Hemorrhagic colonic ulcers caused by dasatinib for chronic myelogenous leukemia

Abstract

Dasatinib, a multi-kinase inhibitor that is active against BCR-ABL1 and SRC family kinases, has been reported to exert notable efficacy in the treatment of imatinib-resistant or -intolerant chronic myeloid leukemia (CML) in all phases [1–5]. Dasatinib therapy is generally well tolerated, although severe hematological and non-hematological adverse events are observed. The most common non-hematological adverse events are gastrointestinal symptoms, fluid retention, and skin rash [1–5]. It is notable that gastrointestinal bleeding accounts for 14–26% of gastrointestinal adverse events due to dasatinib [1–6]. A recent report evaluating the bleeding diathesis due to dasatinib revealed that more than 80% of the bleeding was observed in the gastrointestinal tract [7]. However, the characteristics and clinical courses of gastrointestinal bleeding due to dasatinib are yet to be fully elucidated. Herein, we present a case of melena due to multiple colonic ulcers under dasatinib treatment for CML, in which colonic ulcers completely resolved within 12 days after discontinuation of dasatinib. A 43-year-old woman with chronic-phase CML had been initially treated with imatinib at a daily dose of 400 mg. A complete molecular response was achieved at 1 year after treatment with imatinib. However, 4 years after initiating imatinib therapy, leukocytosis (42.6 9 10/L) together with blasts in the peripheral blood (17%) was observed. Bone marrow examination showed increased blasts (11.8%) and additional chromosomal abnormality of t(21;21)(q22;q22), indicating a progression to the accelerated phase. Dasatinib (70 mg) was initiated twice daily, which successfully led to normalization of white blood cell count and disappearance of blasts from the peripheral blood. However, anemia and thrombocytopenia persisted, and red blood cell and platelet transfusions were required. She had had mild diarrhea shortly after initiating dasatinib, and suddenly developed melena 3 months after initiating dasatinib, when the platelet count was 21 9 10/L. Her white blood cell count was 3.8 9 10/L with 77% of neutrophils and 11% of lymphocytes. Endoscopic examination of the lower gastrointestinal tract showed multiple aphthous ulcers of the colon (Fig. 1a). Dasatinib was discontinued, and melena ceased in 2 days. As much as 12 days after the discontinuation of dasatinib, another endoscopic examination was performed, and showed almost complete resolution of ulcerative lesions of the colon (Fig. 1b). She then received total body irradiation (12 Gy), high-dose cytarabine, and cyclophosphamide as a conditioning for allogeneic cord blood transplantation, and has shown mild gastrointestinal toxicities, but has not developed melena since. In this case, we confirmed by endoscopy that hemorrhagic colonic ulcers probably caused by dasatinib almost completely healed within 12 days after discontinuation of dasatinib. The mechanism of dasatinib-induced gastrointestinal bleeding is yet to be understood. Its inhibitory activity against platelet-derived growth factor receptor (PDGFR) kinase might be a possible explanation, since PDGFR-b plays an important role in angiogenesis and Y. Ono T. Mori (&) J. Kato A. Yamane S. Okamoto Division of Hematology, Department of Medicine, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan e-mail: tmori@sc.itc.keio.ac.jp