Successful use of eculizumab in an 86-year-old patient with paroxysmal nocturnal hemoglobinuria in Japan
© Ooe and Nagai; licensee Springer. 2014
Received: 13 August 2013
Accepted: 2 December 2013
Published: 4 January 2014
Eculizumab was used to treat an 86-year-old male patient with paroxysmal nocturnal hemoglobinuria, the oldest reported case in Japan. As observed in younger patients, this drug rapidly suppressed hemolysis in the present patient, which allowed weaning from blood transfusion. Eculizumab treatment has been continued for 2 years and resulted in the alleviation of renal dysfunction. Despite the patient’s advanced age, the inhibition of complement activity caused by this drug did not result in infection, indicating that it is safe to use in elderly patients.
KeywordsRenal function Oldest Japanese patient Paroxysmal nocturnal hemoglobinuria Eculizumab
The complement regulatory proteins CD55 and CD59 bind to glycosylphosphatidylinositol (GPI) on red blood cell membranes and inhibit complement activity, thus preventing hemolysis. Paroxysmal nocturnal hemoglobinuria (PNH) is a disease that involves hemolysis caused by the lack of CD55- or CD59-mediated complement activity inhibition in the absence of GPI anchor on the surface of red blood cells. This occurs in individuals with a defective phosphatidylinositol glycan class A enzyme that prevents normal GPI anchor synthesis (Takahashi et al. 1993). PNH is a very rare disease that develops in approximately 16 per 1 million people, and its onset does not exhibit any age specificity (Hillmen et al. 1995; Nishimura et al. 2004). Hemoglobin release into the bloodstream as a result of hemolysis could lead to massive nitrogen oxide (NO) scavenging in blood vessels; this increases platelet reactivity and aggregation, possibly inducing pulmonary hypertension and/or thrombosis. Hemolysis can also lead to several disorders including renal dysfunction due to massive hemosiderin deposition in the proximal renal tubules. The immune systems of elderly patients are generally compromised compared with those of younger patients (Naylor et al. 2005; Czesnikiewicz-Guzik et al. 2008). However, whether elderly patients with PNH can be safely treated using medicines that inhibit complement activity remains unknown.
We recently encountered a rare case of PNH diagnosed at the age of 81 years, in which eculizumab treatment was initiated at the age of 84 years. The details of the clinical course of this patient are presented herein.
Laboratory findings on diagnosis (March 6, 2009)
241 × 104/μL
12.6 × 104/μL
Bone marrow aspiration in April 2009 demonstrated hypercellular marrow: nuclear cell count (NCC), 21.3 × 104/mm3; megakaryocytes (MgK), 53/mm3 with bilineage dysplasia (i.e., peroxidase-negative myeloid cells, mononuclear megakaryocytes, and increased total erythroblasts [58.8%]). Chromosome analysis revealed a karyotype of 45X-Y(4)/46XY(16). Therefore, the patient was diagnosed with myelodysplastic syndrome (MDS), i.e., refractory cytopenia with multilineage dysplasia. His anemia gradually progressed, and he occasionally required blood transfusion.
Hematological tests performed immediately before eculizumab treatment initiation yielded the following results: RBC, 280 × 104/μL; Hb, 10.0 g/dL; and reticulocytes, 4.1%. The biochemical test results were as follows: LDH, 1,748 U/L; and total bilirubin, 2.4 mg/dL.
Blood transfusion was no longer required thereafter. The patient experienced persistent suppression of hemolysis and renal function recovery, with sCr levels decreasing from 2.0 mg/dL (eGFR, 25.4 mL·min-1·1.73 m-2) to 1.4 mg/dL (eGFR, 37.5 mL·min-1·1.73 m-2).
