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Challenges in Oncology

Case 3. Depigmentation in a Chronic Myeloid Leukemia Patient Treated With STI-571

The Chaim Sheba Medical Center, Tel-Hashomer, and Sackler School of Medicine, Tel-Aviv University, Tel-Aviv, Israel; and Hammersmith Hospital and Imperial College School of Medicine, London, United Kingdom

A 52-year-old man presented with splenomegaly and a leukocyte count of 500 x 10⁹/L, with expansion in myeloid cells and basophilia. Cytogenetics revealed the presence of the Philadelphia chromosome [t(9;22)], and the diagnosis of chronic myeloid leukemia was made. Because no HLA-matched sibling was found, treatment with interferon alfa, low-dose cytarabine, and hydroxyurea was initiated. Because of interferon resistance, treatment with STI-571 (Gleevec; imatinib mesylate; Novartis Pharmaceuticals Corp, East Hanover, NJ) 400 to 600 mg daily was started 15 months later, and all other medications were stopped. Approximately 6 months after the initiation of STI-571, depigmentation of the penis and distal parts of both hands (Fig 1), accentuated by exposure to the sun, was noticed.

View larger version (64K): [in this window] [in a new window]   Fig 1.

STI-571 is an inhibitor of the bcr-abl tyrosine kinase, which has a major role in the pathogenesis of chronic myeloid leukemia. It is also an inhibitor of the PDGFR and c-kit receptor tyrosine kinases.^2,3 The latter two kinases have critical roles in normal pigmentation. Mutations in their genes, reducing or abrogating the respective enzyme activities, are associated with loss of pigmentation due to interruption of the development and differentiation of melanocytes.^4-6 Accordingly, certain hereditary hypopigmentary disorders like piebaldism and vitiligo are associated with mutations in the c-kit gene causing alterations in the respective tyrosine kinases.^7-8

Our patient demonstrated hypopigmentation, which developed several months after the initiation of STI-571. The suggested mechanism for hypopigmentation in this case is inhibition of the melanocyte c-kit receptor tyrosine kinase by STI-571, leading to alteration in normal pigmentation.

REFERENCES

1. DeSpain JD: Dermatologic toxicity, in Perry MC (ed): The Chemotherapy Source Book. Baltimore, Maryland, Williams & Wilkins, 1992, pp 531-547

2. Heinrich MC, Griffith DJ, Druker BJ, et al: Inhibition of c-kit receptor tyrosine kinase activity by STI 571, a selective tyrosine kinase inhibitor. Blood 96: 925-932, 2000[Abstract/Free Full Text]

3. Buchdunger E, Cioffi CL, Law N, et al: Abl protein-tyrosine kinase inhibitor STI571 inhibits in vitro signal transduction mediated by c-kit and platelet-derived growth factor receptors. J Pharmacol Exp Ther 295: 139-145, 2000[Abstract/Free Full Text]

4. Halaban R, Moellmann G: White mutants in mice shedding light on humans. J Invest Dermatol 100: 176S-185S, 1993 (suppl 2)[CrossRef][Medline]

5. Luo D, Chen H, Searles G, et al: Coordinated mRNA expression of c-Kit with tyrosinase and TRP-1 in melanin pigmentation of normal and malignant human melanocytes and transient activation of tyrosinase by Kit/SCF-R. Melanoma Res 5: 303-309, 1995[CrossRef][Medline]

6. Hou L, Panthier JJ, Arnheiter H: Signaling and transcriptional regulation in the neural crest-derived melanocyte lineage: Interactions between KIT and MITF. Development 127: 5379-5389, 2000[Abstract]

7. Dippel E, Haas N, Grabbe J, et al: Expression of the c-kit receptor in hypomelanosis: A comparative study between piebaldism, naevus depigmentosus and vitiligo. Br J Dermatol 132: 182-189, 1995[Medline]

8. Richards KA, Fukai K, Oiso N, et al: A novel KIT mutation results in piebaldism with progressive depigmentation. J Am Acad Dermatol 44: 288-292, 2001[CrossRef][Medline]

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