to be reversible and potentially dose related. CONCLUSION. Skin hypopigmentation is a benign side effect from imatinib mesylate treatment that appears to be reversible upon discontinuation or dose reduction. Several lines of evidence have previously reported that KIT and its ligand stem cell factor (SCF) have a regulatory role in melanocyte development and survival, suggesting a rational mechanism of action for imatinib mesylate in the pathogenesis of hypopigmentation. The signal transduction mechanism currently is believed to involve SCF ligand binding of KIT and downstream activation of MAP kinase (Erk-2). Microphthalmia (Mi), a basic helix-loop-helix leucine zipper (bhl- HZip) transcription factor, is phosphorylated by MAP kinase at a serine residue (S73). Once phosphorylated, Mi transactivates the tyrosine pigmentation gene promoter and affects pigment production. Cancer 2003;98: American Cancer Society. KEYWORDS: imatinib mesylate, chronic myelogenous leukemia (CML), skin depigmentation, MAP kinase, microphthalmia. Address for reprints: Moshe Talpaz, M.D., Department of Bioimmunotherapy, University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Box 422, Houston, TX 77030; Fax: (713) ; motalpaz@mdanderson.org Received June 10, 2003; revision received August 13, 2003; accepted August 27, Imatinib mesylate (Gleevec [STI-571]; Novartis Pharmaceuticals Corporation, East Hanover, NJ) is a tyrosine kinase inhibitor that targets the BCR-ABL protein in chronic myelogenous leukemia (CML), c-kit (KIT), and platelet-derived growth factor receptors. 1,2 In clinical trials with imatinib mesylate, common side effects of nausea, emesis, diarrhea, periorbital edema, fluid retention, and myelosuppression have been documented. The pathophysiology of diarrhea has been attributed to inhibition of the KIT receptor located on the interstitial cells of Cajal. 2 In the current case series, we describe clinical findings of skin hypopigmentation in six patients with CML who were treated with imatinib mesylate (Table 1). Several lines of evidence have previously reported that KIT and its ligand stem cell 2003 American Cancer Society DOI /cncr.11812

2 2484 CANCER December 1, 2003 / Volume 98 / Number 11 TABLE 1 Summary of Patient Characteristics Age (yrs) Gender Area of hypopigmentation Date of diagnosis of CML CML stage Imatinib mesylate start date Start dose Time to symptoms Dose change Effect on pigmentation CML response 63 F Total body 1997 Blast 11/ mg 3 mos Yes, held for 1 week 32 M Face, bilateral palms (patches up to 1 cm) 1997 Accelerated 4/ mg 1 year Yes, 58 M Face, torso, back 1997 Chronic 8/ mg Since start Yes, increased 77 F Face (patchy), 1995 Blast 12/ mg Since start Yes, upper chest, bilateral palms, upper arms 49 F General body 1999 Chronic 10/ mg Since start Yes, Darker skin during the 1 week Unknown Increased hypopigmentation Darker skin on lower dose Unknown Hematologic and cytogenetic disease 52 F Neck, hands, torso 2001 Chronic 7/ mg Since start No NA Hematologic and cytogenetic disease CML: chronic myelogenous leukemia; F: female; M: male; NA: not available. factor (SCF) play a regulatory role in melanocyte development and survival, suggesting a rational mechanism of action for imatinib mesylate in the pathogenesis of hypopigmentation. 3,4 Case Reports Patient 1 was a 63-year-old African-American female who was diagnosed in August 1997 with CML and treated sequentially with hydroxyurea, interferon- (IFN- ) and cytarabine (Ara-C), and pegylated interferon. In November 2000, she developed clonal evolution with blast crises and treatment with imatinib mesylate was initiated at a dose of 600 mg daily. The patient developed both a hematologic and cytogenetic disease within 3 months. During the initial 3 months of treatment, the patient experienced (NCI Common Toxicity Criteria) Grade 1 diarrhea, Grade 1 periorbital edema, and oral sores as well as total body hypopigmentation (Figs. 1,2). For 1 week of therapy, the patient had a gastrointestinal viral infection and did not receive imatinib mesylate. The patient reported darkening of her skin during that time. Patient 2 was a 32-year-old African-American male who was diagnosed in October 1997 with CML and previously was treated with hydroxyurea and interferon-. After 4 years of treatment, the patient progressed to accelerated-phase CML and treatment with 600 mg of imatinib mesylate daily was initiated in April A hematologic disease was ob- FIGURE 1. Pretreatment photograph of Patient 1, who had chronic myelogenous leukemia.

