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Successful Treatment of Mitomycin-induced Thrombotic Thrombocytopenic Purpura with Rituximab
Volume 20
Number 2
Letters to the Editor
•
275
Figure. (a) Selective angiogram shows an aneurysm in the third section of the splenic artery, with associated stenosis. (b) Embolization proximal to the aneurysm of the splenic artery with GDC coils. (c) Initial follow-up angiogram shows the absence of filling of the aneurysm and the redistribution of the blood flow to the spleen. (d) Follow-up contrast-enhanced CT scan shows the lack of flow in the interior of the pseudoaneurysm. (e) Three-dimensional CT scan shows the absence of contrast medium in the interior of the lesion. (Available in color online at www.jvir.org.)
Successful Treatment of Mitomycin-induced Thrombotic Thrombocytopenic Purpura with Rituximab From: Adedayo A. Onitilo, MD, MSCR, Jessica M. Engel, MSN, FNP-BC, Lawrence H. Clouse, MD, and Kristin M. Gerndt, MD Department of Hematology/Oncology (A.A.O.) Marshfield Clinic–Weston Center 3501 Cranberry Blvd. Weston, WI 54476; and Departments of Hematology/Oncology (J.M.E., L.H.C.) and Interventional Radiology (K.M.G.) Marshfield Clinic Marshfield, Wisconsin
Editor: Mitomycin-induced thrombotic thrombocytopenic purpura (TTP) may occur within weeks to months after standard doses of mitomycin in less than 10% of patients; most present a picture of TTP-hemolytic uremic syndrome and die from renal failure (1,2). The exact physiology of mitomycin-induced TTP is unknown. No effective therapy has been identified, even with plasma exchange, the mainstay therapy for idiopathic TTP. Some success has been reported with the use of vincristine and cyclophosphamide and Staphylococcal protein A immunoabsorption columns (no longer available in the United States) (3,4). Rituximab is a monoclonal antibody targeting CD20-pos-
10.1016/j.jvir.2008.10.025
276
•
Letters to the Editor
February 2009
JVIR
Figure. Laboratory values and treatment.
itive B cells. Although rituximab has been reported as a successful treatment for refractory TTP (5), it has not been described for treatment of mitomycin- or chemoembolization-induced TTP. Here we describe an interesting case of mitomycin-induced TTP from chemoembolization and its successful and prompt response to rituximab. A 71-year-old woman with type 2 diabetes, hypertension, and hyperlipidemia presented with weight loss and diarrhea. Computed tomography (CT) showed multiple liver lesions, and biopsy was positive for adenocarcinoma consistent with a lung, pancreatic, or breast primary neoplasia. Despite extensive testing, a primary lesion was not identified. Treatment included carboplatin (area under the curve, 6) and paclitaxel (175 mg/m2) every 3 weeks for seven cycles, with bevacizumab (15 mg/m2) added beginning with cycle 3. Chemotherapy was well tolerated, without significant cytopenias. Although CT after chemotherapy showed partial response accompanied by significant decrease in tumor markers, treatment was discontinued as a result of peripheral neuropathy. Two months after chemotherapy, the patient underwent selective right hepatic artery chemoembolization with daunorubicin 50 mg, cisplatin 50 mg, mitomycin-C 10 mg, Ethiodol 8 mL, and standard low-dose dexamethasone (4 mg intravenously) preprocedurally. On the day of chemoembolization (day 1), hemoglobin level was 12.3 g/dL, white blood cell count was 3.9 ⫻ 103/L, and platelet count was 118,000/L. Basic coagulation profile and liver function test findings were normal except for chronically increased alkaline phosphatase levels. On day 4, the platelet count decreased to 8,000/L. By day 6, the hemoglobin level was 7.7 g/dL with schistocytes seen on the peripheral blood film; lactate dehydrogenase level increased to 731 U/L (normal, 81–190 U/L) and total bilirubin increased to 10.2 mg/dL. The patient was afebrile with normal renal function. The von Willebrand factor cleaving protease ADAMTS13 level was modestly low at 38% (normal, ⬎67%), with no inhibitor. Fibrinogen level was normal at 401 mg/dL, and the basic coagulation profile was normal with an International Normalized Ratio of 1.0 and an activated partial thromboplastin time of 26 seconds. These findings suggested that disseminated intravascular coagulation was not the likely cause of the patient’s thrombocytopenia. Reticulocyte indices showed adequate response to the degree of anemia, with a reticulocyte count of 13.8% and a reticulocyte index of 4.7. On day 8, daily plasma exchange with concurrent
