Safety and efficacy of the terminal complement inhibitor eculizumab in Japanese patients with paroxysmal nocturnal hemoglobinuria: the AEGIS Clinical Trial

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• 作者：Yuzuru Kanakura (1)
  Kazuma Ohyashiki (2)
  Tsutomu Shichishima (3)
  Shinichiro Okamoto (4)
  Kiyoshi Ando (5)
  Haruhiko Ninomiya (6)
  Tatsuya Kawaguchi (7)
  Shinji Nakao (8)
  Hideki Nakakuma (9)
  Jun-ichi Nishimura (1)
  Taroh Kinoshita (10)
  Camille L. Bedrosian (11)
  Marye Ellen Valentine (11)
  Gus Khursigara (11)
  Keiya Ozawa (12)
  Mitsuhiro Omine (13)
  
• 关键词：Paroxysmal nocturnal hemoglobinuria ; Complement ; inactivating agents ; Hemolysis ; Eculizumab ; Hematopoietic stem cell
• 刊名：International Journal of Hematology
• 出版年：2011
• 出版时间：January 2011
• 年：2011
• 卷：93
• 期：1
• 页码：36-46
• 全文大小：307KB
• 参考文献：1. Aaronson NK, Ahmedzai S, Bergman B, Bullinger M, Cull A, Duez NJ, Filiberti A, Flechtner H, Fleishman SB, de Haes JC. The European Organization for Research and Treatment of Cancer QLQ-C30: a quality-of-life instrument for use in international clinical trials in oncology. J Natl Cancer Inst. 1993;85:365-6.
  2. Audebert HJ, Planck J, Eisenburg M, Schrezenmeier H, Haberl RL. Cerebral ischemic infarction in paroxysmal nocturnal hemoglobinuria report of 2 cases and updated review of 7 previously published patients. J Neurol. 2005;252:1379-6. CrossRef
  3. Bessler M, Mason PJ, Hillmen P, Miyata T, Yamada N, Takeda J, Luzzatto L, Kinoshita T. Paroxysmal nocturnal haemoglobinuria (PNH) is caused by somatic mutations in the PIG-A gene. EMBO J. 1994;13:110-.
  4. Brodsky RA, Young NS, Antonioli E, Risitano AM, Schrezenmeier H, Schubert J, Gaya A, Coyle L, de Castro CC, Fu CL, Maciejewski JP, Bessler M, Kroon HA, Rother RP, Hillmen P. Multicenter phase 3 study of the complement inhibitor eculizumab for the treatment of patients with paroxysmal nocturnal hemoglobinuria. Blood. 2008;111:1840-. CrossRef
  5. Cella D. Manual of the Functional Assessment of Chronic Illness Therapy (FACIT) measurement system. 4th ed. Evanston, IL: Center on Outcomes, Research and Education (CORE), Evanston Northwestern Healthcare and Northwestern University; 1997.
  6. Cella D, et al. The FACIT-Fatigue Scale: description, reliability and validity. Evanston, IL: Center on Outcomes, Research and Education; 2003. p. 1-8.
  7. Cella D, Lai JS, Chang CH, Peterman A, Slavin M. Fatigue in cancer patients compared with fatigue in the general United States population. Cancer. 2002;94:528-8. CrossRef
  8. Christiansen I, Iversen HK, Olesen J. Headache characteristics during the development of tolerance to nitrates: pathophysiological implications. Cephalalgia. 2000;20:437-4. CrossRef
  9. Clark DA, Butler SA, Braren V, Hartmann RC, Jenkins DE Jr. The kidneys in paroxysmal nocturnal hemoglobinuria. Blood. 1981;57:83-.