3 Imatinib Mesylate Changes Skin Pigmentation/Tsao et al FIGURE 2. (A,B) Skin pigmentation changes in Patient 1 after treatment with imatinib mesylate. tained within 1 month but the patient remained without a cytogenetic disease at the time of last follow-up. This patient had difficulty tolerating imatinib mesylate and required several breaks in treatment for Grade 2-3 myelosuppression (neutropenia and thrombocytopenia), Grade 1 muscle cramps, and periorbital edema. The patient noted that approximately 1 year after treatment with imatinib mesylate was initiated, a 1-cm patchy area of skin hypopigmentation appeared on his face and the extensor surface on his hands. Patient 3 was a 58-year-old African-American male who was diagnosed in 1997 with CML and was heavily pretreated before imatinib therapy with interferon-, combined interferon- and Ara-C, hydroxyurea and anagrelide, and 9-nitrocamptothecin. Although still in chronic phase, he had evidence of clonal evolution and treatment with 600 mg of daily imatinib mesylate was initiated in August A hematologic disease and partial cytogenetic disease were achieved within 1 year. The patient noted hypopigmentation to his face and clothing-covered areas at the initiation of therapy. Additional side effects experienced were Grade 0-1 nausea and emesis, Grade 1 periorbital edema, Grade 1 muscle cramps, and Grade 1 anemia. During treatment, the patient s daily dose of imatinib was increased to 800 mg and an additional lightening of the patient s hypopigmented areas occurred. Patient 4 was a 77-year-old African-American female diagnosed in 1995 with CML and treated with interferon- and hydroxyurea. After progressing to blast crises in December 2000, treatment was initiated with 600 mg of daily imatinib mesylate and within 3 months, the patient noticed patches of skin hypopigmentation on the face, upper arms, palms, and torso. A hematologic disease was achieved (but not a cytogenetic disease ) after 1 year of therapy. During treatment, the patient developed Grade 3 myelosuppression, Grade 2 diarrhea, and Grade 2 nausea and emesis leading to a dose reduction to 400 mg. This dose reduction led to darkening of the patient s hypopigmented areas. Patient 5 was a 49-year-old African-American female who was diagnosed with CML in 1999 and treated with interferon-, pegylated interferon, hy-

4 2486 CANCER December 1, 2003 / Volume 98 / Number 11 droxyurea, and anagrelide. After failure to obtain cytogenetic disease, treatment with imatinib mesylate at a dose of 400 mg daily was initiated in October 2000 and the patient achieved a hematologic disease. The patient noticed general body skin lightening at the time the imatinib mesylate treatment began. Because of Grade 3 myelosuppression, the dose was reduced to 300 mg but the patient did not report any changes in her skin coloring. Patient 6 was a 52-year-old African-American female who was diagnosed with chronic phase CML in 2001 and treated with a few weeks of hydroxyurea. The patient was then treated with 800 mg of daily imatinib mesylate and within 1 month noticed hypopigmentation on her hands, neck, and torso. The patient only experienced Grade 1 periorbital edema, diarrhea, leg cramps, and anemia and had not required any dose reductions at the time of last follow-up. She achieved complete hematologic and cytogenetic disease s with this dose regimen. DISCUSSION Although the current case series had a small number of patients, some general trends are notable. The majority of the patients noticed the pigmentation changes at the time treatment with imatinib mesylate was initiated (within 1 month) and had persistent hypopigmentation during therapy. Also, all the patients experienced additional imatinib mesylate toxicities, five patients experienced myelosuppression (Grade 1-3), four reported diarrhea (Grade 1-2), four had muscle cramps (Grade 1), three experienced nausea and emesis (Grade 1), five reported periorbital edema (Grade 1), and one patient experienced mouth sores and a loss of taste. Four of the patients required dose reductions or interruptions of the imatinib mesylate therapy because of myelosuppression and gastrointestinal symptoms. Despite patient susceptibility to drug toxicity, the presence of hypopigmentation does not appear to predict leukemic cell response or clinical outcome. All six of the CML patients in the current study achieved a hematologic response but only two patients were reported to have achieved a complete cytogenetic response. To our knowledge, there is one reported case of imatinib mesylate-induced hypopigmentation in the literature that occurred in a Caucasian male with involvement of the distal aspects of both hands and the penis. 