Tyrosine Kinase Inhibitor Imatinib Mesylate Induces Generalized Skin Hypopigmentation In Chinese Patients with Chronic Myelogenous Leukemia.

Abstract 4475

Imatinib mesylate is a selective tyrosine kinase inhibitor targeting BCR-ABL fusion protein. In the therapy of either interferon refractory or newly diagnosed chronic myeloid leukemia (CML), imatinib significantly improved the prognosis of the disease, albeit with typically mild to moderate adverse effects. In recent years, increasing attention has been focused on the skin hypopigmentation developed after the initiation of imatinib therapy, especially in Asian countries such as India, with the incidence between 33% and 85%, though sparsely reported in western countries. The inhibition of c-kit by imatinib may be a possible explanation, but the exact mechanism for this hypopigmentation caused by imatinib and its potential risk in patients is poorly understood. Here we report our clinical observation of this side effect of imatinib therapy among Chinese CML patients in our institution, as well as a brief in vitro study aiming to investigate the mechanism of the hypopigmentory effect and evaluate its potential risk. Among 116 patients who took imatinib for CML therapy, 90 of them (77.6%) had reported to develop generalized hypopigmentation or whitening in the skin. This side effect usually developed within 3 months after initiation of imatinib, persistent during the therapy, and reversible upon imatinib discontinuation, according to our interviews and observation. More interestingly, in three of these CML patients who originally had vitiligo, the cosmetic appearance seemed to be improved during imatinib therapy due to the whitening effect on normal pigmented skin areas. To further confirm and understand this side effect, we examined the impact of imatinib on cultured normal human melanocytes derived from the foreskins of healthy Chinese adults. Melanocytes were treat with various concentrations of imatinib (1~16 μ M) for different periods of time (1~7 days). Cell proliferation and apoptosis were detected by cell counting kit-8 and flow cytometric assay, respectively. The melanogenic activity of the melanocytes was detected by melanin content assay and tyrosinase activity assay. Moreover, the role of stem cell factor (SCF) and its receptor c-kit in imatinib induced hypopigmentation were investigated. We found that imatinib not only concentration-dependently inhibited melanocyte proliferation in vitro (IC₅₀=6.23 μ M), but also resulted in massive melanocyte apoptosis at concentrations higher than 8 μ M (P<0.01). Even at low concentrations (1-8 μ M), imatinib was able to cause decreases in total melanin content (P<0.05) and tyrosinase activity (P<0.05) which were responsible for skin pigmentation. In addition, imatinib (1-8 μ M) completely abrogated SCF (5 ng/ml) induced melanocyte proliferation (P<0.01) and melanogenesis (P<0.01), through the inhibition of the phosphorylation of c-kit receptor (Tyr 703 and Tyr 719) and the downstream signal transduction, which is pivotal for melanocyte proliferation and melanin synthesis after ultraviolet exposure. These results reveal that imatinib may cause destruction or dysfunction of melanocytes in patients through the inactivation of SCF/c-kit signaling, leading to inability of the skin to produce melanin and perform protection against ultraviolet radiation. Therefore, CML patients who take imatinib are necessarily to be warned for this side effect, and diminish the intensive exposure to sunlight. Although an ethnic or genetic basis for the prevalence difference can not be excluded yet, we tend to believe that the hypopigmentation effect of imatinib was probably underestimated in caucasian patients due to their light skin color. Since the melanocytes used in this study were all isolated from the skin samples of Chinese volunteers, further study may be done to determine whether the similar results can be achieved in primary melanocytes from other ethnic group.