prednisone was begun. Nonessential medications were discontinued. The patient developed significant hyperglycemia and hypertension, both of which were difficult to manage. Single-donor platelet transfusions (3 units) controlled oozing at the dialysis catheter insertion site. A total of 10 units of packed red blood cells were transfused. After 8 days, plasma exchange and prednisone were discontinued as there was no improvement. The patient remained jaundiced with brisk hemolysis and markedly increased lactate dehydrogenase (512–1,374 U/L). Platelet count was 4,000/L–11,000/L. Rituximab 375 mg/m2, initiated on day 15, was given twice weekly for four doses and was well tolerated. Within 1 week, clinical and laboratory parameters began to improve (Figure). Four weeks after starting rituximab, platelet count was 154,000/L, hemoglobin level was 10.7 g/dL, and lactate dehydrogenase level was 227 U/L. Our case is interesting because this patient developed TTP within 1 week of receiving a single intrahepatic dose of mitomycin, indicating that some patients may have increased sensitivity to adverse effects of mitomycin. We were unable to identify any other published reports of TTP induced by mitomycin used for chemoembolization. More importantly, this patient had a successful and prompt response to rituximab. Similar responses have been described in patients with acquired factor VIII inhibitor treated with rituximab, suggesting an immunologic pathophysiologic mechanism involved in this syndrome (6). References 1. Giroux L, Bettez P, Giroux L. Mitomycin-C nephrotoxicity: a clinico-pathologic study of 17 cases. Am J Kidney Dis 1985; 6:28 –39. 2. Cantrell JE Jr, Phillips TM, Schein PS. Carcinoma-associated hemolytic-uremic syndrome: a complication of mitomycin C chemotherapy. J Clin Oncol 1985; 3:723–734. 3. Durand JM, Lefevre P. Mitomycin-induced thrombotic thrombocytopenic purpura: possible successful treatment with vincristine and cyclophosphamide. Haematologica 1991; 76:421– 423. 4. Kasper S, Neurath MF, Huber C, Theobald M, Scharrer I. Protein A immunoadsorption therapy for refractory, mitomycin C-associated thrombotic microangiopathy. Transfusion 2007; 47: 1263–1267. 5. Garvey B. Rituximab in the treatment of autoimmune haematological disorders. Br J Haematol 2008; 141:149 –169. 6. Onitilo AA, Skorupa A, Lal A, et al. Rituximab in the treatment of acquired factor VIII inhibitors. Thromb Haemost 2006; 96:84 – 87.
Number 2
Letters to the Editor
•
275
Figure. (a) Selective angiogram shows an aneurysm in the third section of the splenic artery, with associated stenosis. (b) Embolization proximal to the aneurysm of the splenic artery with GDC coils. (c) Initial follow-up angiogram shows the absence of filling of the aneurysm and the redistribution of the blood flow to the spleen. (d) Follow-up contrast-enhanced CT scan shows the lack of flow in the interior of the pseudoaneurysm. (e) Three-dimensional CT scan shows the absence of contrast medium in the interior of the lesion. (Available in color online at www.jvir.org.)
Successful Treatment of Mitomycin-induced Thrombotic Thrombocytopenic Purpura with Rituximab From: Adedayo A. Onitilo, MD, MSCR, Jessica M. Engel, MSN, FNP-BC, Lawrence H. Clouse, MD, and Kristin M. Gerndt, MD Department of Hematology/Oncology (A.A.O.) Marshfield Clinic–Weston Center 3501 Cranberry Blvd. Weston, WI 54476; and Departments of Hematology/Oncology (J.M.E., L.H.C.) and Interventional Radiology (K.M.G.) Marshfield Clinic Marshfield, Wisconsin
Editor: Mitomycin-induced thrombotic thrombocytopenic purpura (TTP) may occur within weeks to months after standard doses of mitomycin in less than 10% of patients; most present a picture of TTP-hemolytic uremic syndrome and die from renal failure (1,2). The exact physiology of mitomycin-induced TTP is unknown. No effective therapy has been identified, even with plasma exchange, the mainstay therapy for idiopathic TTP. Some success has been reported with the use of vincristine and cyclophosphamide and Staphylococcal protein A immunoabsorption columns (no longer available in the United States) (3,4). Rituximab is a monoclonal antibody targeting CD20-pos-
10.1016/j.jvir.2008.10.025
276
•
Letters to the Editor
February 2009
JVIR
Figure. Laboratory values and treatment.