5 Although all the patients in the current study were of African-American ethnicity, this report indicates that the skin toxicity is not specific to one ethnic background and, most likely, the skin changes are more noticeable and therefore more likely to be reported among patients with darker skin. Imatinib mesylate-induced hypopigmentation appears to be reversible and potentially dose related. In the two cases of dose interruption or reduction reported in the current study, patients reported darkening of their skin pigmentation. In the one patient in whom the dose was interrupted, reinitiation of therapy reversed the skin darkening and led to a light skin tone similar to the color found prior to the dose interruption. The converse also appears to occur with dose escalation; in the 1 patient who was treated with 800 mg of imatinib mesylate, an increase in the degree of skin hypopigmentation was documented. The receptor KIT and its ligand SCF play a critical role in the development and maintenance of human melanocytes. During embryogenesis, SCF and KIT direct melanoblast migration from the neural tube to the skin of the embryo and, in the postnatal period, maintain the survival of melanocytes. 4 Although to our knowledge the exact mechanism by which this occurs is unclear at the present time, melanocyte homeostasis and differentiation also have been attributed to the SCF/KIT pathway. This is supported by the observation that human mutations in the encoded tyrosine kinase region of KIT have been shown to cause piebaldism, an autosomal dominant disorder characterized by white hair and hypopigmented skin patches on the forehead, torso, and extremities. 6,7 In addition, murine models with human xenograft skin were subjected to KIT inhibitory antibody (K44.2), which led to melanocyte loss and a decrease in differentiation antigens and melanocyte dendritic processes. Prolonged KIT inhibition led to melanocyte apoptosis. This finding provides in vitro evidence of a critical role for SCF/KIT in the homeostasis and survival of human melanocytes. 3 The signal transduction mechanism currently is believed to involve SCF ligand binding of KIT and downstream activation of MAP kinase (Erk-2). Microphthalmia (Mi), a basic, helix-loop-helix, leucine zipper (bhlhzip) transcription factor, is phosphorylated by MAP kinase at a serine residue (S73). Once phosphorylated, Mi transactivates the tyrosine pigmentation gene promoter and affects pigment production. 8 Heterozygous Mi mutations in humans is reported to cause type IIA Waardenburg syndrome. 8,9 Recommendations Adverse effects from skin hypopigmentation include photosensitivity. The majority of patients in the current study developed hypopigmentation changes in sun-exposed areas and in two cases sunburn was experienced. Treatment recommendations therefore include avoidance of sun exposure and the use of sun block. Although the emotional impact of the skin

5 Imatinib Mesylate Changes Skin Pigmentation/Tsao et al changes can be significant, to our knowledge few options are available to alter the side effect. Prior studies have evaluated the use of tretinoin treatments on hypopigmented macules in the photodamaged skin of elderly patients. Four months of treatment reportedly led to a partial restoration of pigmentation. 10 This is not currently recommended but can be considered an option if the emotional impact is believed to affect the patient s quality of life. Other additional options include the use of tinted cosmetic products or selftanning topical preparations. Although biopsies were considered in the current series, we were unable to ethically justify subjecting these patients to the procedure. This skin toxicity, although cosmetically a problem, does not pose a substantial medical hazard. However, we would recommend conducting future translational prospective studies with skin biopsies to further evaluate and confirm the mechanism of action for this skin toxicity. REFERENCES 1. Druker BJ, Tamura S, Buchdunger E, et al. Effects of a selective inhibitor of the Abl tyrosine kinase on the growth of Bcr-Abl positive cells. Nat Med. 1996;2: Savage DG, Antman KH. Imatinib mesylate a new oral targeted therapy. N Engl J Med. 2002;346: Grichnik JM, Burch JA, Burchette J, Shea CR. The SCF/KIT pathway plays a critical role in the control of normal human melanocyte homeostasis. J Invest Dermatol. 1998;111: Longley BJ, Carter EL. SCF-KIT pathway in human epidermal melanocyte homeostasis. J Invest Dermatol. 1999;113: Raanani P, Goldman JM, Ben-Bassat I. Challenges in oncology. Case 3. Depigmentation in a chronic myeloid leukemia patient treated with STI-571. J Clin Oncol. 2002;20: Nomura K, Hatayama I, Narita T, Kaneko T, Shiraishi M. A novel KIT gene missense mutation in a Japanese family with piebaldism. J Invest Dermatol. 1998;111: Richards KA, Fukai K, Oiso N, Paller AS. A novel KIT mutation results in piebaldism with progressive depigmentation. J Am Acad Dermatol. 2001;44: Hemesath TJ, Price ER, Takemoto C, Badalian T, Fisher DE. MAP kinase links the transcription factor Microphthalmia to c-kit signalling in melanocytes. Nature. 1998;391: Wu M, Hemesath TJ, Takemoto CM, et al. c-kit triggers dual phosphorylations, which couple activation and degradation of the essential melanocyte factor Mi. Genes Dev. 2000;14: Pagnoni A, Kligman AM, Sadiq I, Stoudemayer T. Hypopigmented macules of photodamaged skin and their treatment with topical tretinoin. Acta Derm Venereol. 1999;79: