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

International Journal of Hematology

Volumn 93, Issue 1, 2011, Pages 36-46

  Kanakura, Yuzuru ^a   Ohyashiki, Kazuma ^b   Shichishima, Tsutomu ^c   Okamoto, Shinichiro ^d   Ando, Kiyoshi ^e   Ninomiya, Haruhiko ^f   Kawaguchi, Tatsuya ^g   Nakao, Shinji ^h   Nakakuma, Hideki ⁱ   Nishimura, Jun Ichi ^a   Kinoshita, Taroh ^j   Bedrosian, Camille L ^k   Valentine, Marye Ellen ^k   Khursigara, Gus ^k   Ozawa, Keiya ^l   Omine, Mitsuhiro ^m  

^a OSAKA UNIVERSITY HOSPITAL   (Japan)

^b TOKYO MEDICAL UNIVERSITY HOSPITAL   (Japan)

^c FUKUSHIMA MEDICAL UNIVERSITY   (Japan)

^d KEIO UNIVERSITY   (Japan)

^e TOKAI UNIVERSITY   (Japan)

^f UNIVERSITY OF TSUKUBA   (Japan)

^g KUMAMOTO UNIVERSITY   (Japan)

^h KANAZAWA UNIVERSITY   (Japan)

ⁱ WAKAYAMA MEDICAL UNIVERSITY   (Japan)

^j OSAKA UNIVERSITY   (Japan)

^k ALEXION PHARMACEUTICALS   (United States)

^l JICHI MEDICAL UNIVERSITY   (Japan)

^m SHOWA UNIVERSITY FUJIGAOKA HOSPITAL   (Japan)

more..

Author keywords

Complement inactivating agents; Eculizumab; Hematopoietic stem cell; Hemolysis; Paroxysmal nocturnal hemoglobinuria

Indexed keywords

CORTICOSTEROID; D DIMER; ECULIZUMAB; HEMOGLOBIN; MENINGOCOCCUS VACCINE;

ADULT; AGED; ARTICLE; CEREBROVASCULAR ACCIDENT; CHRONIC KIDNEY DISEASE; CLINICAL ARTICLE; CLINICAL TRIAL; DEEP VEIN THROMBOSIS; DIARRHEA; DRUG BLOOD LEVEL; DRUG EFFECT; DRUG EFFICACY; DRUG INDUCED HEADACHE; DRUG SAFETY; DRUG TOLERABILITY; DYSPNEA; ECZEMA; ERYTHROCYTE; FATIGUE; FEMALE; FEVER; HEMOGLOBIN BLOOD LEVEL; HUMAN; INTRAVASCULAR HEMOLYSIS; JAPANESE; MALE; NAUSEA AND VOMITING; PAROXYSMAL NOCTURNAL HEMOGLOBINURIA; PHASE 2 CLINICAL TRIAL; QUALITY OF LIFE; RHINOPHARYNGITIS; TREATMENT OUTCOME;

ADULT; AGED; ANTIBODIES, MONOCLONAL; ASIAN CONTINENTAL ANCESTRY GROUP; COMPLEMENT ACTIVATION; COMPLEMENT C5; FEMALE; FIBRIN FIBRINOGEN DEGRADATION PRODUCTS; HEMOGLOBINURIA, PAROXYSMAL; HEMOLYSIS; HUMANS; JAPAN; MALE; MIDDLE AGED; RISK FACTORS; THROMBOSIS;

EID: 78751581550     PISSN: 09255710     EISSN: None     Source Type: Journal    
DOI: 10.1007/s12185-010-0748-9     Document Type: Article

References (41)