  10. de Latour RP, Mary JY, Salanoubat C, Terriou L, Etienne G, Mohty M, Roth S, de Guibert S, Maury S, Cahn JY, Socie G. Paroxysmal nocturnal hemoglobinuria: natural history of disease subcategories. Blood. 2008;112:3099-06. CrossRef
  11. Delles C, Klingbeil AU, Schneider MP, Handrock R, Schaufele T, Schmieder RE. The role of nitric oxide in the regulation of glomerular haemodynamics in humans. Nephrol Dial Transpl. 2004;19:1392-. CrossRef
  12. Gabbai FB. Effects of nitric oxide synthase blockers on renal function. Nephrol Dial Transpl. 2001;16(Suppl 1):10-.
  13. Helley D, de Latour RP, Porcher R, Arrais C, Fauroux I, Matheron J, Duval A, Shved JF, Fischer AM, Socie G. Eculizumab inhibits clot generation and endothelial dysfunction in patients with paroxysmal nocturnal haemoglobinuria. Haematologica. 2010;95:574-1. CrossRef
  14. Hill A, Muus P, Duhrsen U, Socie G, Risitano A, De Paz R, Van den Neste E, Zanella A, Lai J, Hillmen P, Rother R, Cella D. Improvement in fatigue with eculizumab treatment of patients with PNH occurs independent of changes in anemia. EHA. 2008.
  15. Hill A, Rother RP, Wang X, Morris SM, Quinn-Senger K, Richards SJ, Bessler M, Kelly R, Hillmen P, Gladwin M. Effect of eculizumab on haemolysis-associated nitric oxide depletion, dyspnoea, and measures of pulmonary hypertension in patients with paroxysmal nocturnal haemoglobinuria. Br J Haematol. 2010;149:414-5. CrossRef
  16. Hill A, Reid SA, Rother RP, Gladwin MT, Collinson PO, Gaze DC, Lowe A, Guthrie A, Sivananthan MU, Hillmen P. High definition contrast-enhanced mr imaging in paroxysmal nocturnal hemoglobinuria (PNH) suggests a high frequency of subclinical thrombosis. Blood. 2006;108(11) (Abstract 979).
  17. Hill A, Hillmen P, Richards SJ, Elebute D, Marsh JC, Chan J, Mojcik CF, Rother RP. Sustained response and long-term safety of eculizumab in paroxysmal nocturnal hemoglobinuria. Blood. 2005;106:2559-5. CrossRef
  18. Hill A, Richards SJ, Hillmen P. Recent developments in the understanding and management of paroxysmal nocturnal haemoglobinuria. Br J Haematol. 2007;137:181-2. CrossRef
  19. Hillmen P, Elebute M, Kelly R, Urbano-Ispizua A, Rother R, Khursigara G, Fu CL, Browne P, Rosse W. Long-term effect of the complement inhibitor eculizumab on kidney function in patients with paroxysmal nocturnal hemoglobinuria. Am J Hematol. 2010;85(8):553-.
  20. Hillmen P, Lewis SM, Bessler M, Luzzatto L, Dacie JV. Natural history of paroxysmal nocturnal hemoglobinuria. N Engl J Med. 1995;333:1253-. CrossRef
  21. Hillmen P, Muus P, Duhrsen U, Risitano AM, Schubert J, Luzzatto L, Schrezenmeier H, Szer J, Brodsky RA, Hill A, Socie G, Bessler M, Rollins SA, Bell L, Rother RP, Young NS. Effect of the complement inhibitor eculizumab on thromboembolism in patients with paroxysmal nocturnal hemoglobinuria. Blood. 2007;110:4123-. CrossRef
  22. Hillmen P, Young NS, Schubert J, Brodsky RA, Socie G, Muus P, Roth A, Szer J, Elebute MO, Nakamura R, Browne P, Risitano AM, Hill A, Schrezenmeier H, Fu CL, Maciejewski J, Rollins SA, Mojcik CF, Rother RP, Luzzatto L. The complement inhibitor eculizumab in paroxysmal nocturnal hemoglobinuria. N Engl J Med. 2006;355:1233-3. CrossRef
  23. Kanakura Y, Ohyashiki K, Shichishima T, Okamoto S, Ando K, Ninomiya H, Kawaguchi T, Nakao S, Nakakuma H, Nishimura J, Kinoshita T, Bedrosian C, Valentine ME, Ozawa K, Omine M. Chronic renal insufficiency in japanese patients with paroxysmal nocturnal hemoglobinuria (PNH): improvement with eculizumab treatment in the long-term follow-up of the AEGIS Study. Blood. 2009;114 (Abstract 1980).
