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 Table of Contents  
LETTER TO EDITOR
Year : 2020  |  Volume : 6  |  Issue : 1  |  Page : 37-39

Melasma-like pigmentation during imatinib therapy for chronic myeloid leukemia


Department of Dermatology, Venereology and Leprology, Government Medical College, Nagpur, Maharashtra, India

Date of Submission01-Nov-2019
Date of Decision08-Jan-2020
Date of Acceptance06-May-2020
Date of Web Publication23-Jun-2020

Correspondence Address:
Dr. Bhagyashree B Supekar
Department of Dermatology, Venereology, Leprosy, Government Medical College and Hospital, Nagpur, Maharashtra
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ijdd.ijdd_59_19

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How to cite this article:
Tomar SS, Supekar BB, Kulkarni MM, Mukhi J, Singh RP. Melasma-like pigmentation during imatinib therapy for chronic myeloid leukemia. Indian J Drugs Dermatol 2020;6:37-9

How to cite this URL:
Tomar SS, Supekar BB, Kulkarni MM, Mukhi J, Singh RP. Melasma-like pigmentation during imatinib therapy for chronic myeloid leukemia. Indian J Drugs Dermatol [serial online] 2020 [cited 2020 Oct 24];6:37-9. Available from: https://www.ijdd.in/text.asp?2020/6/1/37/287437



Sir,

Imatinib mesylate is a tyrosine kinase inhibitor, Food and Drug Administration approved for treatment of Philadelphia chromosome-positive chronic myeloid leukemia (CML), acute myeloid leukemia, myelofibrosis, hypereosinophilia syndrome, gastrointestinal stromal tumor, refractory dermatofibrosarcoma protuberans, systemic mastocytosis, and metastatic malignant melanoma.[1],[2] Among pigmentary changes during imatinib therapy, depigmentation or hypopigmentation (localized or generalized) is the most common predictable side effect.[3] However, there are very few case reports of imatinib-induced hyperpigmentation in the literature.

A 36-year-old male patient, a diagnosed case of CML came to the dermatology outpatient department with complaints of asymptomatic brown discoloration of face, ears and hands since past 1 year. The patient was on treatment with imatinib mesylate in the dose of 400 mg once a day orally since 1½ years. The onset of the lesions was insidious. The lesions first appeared over the nose and gradually progressed to involve bilateral cheeks, forehead, bilateral ears, and bilateral hands in that order. There was no history of any topical application or systemic drug intake prior to onset of lesions, use of hair dyes, concomitant endocrine disorder, photosensitivity, or prior active skin disease. He had no history of pigmentation over face in past.

General examination and systemic examination were normal. There were multiple irregular brownish macules coalescing to form patches over the face predominantly involving bilateral malar, zygomatic, mandibular, maxillary areas, lower one-third of forehead, and bilateral earlobes [Figure 1]. Mild diffuse hyperpigmentation was also present over the extensor aspect of bilateral forearms and hands [Figure 2]. Pigmentation was not evident over scalp, oral or other mucosa, teeth, palms-soles, and nails. Hematological investigations revealed anemia (hemoglobin <8 g%), leukocytosis (3500/mm3), and thrombocytopenia (<80,000/mm3). Peripheral blood smear revealed the presence of 8% blast cells, 3% promyelocytes, 7% myelocytes, and 6% metamyelocytes suggestive of CML. Abdominal sonography revealed mild splenomegaly. Histopathological examination from the patch over right malar area revealed increase in melanin pigment in basal layer of the epidermis suggestive of melasma-like pigmentation [Figure 3]. There was no evidence of basal layer vacuolar degeneration, melanin incontinence or lichenoid infiltrate in the dermis. Masson Fontana stain of patch over face revealed hyperpigmentation of basal layer of epidermis with normal melanocyte count and increase pigment granules [Figure 4].
Figure 1: (a and b) Multiple irregular brownish macules coalescing to form patches over the face predominantly involving bilateral malar, zygomatic, mandibular, maxillary areas, lower one third of forehead and bilateral earlobes

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Figure 2: Mild diffuse hyperpigmentation was also present over the extensor aspect of bilateral forearms and hands

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Figure 3: (a and b) Histopathological examination from the patch over right malar arearevealed increase in melanin pigment in basal layer of the epidermis suggestive of melasma like pigmentation (H and E, ×10, ×40)

