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      Low-dose prednisolone in patients with paroxysmal nocturnal hemoglobinuria and inadequate response to eculizumab

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          TO THE EDITOR: Corticosteroids have been widely used in patients with paroxysmal nocturnal hemoglobinuria (PNH), based on the notion that administration may ameliorate hemolysis. However, there is no strong evidence of clinical benefit in the inhibition of complement-mediated hemolysis associated with corticosteroids. The short-term use of prednisolone (Pd) may be beneficial in some situations, but long-term use is generally not recommended because of concerns regarding complications [1 2]. Eculizumab is a humanized monoclonal antibody that blocks terminal complement by binding to C5. This antibody is a standard therapeutic modality for PNH and has altered the natural history of the disease [3 4]. A subpopulation of patients placed on eculizumab, however, still require red blood cell (RBC) transfusion [5], and standard salvage therapies for these patients have yet to be determined. We retrospectively analyzed the therapeutic effects of low-dose Pd in patients with PNH who show inadequate responses to eculizumab treatment. Seven patients were treated with eculizumab between February 2012 and April 2016 at Chungnam National University Hospital. All patients were men and the median duration of the disease was 19.1 years (range, 5.1–24.5 yr). At the time of analysis, all patients were still taking eculizumab, and the median duration of eculizumab treatment was 36.3 months (range, 6.9–39.1 mo). After 6 months of eculizumab treatment, all patients showed improvement of anemia and hemolysis. Four (57.1%) patients showed an optimal response, one (14.2%) showed a major response and 2 (28.5%) showed a partial response, according to a modification of a previously reported stratification [6 7]. During the first 12 months of eculizumab treatment, 4 patients no longer required RBC transfusion; however, 3 patients continued to require transfusion, although the transfusion requirements were reduced. Low-dose Pd (5 mg/day) was additionally administered to these 3 patients. Of the 3 patients requiring transfusion, patient 1 was previously diagnosed with aplastic anemia (AA) and patient 2 had concurrent chronic kidney disease. At the time of initiation of low-dose Pd therapy, the hemoglobin (Hb) levels were 8.9, 8.9, and 8.3 g/dL, respectively, and the lactate dehydrogenase (LDH) levels were 418, 655, and 1,069 IU/L, respectively, in these 3 patients. The direct Coombs test was positive in all 3 patients, and the CH50 levels after 6 months of eculizumab treatment were 4.4 U/mL, <2.0 U/mL, and 20.9 U/mL, respectively (<2.0 U/mL, 10.3 U/mL, 5.4 U/mL, and 5.2 U/mL, respectively, in patients with optimal response). Low-dose Pd (5 mg/day) was administered to these 3 patients, and the Hb levels gradually increased over 12 months. The LDH levels were maintained or modestly decreased. Patient 3 experienced 2 infection episodes (upper respiratory infection with fever and tenosynovitis of the right wrist). Decreases in the Hb level and increases in the LDH level were observed during each event. During the 12 months of additional low-dose Pd therapy, the requirements for RBC transfusion in these 3 patients were modestly decreased. While a total of 26 packs of RBC transfusion were needed before Pd therapy, only 10 packs were needed after 12 months, indicating that low-dose Pd induced a favorable effect of about 60% reduction in RBC transfusion requirements (Table 1). There were no severe adverse events related to low-dose Pd therapy. Patient 1 experienced a mild upper respiratory infection after 1 month of Pd, and this spontaneously resolved. As mentioned above, patient 3 experienced 2 mild infections that were manageable with oral antibiotics. In the present analysis, 3 of 7 patients required RBC transfusion, even after long-term eculizumab treatment. Inadequate hematologic benefit in some patients may be related to complement protein C3. Because eculizumab inhibits the terminal complement cascade and has no effect on proximal components, C3 and its fragments accumulate on RBCs in PNH patients. This phenomenon leads to destruction of RBCs in the spleen and liver. As a result, extravascular hemolysis is increased and might result in dependence on RBC transfusion [7]. Considering such a mechanism, corticosteroids and splenectomy may be a treatment option for patients demonstrating enhanced extravascular hemolysis following eculizumab therapy [7 8]. Bone marrow function affects erythropoiesis and thus the outcome of eculizumab treatment. A red cell production index (RPI) >2.5 in anemia suggests sufficient erythropoiesis. In a previous report, patients with low RPI did not respond well to eculizumab [6]. Interestingly, Peffault de Latour et al. reported that CH50 activity is a simple biomarker related to intravascular hemolysis and circulating free eculizumab levels. In this study, low CH50 activity (CH50 ≤10% of normal) was significantly associated with low LDH levels. Furthermore, low circulating free eculizumab correlated with CH50 >10% and the need for transfusions [9]. In the present analysis, patient 3 showed a low (1.1) RPI and a very high (1,069 IU/L) LDH level at the time of initiation of Pd therapy. Furthermore, the patient showed a slightly higher level of CH50 compared with other patients. Considering these findings, this patient might have had components of both ineffective erythropoiesis and extravascular hemolysis. After 12 months of Pd therapy, the level of CH50 decreased from 20.9 to 6.7 U/mL, and both the need for RBC transfusion and the LDH level also decreased. Patient No. 1 had AA prior to the diagnosis of PNH, and thus defective bone marrow function might have led, at least in part, to the inadequate response to eculizumab. Patient 2 showed a serum erythropoietin (EPO) level of 56.8 mIU/mL (reference range, 3.7–31.5 mIU/mL), just above the normal range, suggesting the presence of an inadequate EPO response to anemia since EPO levels tend to be very high in PNH patients [10]. Taken together, factors other than enhanced extravascular hemolysis appeared to have a role in these 3 patients. These results indicates that low-dose Pd might be helpful in patients who continue to be dependent on RBC transfusion despite long-term eculizumab, although its mechanisms of action remain unclear. There has been little information on the use of corticosteroid therapy to control extravascular hemolysis occurring after eculizumab treatment. Furthermore, the results of the small series conducted to date have not been consistent. Berzuini et al. [11] reported that prednisolone at an initial dose of 75 mg per day led to satisfactory results in one patient. In contrast, Risitano et al. [12] reported unsatisfactory results in 14 patients. Notably, long-term use of high-dose corticosteroid is always accompanied by concerns related to its well-known complications. That is the reason why we used low-dose Pd in this study. The results of the current study suggest that low-dose Pd might be helpful in patients who remain dependent on RBC transfusion despite long-term eculizumab treatment. In summary, we suggest that low-dose Pd reduces red cell transfusion requirements in some PNH patients with inadequate response to eculizumab. However, the long-term efficacy and adverse effects of the low-dose Pd treatment need to be determined.