  24. Muus P, Risitano A, Castro-Malaspina H, Jones C, Fuller S, Socie G. Clinical impact of unregulated terminal complement activity in never-transfused patients with paroxysmal nocturnal hemoglobinuria. Blood. 2009;114 (Abstract).
  25. Nath KA, Vercellotti GM, Grande JP, Miyoshi H, Paya CV, Manivel JC, Haggard JJ, Croatt AJ, Payne WD, Alam J. Heme protein-induced chronic renal inflammation: suppressive effect of induced heme oxygenase-1. Kidney Int. 2001;59:106-7. CrossRef
  26. National Kidney Foundation. K/DOQI clinical practice guidelines for chronic kidney disease: evaluation, classification, and stratification. 2002.
  27. Nishimura J, Kanakura Y, Ware RE, Shichishima T, Nakakuma H, Ninomiya H, Decastro CM, Hall S, Kanamaru A, Sullivan KM, Mizoguchi H, Omine M, Kinoshita T, Rosse WF. Clinical course and flow cytometric analysis of paroxysmal nocturnal hemoglobinuria in the United States and Japan. Medicine (Baltimore). 2004;83:193-07. CrossRef
  28. Parker C, Omine M, Richards S, Nishimura J, Bessler M, Ware R, Hillmen P, Luzzatto L, Young N, Kinoshita T, Rosse W, Socie G. Diagnosis and management of paroxysmal nocturnal hemoglobinuria. Blood. 2005;106:3699-09. CrossRef
  29. Parker CJ. The pathophysiology of paroxysmal nocturnal hemoglobinuria. Exp Hematol. 2007;35:523-3. CrossRef
  30. Rinder CS, Rinder HM, Smith BR, Fitch JC, Smith MJ, Tracey JB, Matis LA, Squinto SP, Rollins SA. Blockade of C5a and C5b-9 generation inhibits leukocyte and platelet activation during extracorporeal circulation. J Clin Invest. 1995;96:1564-2. CrossRef
  31. Rosse W. Paroxysmal nocturnal hemoglobinuria. In: Hoffman R, editor. Hematology: basic principles and practice. 3rd ed. Philadelphia: Churchill Livingstone, Inc. 2000.
  32. Rother RP, Bell L, Hillmen P, Gladwin MT. The clinical sequelae of intravascular hemolysis and extracellular plasma hemoglobin: a novel mechanism of human disease. JAMA. 2005;293:1653-2. CrossRef
  33. Rother RP, Rollins SA, Mojcik CF, Brodsky RA, Bell L. Discovery and development of the complement inhibitor eculizumab for the treatment of paroxysmal nocturnal hemoglobinuria. Nat Biotechnol. 2007;25:1256-4. CrossRef
  34. Schlaich MP, Schmitt D, Ott C, Schmidt BM, Schmieder RE. Basal nitric oxide synthase activity is a major determinant of glomerular haemodynamics in humans. J Hypertens. 2008;26:110-. CrossRef
  35. Schneider R, Raff U, Vornberger N, Schmidt M, Freund R, Reber M, Schramm L, Gambaryan S, Wanner C, Schmidt HH, Galle J. l -Arginine counteracts nitric oxide deficiency and improves the recovery phase of ischemic acute renal failure in rats. Kidney Int. 2003;64:216-5. CrossRef
  36. Socie G, Mary JY, de Gramont A, Rio B, Leporrier M, Rose C, Heudier P, Rochant H, Cahn JY, Gluckman E. Paroxysmal nocturnal haemoglobinuria: long-term follow-up and prognostic factors. French Society of Haematology. Lancet. 1996;348:573-. CrossRef
  37. Socie G, Hillmen P, Muus P, Schubert J, Duhrsen U, Risitano AM, Rother RP, Brodsky RA, Szer J. Sustained improvements in transfusion requirements, fatigue and thrombosis with eculizumab treatment in paroxysmal nocturnal hemoglobinuria. ASH Annu Meet Abstr. 2007;110:3672.