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Figure 4: (a and b) Masson Fontana stain of patch over face revealed hyperpigmentation of basal layers of epidermis with normal melanocyte count and increase pigment granules (a: ×10, b: ×40)

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Based on history, clinical findings and histopathology findings, a diagnosis of Imatinib induced melasma-like pigmentation was reached. This adverse effect was reported to the Pharmacovigilance Programme of India (PvPI). According to the WHO-UMC criteria, it was an adverse drug reaction (ADR) secondary to Imatinib (PvPI Report No. 2019-30292). Based on modified Hartwig and Siegel severity assessment scale, this ADR falls in mild category (level 1). The patient was counseled regarding the benign and reversible nature of pigmentation and asked to continue treatment with imatinib. He was also advised strict photoprotection along with the use of sunscreen and was started on topical modified Kligman formula. However, he was lost to follow-up.

Imatinib targets the ATP binding site of break cluster region-Abelson tyrosine kinase, as well as the tyrosine kinases of platelet-derived growth factor receptor. C-kit is normally expressed in basal cells of skin, melanocytes, epithelial cells of the breast, tissue mast cells, and other cells.[4] Recently, it has been postulated that C-kit and its ligand stem-cell factor have a major role in melanogenesis, melanocyte homeostasis and ultraviolet ultraviolet B induced pigmentation.[5] The common nonhematological adverse effects include nausea, superficial edema, muscle cramps, musculoskeletal pain, and skin rashes.[6] Majority of dermatological side effects are caused by inhibition of physiological function of cutaneous protein kinases and are dose dependent. Various dermatological side effects that have been described during imatinib therapy are maculopapular drug rash, xerosis, photosensitivity, angular cheilitis, psoriasiform rash, alopecia, pruritus, and pigmentary changes. Rarer adverse effects include urticaria or angioedema, neutrophilic dermatitis, acute generalized exanthematous pustulosis, lichenoid reaction, exfoliative dermatitis, and IgA pemphigus.[7],[8]

Among the pigmentary changes seen with this drug, hypopigmentation has been most commonly reported. It can be explained by inhibition of melanogenesis by binding of ligand to melanocyte c-kit receptor tyrosine kinase.[3] In a study conducted by Arora et al., 41% of patients receiving imatinib were reported to develop hypopigmentation.[9] The morphological variants of hypopigmentation include generalized skin lightening, vitiligo-like lesions, and hair graying.

There are very few case reports of imatinib-induced hyperpigmentation that are described in literature. Till date, the mechanism of hyperpigmentation is not clear. It has been attributed to paradoxical stimulation of melanogenesis following c-kit inhibition due to genetic defect in c-kit genome. Other postulated mechanisms that have described are formation of a drug-melanin metabolite, accumulation of drug, drug-induced cytotoxic response to epidermal neoantigen, and the presence of a specific KIT mutation and its interaction with other receptors.[7],[10] For the first time, Arora et al. reported hyperpigmentation induced by imatinib with doses varying between 400 and 600 mg/din 3.6% of cases in 2004.[9] The median time of onset of pigmentary changes reported was 4 weeks (range 2–14) after start of therapy. At the onset the changes were generally localized, becoming diffuse over the next few weeks. Hyperpigmentation may not only involve face, chest, and abdomen but also the palatal mucosa, nails, teeth, hair, and gums.[7],[10],[11] In 2011, Valizadeh, for the first time reported development of chloasma-like facial hyperpigmentation after 6 months of therapy with imatinib in 28 years male, a known case of CML.[1] Extrafacial melasma-like pigmentation due to imatinib therapy was reported for the first time in 2016, by Ghunawat et al.[12] There is paucity of literature describing melasma-like pigmentation during imatinib therapy, and extra facial melasma-like pigmentation is even rarer [Table 1]. Thus we report a case of imatinib induced extrafacial melasma-like pigmentation after 24 weeks of start of therapy in case of CML. WHO-UMC criteria was developed in the year 1978 for drug causality assessment and comprises of six causality categories. Accordingly, this ADR falls into probable causality category.[16] Based on modified Hartwig and Siegel severity assessment scale, ADRs can fall into three categories, namely mild, moderate, and severe out of which our case belongs to mild category (level 1).[17] Hyperpigmentation during imatinib therapy does not warrant discontinuation of drug because of its reversible nature.[11],[12]
Table 1: Literature review of imatinib-induced melasmalike pigmentation

