Long‐term safety and efficacy of sustained eculizumab treatment in patients with paroxysmal nocturnal haemoglobinuria

Abstract

Summary Paroxysmal nocturnal haemoglobinuria ( PNH ) is characterized by chronic, uncontrolled complement activation resulting in elevated intravascular haemolysis and morbidities, including fatigue, dyspnoea, abdominal pain, pulmonary hypertension, thrombotic events ( TE s) and chronic kidney disease ( CKD ). The long‐term safety and efficacy of eculizumab, a humanized monoclonal antibody that inhibits terminal complement activation, was investigated in 195 patients over 66 months. Four patient deaths were reported, all unrelated to treatment, resulting in a 3‐year survival estimate of 97·6%. All patients showed a reduction in lactate dehydrogenase levels, which was sustained over the course of treatment (median reduction of 86·9% at 36 months), reflecting inhibition of chronic haemolysis. TE s decreased by 81·8%, with 96·4% of patients remaining free of TE s. Patients also showed a time‐dependent improvement in renal function: 93·1% of patients exhibited improvement or stabilization in CKD score at 36 months. Transfusion independence increased by 90·0% from baseline, with the number of red blood cell units transfused decreasing by 54·7%. Eculizumab was well tolerated, with no evidence of cumulative toxicity and a decreasing occurrence of adverse events over time. Eculizumab has a substantial impact on the symptoms and complications of PNH and results a significant improvement in patient survival.

Shown for reading. Its publisher allows quoting it, not republishing it.

References 34

1. 1.

   van Bijnen ST, van Rijn RS, Koljenovic S, Te Boekhorst P, Muus P. Possible high risk of thrombotic events in patients with paroxysmal nocturnal haemoglobinuria after discontinuation of eculizumab. British Journal of Haematology. 2012;157:762-763.

   Not in our library10.1111/j.1365-2141.2012.09073.x

2. 2.

   Brodsky RA. How I treat paroxysmal nocturnal hemoglobinuria. Blood. 2009;113:6522-6527.

   Not in our library10.1182/blood-2009-03-195966

3. 3.

   Brodsky RA, Young NS, Antonioli E, Risitano AM, Schrezenmeier H, Schubert J, Gaya A, Coyle L, de Castro C, 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;111:1840-1847.

   Not in our library10.1182/blood-2007-06-094136

4. 4.

   Clark DA, Butler SA, Braren V, Hartmann RC, Jenkins DE. The kidneys in paroxysmal nocturnal hemoglobinuria. Blood. 1981;57:83-89.

   Not in our library

5. 5.

   Emadi A, Brodsky RA. Successful discontinuation of anticoagulation following eculizumab administration in paroxysmal nocturnal hemoglobinuria. American Journal of Hematology. 2009;84:699-701.

   Not in our library10.1002/ajh.21506

6. 6.

   Figueroa JE, Densen P. Infectious diseases associated with complement deficiencies. Clinical Microbiology Reviews. 1991;4:359-395.

   Not in our library10.1128/cmr.4.3.359

7. 7.

   Hill A, Rother RP, Hillmen P. Improvement in the symptoms of smooth muscle dystonia during eculizumab therapy in paroxysmal nocturnal haemoglobinuria. Haematologica. 2005a;90:40.

   Not in our library

8. 8.

   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. 2005b;106:2559-2565.

   Not in our library10.1182/blood-2005-02-0564

9. 9.

   Hill A, Rother RP, Wang X, Morris SM, Quinn-Senger K, Kelly R, Richards SJ, Bessler M, Bell L, Hillmen P, Gladwin MT. Effect of eculizumab on haemolysis-associated nitric oxide depletion, dyspnoea, and measures of pulmonary hypertension in patients with paroxysmal nocturnal haemoglobinuria. British Journal of Haematology. 2010;149:414-425.

   Not in our library10.1111/j.1365-2141.2010.08096.x

10. 10.

    Hill A, Sapsford RJ, Scally A, Kelly R, Richards SJ, Khurisgara G, Sivananthan MU, Hillmen P. Under-recognized complications in patients with paroxysmal nocturnal haemoglobinuria: raised pulmonary pressure and reduced right ventricular function. British Journal of Haematology. 2012;158:409-414.

    Not in our library10.1111/j.1365-2141.2012.09166.x

11. 11.

    Hillmen P, Lewis SM, Bessler M, Luzzatto L, Dacie JV. Natural history of paroxysmal nocturnal hemoglobinuria. New England Journal of Medicine. 1995;333:1253-1258.

    Not in our library10.1056/nejm199511093331904

12. 12.

    Hillmen P, Hall C, Marsh JC, Elebute M, Bombara MP, Petro BE, Cullen MJ, Richards SJ, Rollins SA, Mojcik CF, Rother RP. Effect of eculizumab on hemolysis and transfusion requirements in patients with paroxysmal nocturnal hemoglobinuria. New England Journal of Medicine. 2004;350:552-559.

    Not in our library10.1056/nejmoa031688

13. 13.

    Hillmen P, Young NS, Schubert J, Brodsky RA, Socié 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. New England Journal of Medicine. 2006;355:1233-1243.

    Not in our library10.1056/nejmoa061648

14. 14.

    Hillmen P, Muus P, Dührsen U, Risitano AM, Schubert J, Luzzatto L, Schrezenmeier H, Szer J, Brodsky RA, Hill A, Socié 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;110:4123-4128.

    Not in our library10.1182/blood-2007-06-095646

15. 15.

