A 66-year-old man with hypertension was diagnosed with chronic myelogenous leukemia in 1996. Treatment was started with hydroxycarbamide and imatinib 400 mg in 1996 + 6, which was increased to 600 mg. Although he achieved a complete cytogenic response in 1996 + 9, he could not continue imatinib because of edema; the regimen was changed to nilotinib 800 mg in 1996 + 13. After he achieved a molecular response better than 4.5 in 1996 + 19, he was referred to our hospital. His urinalysis had shown urine protein since 1996 + 13, and his creatinine level increased in 1996 + 16. Renal biopsy, performed in 1996 + 20, revealed abdominal distention and massive ascites. After the nilotinib dosage was reduced to 400 mg, liver biopsy, also performed in 1996 + 20, revealed hypertrophy of renal small blood vessels and endothelial cells of the hepatic artery and loss of endothelial cells of the renal glomeruli, portal vein, and hepatic sinusoids. Both renal and liver biopsies revealed marked pathological vascular damage. The patient took oral imatinib for approximately 3.5 years and nilotinib for 11 years. Pathological findings indicated a tendency for thrombosis, which could induce vascular occlusive disease. Accumulation of cases, such as the present case, is needed to further analyze the pathophysiological processes.
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Hochhaus A, Larson RA, Guilhot F, Radich JP, Branford S, Hughes TP, et al. IRIS Investigators. Long-term outcomes of imatinib treatment for chronic myeloid leukemia. N Engl J Med. 2017;376:917–27.
Hochhaus A, Saglio G, Hughes TP, Larson RA, Kim DW, Issaragrisil S, et al. Long-term benefits and risks of frontline nilotinib vs imatinib for chronic myeloid leukemia in chronic phase: 5-year update of the randomized ENESTnd trial. Leukemia. 2016;30:1044–54.
Cortes JE, Saglio G, Kantarjian HM, Baccarani M, Mayer J, Boqué C, et al. Final 5-year study results of DASISION: the dasatinib versus imatinib study in treatment-naïve chronic myeloid leukemia patients trial. J Clin Oncol. 2016;34:2333–400.
Saußele S, Krauß M, Hehlmann R, Lauseker M, Proetel U, Kalmanti L. Impact of comorbidities on overall survival in patients with chronic myeloid leukemia: results of the randomized CML Study IV. Blood. 2015;126:42–9.
Etienne G, Guilhot J, Rea D, Rigal-Huguet F, Nicolini F, Chrbonnier A, et al. Long-term follow-up of the French stop imatinib (STIM1) study in patients with chronic myeloid leukemia. J Clin Oncol. 2017;35:298–305.
Mahon FX. Discontinuation of TKI therapy and ‘functional’ cure for CML. Best Pract Res Clin Haematol. 2016;29:308–13.
Takahashi N, Tauchi T, Kitamura K, Miyamura K, Saburi Y, Hatta Y, et al. Deeper molecular response is a predictive factor for treatment-free remission after imatinib discontinuation in patients with chronic phase chronic myeloid leukemia: the JALSG-STIM213 study. Int J Hematol. 2018;108:185–93.
Kizaki M, Takahashi N, Iriyama N, Okamoto S, Ono T, Usui N, et al. Efficacy and safety of tyrosin kinase inhibitors for newly diagnosed chronic-phase chronic myeloid leukemia over a 5-year period: results from the Japanese registry obtained by the TARGET system. Int J Hematol. 2019;109:426–39.
Steegmann JL, Cervantes F, le Coutre P, Porkka K, Saglio G. Off-target effects of BCR-ABL1 inhibitors and their potential long-term implications in patients with chronic myeloid leukemia. Leuk Lymphoma. 2012;53:2351–61.
Carneiro BA, Kaplan JB, Giles FJ. Tyrosine kinase inhibitor therapy in chronic myeloid leukemia: update on key adverse events. Expert Rev Hematol. 2015;8:457–79.
Valent P, Hadzijusufovic E, Hoermann G, Füreder W, Schernthaner GH, Sperr WR, et al. Risk factors and mechanisms contributing to TKI-induced vascular events in patients with CML. Leuk Res. 2017;59:47–54.
Hadzijusufovic E, Albrecht-Schgoer K, Huber K, Hoermann G, Grebien F, Eisenwort G, et al. Nilotinib-induced vasculopathy: identification of vascular endothelial cells as a primary target site. Leukemia. 2017;31:2388–97.
Sukegawa M, Wang X, Nishioka C, Pan B, Xu K, Ohkawara H, et al. The BCR/ABL tyrosine kinase inhibitor, nilotinib, stimulates expression of IL-1β in vascular endothelium in association with downregulation of miR-3p. Leuk Res. 2017;58:83–90.
Alhawiti N, Burbury KL, Kwa FA, O'Malley CJ, Shuttleworth P, Alzard M, et al. The tyrosine kinase inhibitor, nilotinib potentiates a prothrombotic state. Thromb Res. 2016;145:54–64.
Douxfils J, Haguet H, Mullier F, Chatelain C, Graux C, Dogné JM. Association between BCR-ABL tyrosine kinase inhibitors for chronic myeloid leukemia and cardiovascular events, major molecular response, and overall survival: a systematic review and meta-analysis. JAMA Oncol. 2016;2:625–32.
Min W, Yamanaka N. Three-dimensional analysis of increased vasculature around the glomerular vascular pole in diabetic nephropathy. Virchows Arch A Pathol Anat Histopathol. 1993;423:201–7.
Gupta S, Bhatt V, Varma S. Recurrent imatinib-induced hepatotoxicity in a chronic myeloid leukemia patient successfully managed with prednisone. BMJ Case Rep. 2011. https://doi.org/10.1136/bcr.11.2010.3516.
Harbaum L, Marx A, Goekkurt E, Schafhausen P, Atanackovic D. Treatment with dasatinib for chronic myeloid leukemia following imatinib-induced hepatotoxicity. Int J Hematol. 2014;99:91–4.
Moslehi JJ, Deininger M. Tyrosine kinase inhibitor-associated cardiovascular toxicity in chronic myeloid leukemia. J Clin Oncol. 2015;33:4210–8.
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Seki, Y., Nagano, O., Koda, R. et al. Pathological findings suggesting vascular endothelial damage in multiple organs in chronic myelogenous leukemia patients on long-term tyrosine kinase inhibitor therapy. Int J Hematol (2020). https://doi.org/10.1007/s12185-020-02913-x
- Chronic myelogeous leukemia
- Tyrosin kinase inhibitor
- Vascular endothelial damage
- Off target effect