  38. Takeda J, Miyata T, Kawagoe K, Iida Y, Endo Y, Fujita T, Takahashi M, Kitani T, Kinoshita T. Deficiency of the GPI anchor caused by a somatic mutation of the PIG-A gene in paroxysmal nocturnal hemoglobinuria. Cell. 1993;73:703-1. CrossRef
  39. Thomas TC, Rollins SA, Rother RP, Giannoni MA, Hartman SL, Elliott EA, Nye SH, Matis LA, Squinto SP, Evans MJ. Inhibition of complement activity by humanized anti-C5 antibody and single-chain Fv. Mol Immunol. 1996;33:1389-01. CrossRef
  40. Weitz IC, Ghods M, Rochanda L, Prazavi P, Zwicker J, Furie B, Liebman H. Eculizumab therapy results in rapid and sustained decreases in markers of thrombin generation and inflammation in patients with PNH. ASH Annu Meet Abstr. 2008;112:407.
  41. Yamada N, Miyata T, Maeda K, Kitani T, Takeda J, Kinoshita T. Somatic mutations of the PIG-A gene found in Japanese patients with paroxysmal nocturnal hemoglobinuria. Blood. 1995;85:885-2.
  
• 作者单位：Yuzuru Kanakura (1)
  Kazuma Ohyashiki (2)
  Tsutomu Shichishima (3)
  Shinichiro Okamoto (4)
  Kiyoshi Ando (5)
  Haruhiko Ninomiya (6)
  Tatsuya Kawaguchi (7)
  Shinji Nakao (8)
  Hideki Nakakuma (9)
  Jun-ichi Nishimura (1)
  Taroh Kinoshita (10)
  Camille L. Bedrosian (11)
  Marye Ellen Valentine (11)
  Gus Khursigara (11)
  Keiya Ozawa (12)
  Mitsuhiro Omine (13)
  
  1. Department of Hematology and Oncology, Osaka University Hospital, Suita, Japan
  2. Tokyo Medical University Hospital, Tokyo, Japan
  3. Fukushima Medical University, Fukushima, Japan
  4. Division of Hematology, Keio University School of Medicine, Tokyo, Japan
  5. Department of Hematology and Oncology, Tokai University, Isehara, Japan
  6. University of Tsukuba, Tsukuba, Japan
  7. Kumamoto University, Kumamoto, Japan
  8. Cellular Transplantation Biology, Kanazawa University, Kanazawa, Japan
  9. Department of Hematology/Oncology, Wakayama Medical University, Wakayama, Japan
  10. Research Institute for Microbial Diseases, Osaka University Hospital, Suita, Japan
  11. Alexion Pharmaceuticals, Cheshire, CT, USA
  12. Jichi Medical University Hospital, Tochigi, Japan
  13. Showa University Fujigaoka Hospital, Yokohama, Japan
  

文摘

Paroxysmal nocturnal hemoglobinuria (PNH) is a progressive and life-threatening disease characterized by complement-mediated chronic hemolysis, resulting in serious life-threatening complications and early mortality. Eculizumab, a humanized anti-C5 monoclonal antibody that inhibits terminal complement activation, has been shown to reduce hemolysis in PNH patients. The pivotal open-label, 12-week phase II registration study (AEGIS) was designed to evaluate the efficacy and safety of eculizumab in Japanese patients with PNH. This trial achieved its primary endpoint of reducing intravascular hemolysis with high statistical significance. Twenty-seven of the 29 patients responded to eculizumab treatment, resulting in an 87% reduction in hemolysis (P?<?0.0001) and subsequent improvement in anemia (P?=?0.0003) despite reduction in transfusion requirements (P?=?0.006). Fatigue and dyspnea significantly improved within 1-?weeks of eculizumab treatment and the improvement was independent of changes in hemoglobin. Chronic kidney disease (CKD) was common (66%) and eculizumab treatment improved CKD in 41% of patients at 12?weeks (P?<?0.001). Elevated thrombotic risk was evident in Japanese PNH patients and eculizumab treatment normalized d-dimer levels in 45% of patients with elevated d-dimers at baseline (P?<?0.001). The AEGIS results demonstrate that eculizumab is effective, safe and well tolerated in Japanese patients with PNH.