Discussion and evaluation
Patients with PNH associated with hemolysis are known to present with symptoms including abdominal pain, dysphagia, and pulmonary hypertension due to excessive NO scavenging by hemoglobin released into the blood or thrombosis at various sites as a result of stimulated platelet aggregation (Hill et al. 2010; Rother et al. 2005). Anemia secondary to hemolysis used to be treated with blood transfusion, steroids, or the anticoagulant warfarin (Parker et al. 2005; Hillmen et al. 2007). However, the use of eculizumab, which specifically inhibits complement C5, was approved in Japan in 2010. The complement regulatory proteins CD55 and CD59 play roles in hemolysis prevention. While CD55 regulates the first half of the complement activation pathway by stimulating the destruction of the C3/C5 converting enzyme, CD59 acts on C9 and inhibits the formation of the membrane attack complex (Nicholson-Weller et al. 1981; Sugita et al. 1988; Davies et al. 1989). When the present patient was diagnosed with PNH, the percentages of CD55(-) and CD59(-) cells were 1.31% and 49.1%, respectively. The sensitivity of the complement system increases particularly when CD59 is defective; this can lead to the hemolysis of PNH-affected blood cells. Therefore, this mechanism likely led to PNH development in the present case despite the lower percentage of CD55-negative cells detected. Eculizumab reduces LDH levels soon after treatment initiation (Hillmen et al. 2007). Furthermore, as hemolysis is alleviated by this drug, Hb levels gradually increase (Hillmen et al. 2007; Kanakura et al. 2011). The present patient was initially diagnosed with MDS and exhibited increased WBC counts in response to treatment with methenolone and prednisolone. However, because compromised renal function was still observed, the possibility of PNH-induced chronic renal failure and a subsequent poor prognosis was considered. Therefore, treatment with eculizumab was initiated. Compromised renal function is relatively frequent in patients with PNH. In the AEGIS Study, an indication study in Japan, as much as 66% of the patients studied were associated with abnormal renal function. Another study reports that 18% of Japanese patients with PNH died from renal failure (Nishimura et al. 2004). Furthermore, Japanese and global studies demonstrate improved renal function in 30–40% of all patients receiving prolonged eculizumab treatment (Kanakura et al. 2011; Hillmen et al. 2010). Therefore, eculizumab treatment could be effective for patients with PNH and compromised renal function.
In the present case, the LDH level immediately prior to treatment initiation was 1,491 U/L; it started decreasing soon after eculizumab treatment initiation, returning to normal (i.e., 234 U/L) 4 weeks later. Eculizumab protects red blood cells that lack CD55 or CD59 (also known as “PNH-type red blood cells”) from hemolysis, resulting in higher percentages of PNH-type red blood cells in patients with PNH (Hillmen et al. 2010). In fact, high percentages of PNH-type red blood cells were observed in the present patient after eculizumab treatment (54% and 47% of CD55(-) and CD59(-) cells, respectively). This suggests that PNH-type red blood cells survived and did not undergo hemolytic destruction.
In view of age-associated reduction in immune function and the effect of eculizumab on the suppression of the terminal complement pathway (i.e., C5 and subsequent components), one concern is that treatment with eculizumab may elevate the risk of infection in elderly patients (Naylor et al. 2005; Czesnikiewicz-Guzik et al. 2008). Indication studies of eculizumab have been performed globally including Japan. However, because of the nature of these studies, patients aged >80 years were rarely enrolled; the oldest patient enrolled in Japan was aged 70 years. The major adverse events observed in that study were headache (52%), nasopharyngitis (41%), nausea (21%), and diarrhea (13%); however, no infectious adverse events possibly associated with eculizumab treatment were reported (Hillmen et al. 2010). The present patient was diagnosed with PNH at the age of 81 years and began receiving eculizumab treatment at the age of 84 years. This is a rare case of an elderly patient treated with eculizumab. Moreover, the renal function of this patient improved from CKD stage 4 to stage 3 during eculizumab treatment.
Our experience with the present case indicates that even patients aged >80 years with compromised renal function can be safely treated with eculizumab. The findings of this case suggest that eculizumab treatment is effective and useful for improving renal function, facilitating weaning from blood transfusion, and alleviating PNH patients’ fear of experiencing a hemolytic attack.