itive B cells. Although rituximab has been reported as a successful treatment for refractory TTP (5), it has not been described for treatment of mitomycin- or chemoembolization-induced TTP. Here we describe an interesting case of mitomycin-induced TTP from chemoembolization and its successful and prompt response to rituximab. A 71-year-old woman with type 2 diabetes, hypertension, and hyperlipidemia presented with weight loss and diarrhea. Computed tomography (CT) showed multiple liver lesions, and biopsy was positive for adenocarcinoma consistent with a lung, pancreatic, or breast primary neoplasia. Despite extensive testing, a primary lesion was not identified. Treatment included carboplatin (area under the curve, 6) and paclitaxel (175 mg/m2) every 3 weeks for seven cycles, with bevacizumab (15 mg/m2) added beginning with cycle 3. Chemotherapy was well tolerated, without significant cytopenias. Although CT after chemotherapy showed partial response accompanied by significant decrease in tumor markers, treatment was discontinued as a result of peripheral neuropathy. Two months after chemotherapy, the patient underwent selective right hepatic artery chemoembolization with daunorubicin 50 mg, cisplatin 50 mg, mitomycin-C 10 mg, Ethiodol 8 mL, and standard low-dose dexamethasone (4 mg intravenously) preprocedurally. On the day of chemoembolization (day 1), hemoglobin level was 12.3 g/dL, white blood cell count was 3.9 ⫻ 103/L, and platelet count was 118,000/L. Basic coagulation profile and liver function test findings were normal except for chronically increased alkaline phosphatase levels. On day 4, the platelet count decreased to 8,000/L. By day 6, the hemoglobin level was 7.7 g/dL with schistocytes seen on the peripheral blood film; lactate dehydrogenase level increased to 731 U/L (normal, 81–190 U/L) and total bilirubin increased to 10.2 mg/dL. The patient was afebrile with normal renal function. The von Willebrand factor cleaving protease ADAMTS13 level was modestly low at 38% (normal, ⬎67%), with no inhibitor. Fibrinogen level was normal at 401 mg/dL, and the basic coagulation profile was normal with an International Normalized Ratio of 1.0 and an activated partial thromboplastin time of 26 seconds. These findings suggested that disseminated intravascular coagulation was not the likely cause of the patient’s thrombocytopenia. Reticulocyte indices showed adequate response to the degree of anemia, with a reticulocyte count of 13.8% and a reticulocyte index of 4.7. On day 8, daily plasma exchange with concurrent
prednisone was begun. Nonessential medications were discontinued. The patient developed significant hyperglycemia and hypertension, both of which were difficult to manage. Single-donor platelet transfusions (3 units) controlled oozing at the dialysis catheter insertion site. A total of 10 units of packed red blood cells were transfused. After 8 days, plasma exchange and prednisone were discontinued as there was no improvement. The patient remained jaundiced with brisk hemolysis and markedly increased lactate dehydrogenase (512–1,374 U/L). Platelet count was 4,000/L–11,000/L. Rituximab 375 mg/m2, initiated on day 15, was given twice weekly for four doses and was well tolerated. Within 1 week, clinical and laboratory parameters began to improve (Figure). Four weeks after starting rituximab, platelet count was 154,000/L, hemoglobin level was 10.7 g/dL, and lactate dehydrogenase level was 227 U/L. Our case is interesting because this patient developed TTP within 1 week of receiving a single intrahepatic dose of mitomycin, indicating that some patients may have increased sensitivity to adverse effects of mitomycin. We were unable to identify any other published reports of TTP induced by mitomycin used for chemoembolization. More importantly, this patient had a successful and prompt response to rituximab. Similar responses have been described in patients with acquired factor VIII inhibitor treated with rituximab, suggesting an immunologic pathophysiologic mechanism involved in this syndrome (6). References 1. Giroux L, Bettez P, Giroux L. Mitomycin-C nephrotoxicity: a clinico-pathologic study of 17 cases. Am J Kidney Dis 1985; 6:28 –39. 2. Cantrell JE Jr, Phillips TM, Schein PS. Carcinoma-associated hemolytic-uremic syndrome: a complication of mitomycin C chemotherapy. J Clin Oncol 1985; 3:723–734. 3. Durand JM, Lefevre P. Mitomycin-induced thrombotic thrombocytopenic purpura: possible successful treatment with vincristine and cyclophosphamide. Haematologica 1991; 76:421– 423. 4. Kasper S, Neurath MF, Huber C, Theobald M, Scharrer I. Protein A immunoadsorption therapy for refractory, mitomycin C-associated thrombotic microangiopathy. Transfusion 2007; 47: 1263–1267. 5. Garvey B. Rituximab in the treatment of autoimmune haematological disorders. Br J Haematol 2008; 141:149 –169. 6. Onitilo AA, Skorupa A, Lal A, et al. Rituximab in the treatment of acquired factor VIII inhibitors. Thromb Haemost 2006; 96:84 – 87.