    Hillmen P, Elebute M, Kelly R, Urbano-Ispizua A, Hill A, Rother RP, Khursigara G, Fu CL, Omine M, Browne P, Rosse W. Long-term effect of the complement inhibitor eculizumab on kidney function in patients with paroxysmal nocturnal hemoglobinuria. American Journal of Hematology. 2010;85:553-559.

    Not in our library10.1002/ajh.21757

16. 16.

    Kelly R, Richards S, Hillmen P, Hill A. The pathophysiology of paroxysmal nocturnal hemoglobinuria and treatment with eculizumab. Therapeutics and Clinical Risk Managment. 2009;5:911-921.

    Not in our library10.2147/tcrm.s3334

17. 17.

    Kelly R, Arnold L, Richards S, Hill A, Bomken C, Hanley J, Loughney A, Beauchamp J, Khursigara G, Rother RP, Chalmers E, Fyfe A, Fitzsimons E, Nakamura R, Gaya A, Risitano AM, Schubert J, Norfolk D, Simpson N, Hillmen P. The management of pregnancy in paroxysmal nocturnal haemoglobinuria on long term eculizumab. British Journal of Haematology. 2010;149:446-450.

    Not in our library10.1111/j.1365-2141.2010.08099.x

18. 18.

    Kelly RJ, Hill A, Arnold LM, Brooksbank GL, Richards SJ, Cullen M, Mitchell LD, Cohen DR, Gregory WM, Hillmen P. Long-term treatment with eculizumab in paroxysmal nocturnal hemoglobinuria: sustained efficacy and improved survival. Blood. 2011;117:6786-6792.

    Not in our library10.1182/blood-2011-02-333997

19. 19.

    Kim JS, Jang JH, Lee JW, Yoon SS, Lee JH, Kim YK, Sohn SK, Chung JS. Renal impairment ia a risk factor for early mortality in patients with paroxysmal nocturnal haemoglobinuria (PNH). Haematologica. 2011;96:112.

    Not in our library

20. 20.

    de Latour RP, Mary JY, Salanoubat C, Terriou L, Etienne G, Mohty M, Roth S, de Guibert S, Maury S, Cahn JY, Socié G. Paroxysmal nocturnal hemoglobinuria: natural history of disease subcategories. Blood. 2008;112:3099-3106.

    Not in our library10.1182/blood-2008-01-133918

21. 21.

    de Latour RP, Schrezenmeier H, Mary J-Y, Bacigalupo A, de Souza C, Willemze R, Tichelli A, Passweg JR, Socié G. Stem cell transplantation for paroxysmal nocturnal haemoglobinuria: an on going joint study of the AAWP EBMT Group and the French Society of Haematology. (Abstract). Bone Marrow Transplantation. 2009;43:S57-S58.

    Not in our library

22. 22.

    Levey AS, Bosch JP, Lewis JB, Greene T, Rogers N, Roth D. A more accurate method to estimate glomerular filtration rate from serum creatinine: a new prediction equation. Modification of Diet in Renal Disease Study Group. Annals of Internal Medicine. 1999;130:461-470.

    Not in our library10.7326/0003-4819-130-6-199903160-00002

23. 23.

    McKeage K. Eculizumab: a review of its use in paroxysmal nocturnal haemoglobinuria. Drugs. 2011;71:2327-2345.

    Not in our library10.2165/11208300-000000000-00000

24. 24.

    Moyo VM, Mukhina GL, Garrett ES, Brodsky RA. Natural history of paroxysmal nocturnal haemoglobinuria using modern diagnostic assays. British Journal of Haematology. 2004;126:133-138.

    Not in our library10.1111/j.1365-2141.2004.04992.x

25. 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 International. 2001;59:106-117.

    Not in our library10.1046/j.1523-1755.2001.00471.x

26. 26.

    K/DOQI clinical practice guidelines for chronic kidney disease: evaluation, classification, and stratification. American Journal of Kidney Diseases. 2002;39:S1-266.

    Not in our library

27. 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. 2004;83:193-207.

    Not in our library10.1097/01.md.0000126763.68170.46

28. 28.

    Parker CJ. Paroxysmal nocturnal hemoglobinuria and glycosyl phosphatidylinositol anchored proteins that regulate complement. Clinical and Experimental Immunology. 1991;86(Suppl. 1):36-42.

    Not in our library10.1111/j.1365-2249.1991.tb06205.x

29. 29.

    Pu JJ, Brodsky RA. Paroxysmal nocturnal hemoglobinuria from bench to bedside. Clinical and Translational Science. 2011;4:219-224.

    Not in our library10.1111/j.1752-8062.2011.00262.x

30. 30.

    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;293:1653-1662.

    Not in our library10.1001/jama.293.13.1653

31. 31.

    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. Nature Biotechnology. 2007;25:1256-1264.

    Not in our library10.1038/nbt1344

32. 32.

    Socié 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;348:573-577.

    Not in our library10.1016/s0140-6736(95)12360-1

33. 33.

    Stevens LA, Coresh J, Greene T, Levey AS. Assessing kidney function–measured and estimated glomerular filtration rate. New England Journal of Medicine. 2006;354:2473-2483.

    Not in our library10.1056/nejmra054415

34. 34.

    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;73:703-711.

    Not in our library10.1016/0092-8674(93)90250-t

Cited by papers we hold 2

• Anti-complement Treatment for Paroxysmal Nocturnal Hemoglobinuria: Time for Proximal Complement Inhibition? A Position Paper From the SAAWP of the EBMT · 2019
  No notice
• Design and preclinical characterization of ALXN1210: A novel anti-C5 antibody with extended duration of action · 2018
  No notice

Reads

A person counts once a day per paper. We keep no cookie and no address: a reader is a hash that changes every day. Any month under five reads shows no number.