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;85:365-76.
2. HJ Audebert J Planck M Eisenburg H Schrezenmeier RL Haberl 2005 Cerebral ischemic infarction in paroxysmal nocturnal hemoglobinuria report of 2 cases and updated review of 7 previously published patients J Neurol 252 1379 1386 10.1007/s00415-005-0871-3 16021362
3. M Bessler PJ Mason P Hillmen T Miyata N Yamada J Takeda L Luzzatto T Kinoshita 1994 Paroxysmal nocturnal haemoglobinuria (PNH) is caused by somatic mutations in the PIG-A gene EMBO J 13 110 117 1:CAS:528:DyaK2cXhtVekur0%3D 8306954
4. RA Brodsky NS Young E Antonioli AM Risitano H Schrezenmeier J Schubert A Gaya L Coyle CC de Castro CL Fu JP Maciejewski M Bessler HA Kroon RP Rother P Hillmen 2008 Multicenter phase 3 study of the complement inhibitor eculizumab for the treatment of patients with paroxysmal nocturnal hemoglobinuria Blood 111 1840 1847 1:CAS:528:DC%2BD1cXisVeisrs%3D 10.1182/blood-2007-06-094136 18055865
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. 1-18.
7. D Cella JS Lai CH Chang A Peterman M Slavin 2002 Fatigue in cancer patients compared with fatigue in the general United States population Cancer 94 528 538 10.1002/cncr.10245 11900238
8. I Christiansen HK Iversen J Olesen 2000 Headache characteristics during the development of tolerance to nitrates: pathophysiological implications Cephalalgia 20 437 444 1:STN:280:DC%2BD3cvoslCrsw%3D%3D 10.1046/j.1468-2982. 2000.00064.x 11037739
9. DA Clark SA Butler V Braren RC Hartmann DE Jenkins Jr 1981 The kidneys in paroxysmal nocturnal hemoglobinuria Blood 57 83 89 1:STN:280: DyaL3M%2Foslelug%3D%3D 7448417
10. RP de Latour JY Mary C Salanoubat L Terriou G Etienne M Mohty S Roth S de Guibert S Maury JY Cahn G Socie 2008 Paroxysmal nocturnal hemoglobinuria: natural history of disease subcategories Blood 112 3099 3106 10.1182/blood-2008-01-133918 18535202
11. C Delles AU Klingbeil MP Schneider R Handrock T Schaufele RE Schmieder 2004 The role of nitric oxide in the regulation of glomerular haemodynamics in humans Nephrol Dial Transpl 19 1392 1397 1:CAS:528:DC%2BD2cXkt1Sqsro%3D 10.1093/ndt/gfh187
12. FB Gabbai 2001 Effects of nitric oxide synthase blockers on renal function Nephrol Dial Transpl 16 Suppl 1 10 13 1:CAS:528:DC%2BD3MXltVOntrw%3D
13. D Helley RP de Latour R Porcher C Arrais I Fauroux J Matheron A Duval JF Shved AM Fischer G Socie 2010 Eculizumab inhibits clot generation and endothelial dysfunction in patients with paroxysmal nocturnal haemoglobinuria Haematologica 95 574 581 1:CAS:528:DC%2BC3cXhtlWjs7fE 10.3324/haematol.2009. 016121 20081060
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. A Hill RP Rother X Wang SM Morris K Quinn-Senger SJ Richards M Bessler R Kelly P Hillmen M Gladwin 2010 Effect of eculizumab on haemolysis-associated nitric oxide depletion, dyspnoea, and measures of pulmonary hypertension in patients with paroxysmal nocturnal haemoglobinuria Br J Haematol 149 414 425 1:CAS:528:DC%2BC3cXms1yjs7g%3D 10.1111/j.1365-2141.2010.08096.x 20230403
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. A Hill P Hillmen SJ Richards D Elebute JC Marsh J Chan CF Mojcik RP Rother 2005 Sustained response and long-term safety of eculizumab in paroxysmal nocturnal hemoglobinuria Blood 106 2559 2565 1:CAS:528:DC%2BD2MXhtVKqt7rE 10.1182/blood-2005-02-0564 15985537
18. A Hill SJ Richards P Hillmen 2007 Recent developments in the understanding and management of paroxysmal nocturnal haemoglobinuria Br J Haematol 137 181 192 1:CAS:528:DC%2BD2sXmtVGrsb0%3D 10.1111/j.1365-2141.2007. 06554.x 17408457
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):553-9.
20. P Hillmen SM Lewis M Bessler L Luzzatto JV Dacie 1995 Natural history of paroxysmal nocturnal hemoglobinuria N Engl J Med 333 1253 1258 1:STN:280:DyaK28%2Fit1Wgtw%3D%3D 10.1056/NEJM199511093331904 7566002
21. P Hillmen P Muus U Duhrsen AM Risitano J Schubert L Luzzatto H Schrezenmeier J Szer RA Brodsky A Hill G Socie M Bessler SA Rollins L Bell RP Rother NS Young 2007 Effect of the complement inhibitor eculizumab on thromboembolism in patients with paroxysmal nocturnal hemoglobinuria Blood 110 4123 4128 1:CAS:528:DC%2BD2sXhtl2qsbzF 10.1182/blood-2007-06-095646 17702897
22. P Hillmen NS Young J Schubert RA Brodsky G Socie P Muus A Roth J Szer MO Elebute R Nakamura P Browne AM Risitano A Hill H Schrezenmeier CL Fu J Maciejewski SA Rollins CF Mojcik RP Rother L Luzzatto 2006 The complement inhibitor eculizumab in paroxysmal nocturnal hemoglobinuria N Engl J Med 355 1233 1243 1:CAS:528:DC%2BD28XpvFKgt7k%3D 10.1056/NEJMoa061648 16990386