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          Most cited references 9

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          Complement fraction 3 binding on erythrocytes as additional mechanism of disease in paroxysmal nocturnal hemoglobinuria patients treated by eculizumab.

          In paroxysmal nocturnal hemoglobinuria (PNH) hemolytic anemia is due mainly to deficiency of the complement regulator CD59 on the surface of red blood cells (RBCs). Eculizumab, an antibody that targets complement fraction 5 (C5), has proven highly effective in abolishing complement-mediated intravascular hemolysis in PNH; however, the hematologic benefit varies considerably among patients. In the aim to understand the basis for this variable response, we have investigated by flow cytometry the binding of complement fraction 3 (C3) on RBCs from PNH patients before and during eculizumab treatment. There was no evidence of C3 on RBCs of untreated PNH patients; by contrast, in all patients on eculizumab (n = 41) a substantial fraction of RBCs had C3 bound on their surface, and this was entirely restricted to RBCs with the PNH phenotype (CD59(-)). The proportion of C3(+) RBCs correlated significantly with the reticulocyte count and with the hematologic response to eculizumab. In 3 patients in whom (51)Cr labeling of RBCs was carried out while on eculizumab, we have demonstrated reduced RBC half-life in vivo, with excess (51)Cr uptake in spleen and in liver. Binding of C3 by PNH RBCs may constitute an additional disease mechanism in PNH, strongly enhanced by eculizumab treatment and producing a variable degree of extravascular hemolysis.
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            How I treat paroxysmal nocturnal hemoglobinuria.

             R Brodsky (2009)
            Paroxysmal nocturnal hemoglobinuria (PNH) is a rare clonal blood disorder that manifests with hemolytic anemia, bone marrow failure, and thrombosis. Many of the clinical manifestations of the disease result from complement-mediated intravascular hemolysis. Allogeneic bone marrow transplantation is the only curative therapy for PNH. Eculizumab, a monoclonal antibody that blocks terminal complement activation, is highly effective in reducing hemolysis, improving quality of life, and reducing the risk for thrombosis in PNH patients. Insights into the relevance of detecting PNH cells in PNH and other bone marrow failure disorders are highlighted, and indications for treating PNH patients with bone marrow transplantation and eculizumab are explored.
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              Assessing complement blockade in patients with paroxysmal nocturnal hemoglobinuria receiving eculizumab.

              Paroxysmal nocturnal hemoglobinuria (PNH) is characterized by intravascular hemolysis, which is effectively controlled with eculizumab, a humanized monoclonal antibody that binds complement protein 5 (C5). The residual functional activity of C5 can be screened using a 50% hemolytic complement (CH50) assay, which is sensitive to the reduction, absence, and/or inactivity of any components of the classical and terminal complement pathway. Little data exist on complement blockade during treatment. From 2010 to 2012, clinical data, hemolysis biomarkers, complement assessment, and free eculizumab circulating levels were systematically measured immediately before every injection given to 22 patients with hemolytic PNH while receiving eculizumab therapy. During the study, 6 patients received ≥1 red blood cell transfusion. Lack of detectable CH50 activity (defined by CH50 ≤ 10% of normal values) was found in 184 samples (51%) and was significantly associated with lower lactate dehydrogenase levels (P = .002). Low levels of circulating free eculizumab ( 10%; P = .004), elevated bilirubin levels (P < .0001), and the need for transfusions (P = .034). This study suggests that both CH50 activity and circulating free eculizumab levels may help physicians to manage PNH patients receiving eculizumab.

                Author and article information

                Blood Res
                Blood Res
                Blood research
                Korean Society of Hematology; Korean Society of Blood and Marrow Transplantation; Korean Society of Pediatric Hematology-Oncology; Korean Society on Thrombosis and Hemostasis
                December 2017
                26 December 2017
                : 52
                : 4
                : 337-339
                Department of Internal Medicine, Chungnam National University Hospital, Daejeon, Korea.
                Author notes
                Correspondence to Deog-Yeon Jo. Department of Internal Medicine, Chungnam National University Hospital, 282 Munhwa-ro, Jung-gu, Daejeon 35015, Korea. deogyeon@ 123456cnu.ac.kr
                © 2017 Korean Society of Hematology

                This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License ( http://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

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