Paroxysmal nocturnal hemoglobinuria
Red blood cell
White blood cell
Nuclear cell count
Estimated glomerular filtration rate
Chronic kidney disease.
- Czesnikiewicz-Guzik M, Lee WW, Cui D, Hiruma Y, Lamar DL, Yang ZZ, Ouslander JG, Weyand CM, Goronzy JJ: T cell subset-specific susceptibility to aging. Clin Immunol 2008, 127: 107-118. 10.1016/j.clim.2007.12.002View ArticleGoogle Scholar
- Davies A, Simmons DL, Hale G, Harrison RA, Tighe H, Lachmann PJ, Waldmann H: CD59, an LY-6-like protein expressed in human lymphoid cells, regulates the action of the complement membrane attack complex on homologous cells. J Exp Med 1989, 170: 637-654. 10.1084/jem.170.3.637View ArticleGoogle Scholar
- Hill A, Rother RP, Wang X, Morris SM Jr, 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. Br J Haematol 2010, 149: 414-425. 10.1111/j.1365-2141.2010.08096.xView ArticleGoogle Scholar
- Hillmen P, Lewis SM, Bessler M, Luzzatto L, Dacie JV: Natural history of paroxysmal nocturnal hemoglobinuria. N Engl J Med 1995, 333: 1253-1258. 10.1056/NEJM199511093331904View ArticleGoogle Scholar
- 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. 10.1182/blood-2007-06-095646View ArticleGoogle Scholar
- 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. Am J Hematol 2010, 85: 553-559. 10.1002/ajh.21757View ArticleGoogle Scholar
- Kanakura Y, Ohyashiki K, Shichishima T, Okamoto S, Ando K, Ninomiya H, Kawaguchi T, Nakao S, Nakakuma H, Nishimura J, Kinoshita T, Bedrosian CL, Valentine ME, Khursigara G, Ozawa K, Omine M: Safety and efficacy of the terminal complement inhibitor eculizumab in Japanese patients with paroxysmal nocturnal hemoglobinuria: the AEGIS clinical trial. Int J Hematol 2011, 93: 36-46. 10.1007/s12185-010-0748-9View ArticleGoogle Scholar
- Naylor K, Li G, Vallejo AN, Lee WW, Koetz K, Bryl E, Witkowski J, Fulbright J, Weyand CM, Goronzy JJ: The influence of age on T cell generation and TCR diversity. J Immunol 2005, 174: 7446-7452.View ArticleGoogle Scholar
- Nicholson-Weller A, Burge J, Austen KF: Purification from guinea pig erythrocyte stroma of a decay-accelerating factor for the classical c3 convertase, C4b,2a. J Immunol 1981, 127: 2035-2039.Google Scholar
- 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. 10.1097/01.md.0000126763.68170.46View ArticleGoogle Scholar
- Parker C, Omine M, Richards S, Nishimura J, Bessler M, Ware R, Hillmen P, Luzzatto L, Young N, Kinoshita T, Rosse W, Socié G: Diagnosis and management of paroxysmal nocturnal hemoglobinuria. Blood 2005, 106: 3699-3709. 10.1182/blood-2005-04-1717View ArticleGoogle Scholar
- 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. 10.1001/jama.293.13.1653View ArticleGoogle Scholar
- Sugita Y, Nakano Y, Tomita M: Isolation from human erythrocytes of a new membrane protein which inhibits the formation of complement transmembrane channels. J Biochem 1988, 104: 633-637.Google Scholar
- Takahashi M, Takeda J, Hirose S, Hyman R, Inoue N, Miyata T: Deficient biosynthesis of N -acetylglucosaminyl-phosphatidylinositol, the first intermediate of glycosyl phosphatidylinositol anchor biosynthesis, in cell lines established from patients with paroxysmal nocturnal hemoglobinuria. J Exp Med 1993, 177: 517-521. 10.1084/jem.177.2.517View ArticleGoogle Scholar
This article is published under license to BioMed Central Ltd. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.