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. KA Nath GM Vercellotti JP Grande H Miyoshi CV Paya JC Manivel JJ Haggard AJ Croatt WD Payne J Alam 2001 Heme protein-induced chronic renal inflammation: suppressive effect of induced heme oxygenase-1 Kidney Int 59 106 117 1:CAS:528:DC%2BD3MXot1ynuw%3D%3D 10.1046/j.1523-1755.2001.00471.x 11135063
26. National Kidney Foundation. K/DOQI clinical practice guidelines for chronic kidney disease: evaluation, classification, and stratification. 2002.
27. J Nishimura Y Kanakura RE Ware T Shichishima H Nakakuma H Ninomiya CM Decastro S Hall A Kanamaru KM Sullivan H Mizoguchi M Omine T Kinoshita WF Rosse 2004 Clinical course and flow cytometric analysis of paroxysmal nocturnal hemoglobinuria in the United States and Japan Medicine (Baltimore) 83 193 207 10.1097/01.md.0000126763.68170.46
28. C Parker M Omine S Richards J Nishimura M Bessler R Ware P Hillmen L Luzzatto N Young T Kinoshita W Rosse G Socie 2005 Diagnosis and management of paroxysmal nocturnal hemoglobinuria Blood 106 3699 3709 1:CAS:528: DC%2BD2MXht12ksbvL 10.1182/blood-2005-04-1717 16051736
29. CJ Parker 2007 The pathophysiology of paroxysmal nocturnal hemoglobinuria Exp Hematol 35 523 533 1:CAS:528:DC%2BD2sXjsVeksL0%3D 10.1016/j.exphem.2007.01. 046 17379062
30. CS Rinder HM Rinder BR Smith JC Fitch MJ Smith JB Tracey LA Matis SP Squinto SA Rollins 1995 Blockade of C5a and C5b-9 generation inhibits leukocyte and platelet activation during extracorporeal circulation J Clin Invest 96 1564 1572 1:CAS:528:DyaK2MXnvVGqurs%3D 10.1172/JCI118195 7657827
31. Rosse W. Paroxysmal nocturnal hemoglobinuria. In: Hoffman R, editor. Hematology: basic principles and practice. 3rd ed. Philadelphia: Churchill Livingstone, Inc. 2000.
32. RP Rother L Bell P Hillmen MT Gladwin 2005 The clinical sequelae of intravascular hemolysis and extracellular plasma hemoglobin: a novel mechanism of human disease JAMA 293 1653 1662 1:CAS:528:DC%2BD2MXjtV2qtL8%3D 10.1001/jama.293.13.1653 15811985
33. RP Rother SA Rollins CF Mojcik RA Brodsky L Bell 2007 Discovery and development of the complement inhibitor eculizumab for the treatment of paroxysmal nocturnal hemoglobinuria Nat Biotechnol 25 1256 1264 1:CAS:528:DC%2BD2sXht1Oru7zE 10.1038/nbt1344 17989688
34. MP Schlaich D Schmitt C Ott BM Schmidt RE Schmieder 2008 Basal nitric oxide synthase activity is a major determinant of glomerular haemodynamics in humans J Hypertens 26 110 116 1:CAS:528:DC%2BD2sXhsVCjsrjJ 10.1097/HJH. 0b013e3282f1a93e 18090547
35. R Schneider U Raff N Vornberger M Schmidt R Freund M Reber L Schramm S Gambaryan C Wanner HH Schmidt J Galle 2003 l-Arginine counteracts nitric oxide deficiency and improves the recovery phase of ischemic acute renal failure in rats Kidney Int 64 216 225 1:CAS:528:DC%2BD3sXlsFeksrY%3D 10.1046/j.1523-1755. 2003.00063.x 12787412
36. G Socie JY Mary A de Gramont B Rio M Leporrier C Rose P Heudier H Rochant JY Cahn E Gluckman 1996 Paroxysmal nocturnal haemoglobinuria: long-term follow-up and prognostic factors. French Society of Haematology Lancet 348 573 577 1:STN:280:DyaK28zntVKksQ%3D%3D 10.1016/S0140-6736(95)12360-1 8774569
37. G Socie P Hillmen P Muus J Schubert U Duhrsen AM Risitano RP Rother RA Brodsky J Szer 2007 Sustained improvements in transfusion requirements, fatigue and thrombosis with eculizumab treatment in paroxysmal nocturnal hemoglobinuria ASH Annu Meet Abstr 110 3672
38. J Takeda T Miyata K Kawagoe Y Iida Y Endo T Fujita M Takahashi T Kitani T Kinoshita 1993 Deficiency of the GPI anchor caused by a somatic mutation of the PIG-A gene in paroxysmal nocturnal hemoglobinuria Cell 73 703 711 1:CAS:528:DyaK3sXks12ntr0%3D 10.1016/0092-8674(93)90250-T 8500164
39. TC Thomas SA Rollins RP Rother MA Giannoni SL Hartman EA Elliott SH Nye LA Matis SP Squinto MJ Evans 1996 Inhibition of complement activity by humanized anti-C5 antibody and single-chain Fv Mol Immunol 33 1389 1401 1:CAS:528:DyaK2sXjsVymsrs%3D 10.1016/S0161-5890(96)00078-8 9171898
40. IC Weitz M Ghods L Rochanda P Prazavi J Zwicker B Furie H Liebman 2008 Eculizumab therapy results in rapid and sustained decreases in markers of thrombin generation and inflammation in patients with PNH ASH Annu Meet Abstr 112 407
41. N Yamada T Miyata K Maeda T Kitani J Takeda T Kinoshita 1995 Somatic mutations of the PIG-A gene found in Japanese patients with paroxysmal nocturnal hemoglobinuria Blood 85 885 892 1:CAS:528:DyaK2MXjs1Ojt7k%3D 7531514