Imatinib induced Hyperpigmentation : A Case Report Authors: Shivani Malik1, Arun Kumar Yadav2, Renu Singh3, Lalit Raj4, Roopali5, Ashok Kumar Arya6All affiliated to Department of Radiation Oncology ,Sarojini Naidu Medical College, AGRA AbstractThe tyrosine kinase inhibitor imatinib mesylate is well known for inhibiting melanocyte growth, which results in hypopigmentation but here we present a case report of imatinib-induced hyperpigmentation in a 42-year-old female belonging to a lower middle socioeconomic status and a resident of a local village . The case report is unique as it provides valuable insights into clinical characterstics, diagnostic challenges and therapeutic considerations for Imatinib induced hyperpigmentation which may contribute to existing literature on this rare and challenging entity particularly in CML. Patient presented to Radiotherapy OPD 2.5 years ago with chief complaints of single episode of oral bleeding and abdominal pain since 15 days. Blood investigations revealed a high TLC count, platelet count, and Hb-10.5 suggestive of some myeloproliferative disorder for which patient was advised bone marrow aspiration biopsy for confirmation . Biopsy findings consistent with CML. That is how we reached to a diagnosis of CML. Imatinib therapy was started with a dose of 400mg od orally daily. She was continued on same dose . As the disease of the patient was partially responding to this dose and patient still had on and off complaints along with abnormal blood parameters, the dose was gradually increased to 600mg od orally but after 2 months of this dose, hyperpigmentation on the cheeks gradually appeared which slowly increased to involving whole of the face . Clinical findings revealed brownish hyperpigmented macules involving the forehead, nose, malar, and mandibular areas. There was no significant family history and no history of similar complaints in the past. There was no history of an allergy to any drug. Dermoscopy showed an irregular dark brown pigmentation network in a pseudo reticular pattern, along with hypopigmented areas in between. Based on theclinical findings and dermoscopy results , the patient was diagnosed with Imatinib induced melasma-like pigmentation. Therapeutic intervention was done. The patient was initiated on topical depigmenting agents, sunscreen, and topical corticosteroids to address the hyperpigmentation, coupled with strict photoprotective measures for comprehensive management. The patient is currently under our care, continuing imatinib therapy with us at the same dose as the patient is having good response to primary disease at this dose and attending regular follow-up appointments at the dermatology clinic showing symptomatic improvement..We conclude that Informing the patient about the possibility of this side effect can increase compliance to therapy. Further insight into the mechanisms of the pigmentary alterations caused by this drug is required for better treatment/prevention of this manifestation. Keywords: chronic myeloid leukemia, imatinib, hyperpigmentation. IntroductionImatinib mesylate, a tyrosine kinase inhibitor, blocks the oncogenic fusion protein BCR-ABL which promtes leukemic cell proliferation in chronic myeloid leukemia (CML) by activating tyrosine kinase pathway abnormally and is therefore a first-line medication for treating CML. 1] Clinical studies revealed very good hematological responses without significant side effects .[1] In recently published articles, Imatinib has been linked to several cutaneous side effects. Even though hyperpigmentation is counterintuitive, hypopigmentation is an expected side effect of imatinib therapy because of its impact on melanocytes. While systemic adverse events characteristic of conventional cytotoxic agents (e.g. myelosuppression, nausea, vomiting) [7] are typically not encountered, dermatologic AEs (affecting the skin, hair, nails, mucosae) are common because some of the signaling pathways inhibited are also essential for cutaneous homeostasis.[8] Imatinib induced hyperpigmentation could be due to mutant changes in C-kit and PDGF receptors present in melanocytes and paradoxic stimulation of melanocyte proliferation and differentiation leading to increase in number of melanocytes in the epidermis.[3] It may be due to deposition of drug metabolite which chelates melanin and iron similar to that caused by other medications such as minocycline and anti-malarial medications.[1] Exact mechanism of this adverse effect is still unclear.. This case report is valuable due to the rarity of hyperpigmentation associated with imatinib mesylate therapy. Thus, this uncommon side effect needs to recognised early and managed appropriately. The treatment options should also be explored for its management. Herewith, we are describing a case of a chronic myeloid leukemia patient who underwent significant hyperpigmentary changes after receiving imatinib therapy for her cure. Case ReportPatient informationA 42-year-old female belonging to a lower middle socioeconomic status and a resident of a local village presented to Radiotherapy OPD 2.5 years ago with complaints of a single episode of bleeding from the mouth 15 days ago along with pain in the abdomen for 1 week. There was no significant family history and no history of similar complaints in the past. There was no history of an allergy to any drug. She was referred to us by a general practitioner.On blood investigations, we found that the TLC count was raised upto 1,10,000, and the platelet count was also raised up to 5.2 lac, with Hb-10.5 suggestive of myeloproliferative neoplasm. On further investigation, serum LDH was raised up to 680 U/L. While examination of whole abdomen, pt. was found to have splenomegaly [size 15.4 cm]. Chest x-ray findings were suggestive of marginal cardiomegaly.A bone marrow aspiration biopsy was done for confirmation of the disorder, and the findings of biopsy were suggestive of myeloproliferative neoplasm morphologically consistent with chronic myeloid leukemia. Results of biopsy reported cellular marrow with M: E- 4:1, predominantly normoblastic rbc, all stages of maturation seen in the myeloid series with blasts 8% and left shift with normal lymphocytes and plasma cells. With adequate megakaryocytosis. No granulomas or hemoparasites were seen.Further, the woman underwent genetic testing to detect BCR-ABL GENE rearrangement or Philadelphia chromosome transcript quantification levels using real-time PCR. A major transcript known as P210 (b3a2, b2a2) was identified with BCR-ABL 1IS of 45.517% indicating a significant molecular response.Based on the clinical,laboratory findings, diagnostic workup, she was diagnosed and confirmed to be a case of CML. She was started on Imatinib therapy with a dose of 400mg orally. The patient defaulted from us due to some personal reasons and went to a private hospital for further management, where she was continued on the same therapy. She came back to us after one year. We also continued her at the same dose for about 4 months but soon her blood reports started deteriorating , with complaints of pain in the abdomen again. So, her dose was increased to 600mg od orally daily. She responded well. Hematologoical and cytogenetic parameters were improving. However, after 2 months of this increased dose, the patient complained of hyperpigmentation on her cheeks which was gradual in onset, which slowly increased to involving whole of her face. There was no evidence of involvement of any other body part besides face..There were no skin lesions or pigmentation before this. No history of photosensitivity present. Her thyroid profile also came out to be normal . History of any other medication intake was also not there. Patient was non- smoker and there was no history of diabetes mellitus also.Clinical findingsFindings revealed brownish hyperpigmented macules on the forehead, nose, malar region and mandibular areas of the face. Pigmentation was more on the lateral aspect of the face, with sparing of the upper and lower eyelids, nasolabial folds, and neck. Buccal mucosa and teeth were normal. The rest of the body was also normal. She was referred to the dermatology clinic for these complaints.Table 1: Symptom Signs Duration Vomiting and diffuse pain abdomen - 1 week Hyperpigmentation on cheek Hyperpigmented macules on malar region After 2 months of increased dose(600mg od) Hyperpigmentation on the whole face hyperpigmented macules involving the forehead, nose, malar, and mandibular areas of the face[more on lateral aspect] Progressive over 3 months