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Acknowledgment

I express my thanks to Mr. Piyush Nama, Pharmacovigilance Associate, Department of Pharmacology, Government Medical College, Nagpur, and National Coordination Centre - PvPI, Indian pharmacopoeia commission, Ghaziabad, India for their guidance and support.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
Valizadeh N. Imatinib induced facial skin hyperpigmentation in a case of chronic myelogenousleukemia. Shiaz E Med J 2011;12:162-4.  Back to cited text no. 1
    
2.
Liu LS, Colegio OR. Molecularly targeted therapies for melanoma. Int J Dermatol 2013;52:523-30.  Back to cited text no. 2
    
3.
Valeyrie L, Bastuji-Garin S, Revuz J, Bachot N, Wechsler J, Berthaud P, et al. Adverse cutaneous reactions to Imatinib (STI-571) in Philadelphia chromosome positive leukemias: A prospective study of 54 patients. J Am Acad Dermatol 2003;48:201-6.  Back to cited text no. 3
    
4.
Lammie A, Drobnjak M, Gerald W, Saad A, Cote R, Cardo CC. Expression of c-kit and kit ligands proteins in normal human tissues. J Histochem Cytochem 1994;42:1417-25.  Back to cited text no. 4
    
5.
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;111:233-8.  Back to cited text no. 5
    
6.
O'Brien SG, Guilhot F, Larson RA, Gathmann I, Baccarani M, Cervantes F, et al. Imatinib compared with interferon and low-dose cytarabine for newly diagnosed chronic phase chronic myeloid leukemia. N Engl J Med 2003;348:994-1004.  Back to cited text no. 6
    
7.
Balagula Y, Pulitzer MP, Maki RG, Myskowski PL. Pigmentary changes in a patient treated with imatinib. J Drugs Dermatol 2011;10:1062-6.  Back to cited text no. 7
    
8.
Sood A, Sinha P, Raman DK, Sinha A. Imatinib-induced IgA pemphigus: Subcorneal pustular dermatosis type. Indian Dermatol Online J 2018;9:331-3.  Back to cited text no. 8
[PUBMED]  [Full text]  
9.
Arora B, Kumar L, Sharma A, Wadhwa J, Kochupillai V. Pigmentary changes in chronic myeloid leukemia patients treated with imatinibmesylate. Ann Oncol 2004;15:358-9.  Back to cited text no. 9
    
10.
Li CC, Malik SM, Blaeser BF, Dehni WJ, Kabani SP, Boyle N, et al. Mucosal pigmentation caused by imatinib: Report of three cases. Head Neck Pathol 2012;6:290-5.  Back to cited text no. 10
    
11.
Di Tullio F, Mandel VD, Scotti R, Padalino C, Pellacani G. Imatinib-induced diffuse hyperpigmentation of the oral mucosa, the skin, and the nails in a patient affected by chronic myeloid leukemia: Report of a case and review of the literature. Int J Dermatol 2018;57:784-90.  Back to cited text no. 11
    
12.
Ghunawat S, Sarkar R, Garg VK. Imatinib induced melasma-like pigmentation: Report of five cases and review of literature. Indian J Dermatol Venereol Leprol 2016;82:409-12.  Back to cited text no. 12
[PUBMED]  [Full text]  
13.
Gupta A, Kumar S, Chaturvedi S, Nirmal A. Melasma like hyperpigmentation on face: A rare side effect of imatinib. Ann Geriatr Educ Med Sci 2018;5:79-80.  Back to cited text no. 13
    
14.
Shah V, Rambhia K, Mukhi J, Singh RP. Imatinib induced melasma like pigmentation: A rare entity. Vidarbha J Internal Med 2017;23:97-8.  Back to cited text no. 14
    
15.
Subhadarshani S, Abhishek GN. Imatinib-induced melasma-like pigmentation. Indian J Dermatol 2019;64:158-9.  Back to cited text no. 15
[PUBMED]  [Full text]  
16.
The use of the WHO-UMC System for Standardized Case Causality Assessment. Uppsala Monitoring Centre. World Health Organization; 2018. Available from: http://www.who-umc.org. [Last accessed on 2020 May 23].  Back to cited text no. 16
    
17.
Hartwig SC, Siegel J, Schneider PJ. Preventability and severity assessment in reporting adverse drug reactions. Am J Hosp Pharm 1992;49:2229-32.  Back to cited text no. 17
    


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