Treatment and prognosis of paroxysmal nocturnal hemoglobinuria
- Robert A Brodsky, MD
Robert A Brodsky, MD
- Professor of Medicine and Oncology
- Johns Hopkins University
Therapy for paroxysmal nocturnal hemoglobinuria (PNH) is evolving rapidly, spurred by the availability of biologic therapies that target the underlying hemolytic defect or the abnormal hematopoietic stem cell. However, many questions remain regarding when to initiate these costly therapies and how to balance therapy for symptoms of hemolysis with therapy for bone marrow failure.
This topic review will discuss the treatment and prognosis of PNH. The pathogenesis, clinical manifestations, and diagnosis of PNH are presented separately. (See "Pathogenesis of paroxysmal nocturnal hemoglobinuria" and "Clinical manifestations and diagnosis of paroxysmal nocturnal hemoglobinuria".)
INITIAL EVALUATION AND MONITORING
Baseline evaluations of the newly diagnosed patient — A newly-diagnosed patient may already have laboratory results available that show the degree of hemolysis and the size of the PNH clone. We review all available records to confirm the diagnosis and the presence or absence of an additional bone marrow disorder such as aplastic anemia (AA) or myelodysplastic syndrome (MDS). (See "Clinical manifestations and diagnosis of paroxysmal nocturnal hemoglobinuria", section on 'Diagnostic evaluation'.)
If not obtained as part of the initial diagnostic evaluation, all patients should have baseline testing that includes a complete blood count (CBC) with differential, reticulocyte count, lactate dehydrogenase (LDH), biochemical profile, and flow cytometry for PNH. We also obtain iron studies (serum iron, total iron binding capacity, and ferritin) and a D-dimer level.
Patients with significant pancytopenia and suspected AA or MDS should have an examination of a bone marrow aspirate and biopsy, including cytogenetic studies, a fluorescence in situ hybridization panel for MDS, a quantitative CD34 cell count, and an iron stain. (See "Aplastic anemia: Pathogenesis; clinical manifestations; and diagnosis", section on 'Bone marrow examination' and "Clinical manifestations and diagnosis of the myelodysplastic syndromes", section on 'Bone marrow aspirate and biopsy'.)
- Brodsky RA. How I treat paroxysmal nocturnal hemoglobinuria. Blood 2009; 113:6522.
- Brodsky RA. Paroxysmal nocturnal hemoglobinuria. Blood 2014; 124:2804.
- Ray JG, Burows RF, Ginsberg JS, Burrows EA. Paroxysmal nocturnal hemoglobinuria and the risk of venous thrombosis: review and recommendations for management of the pregnant and nonpregnant patient. Haemostasis 2000; 30:103.
- Emadi A, Brodsky RA. Successful discontinuation of anticoagulation following eculizumab administration in paroxysmal nocturnal hemoglobinuria. Am J Hematol 2009; 84:699.
- DeZern AE, Dorr D, Brodsky RA. Predictors of hemoglobin response to eculizumab therapy in paroxysmal nocturnal hemoglobinuria. Eur J Haematol 2013; 90:16.
- Parker C. Eculizumab for paroxysmal nocturnal haemoglobinuria. Lancet 2009; 373:759.
- Lindorfer MA, Pawluczkowycz AW, Peek EM, et al. A novel approach to preventing the hemolysis of paroxysmal nocturnal hemoglobinuria: both complement-mediated cytolysis and C3 deposition are blocked by a monoclonal antibody specific for the alternative pathway of complement. Blood 2010; 115:2283.
- Hill A, Rother RP, Arnold L, et al. Eculizumab prevents intravascular hemolysis in patients with paroxysmal nocturnal hemoglobinuria and unmasks low-level extravascular hemolysis occurring through C3 opsonization. Haematologica 2010; 95:567.
- Risitano AM, Notaro R, Marando L, et al. Complement fraction 3 binding on erythrocytes as additional mechanism of disease in paroxysmal nocturnal hemoglobinuria patients treated by eculizumab. Blood 2009; 113:4094.
- Peffault de Latour R, Fremeaux-Bacchi V, Porcher R, et al. Assessing complement blockade in patients with paroxysmal nocturnal hemoglobinuria receiving eculizumab. Blood 2015; 125:775.
- Röth A, Hock C, Konik A, et al. Chronic treatment of paroxysmal nocturnal hemoglobinuria patients with eculizumab: safety, efficacy, and unexpected laboratory phenomena. Int J Hematol 2011; 93:704.
- Hillmen P, Young NS, Schubert J, et al. The complement inhibitor eculizumab in paroxysmal nocturnal hemoglobinuria. N Engl J Med 2006; 355:1233.
- Brodsky RA, Young NS, Antonioli E, et al. Multicenter phase 3 study of the complement inhibitor eculizumab for the treatment of patients with paroxysmal nocturnal hemoglobinuria. Blood 2008; 111:1840.
- Hillmen P, Muus P, Röth A, et al. Long-term safety and efficacy of sustained eculizumab treatment in patients with paroxysmal nocturnal haemoglobinuria. Br J Haematol 2013; 162:62.
- Martí-Carvajal AJ, Anand V, Cardona AF, Solà I. Eculizumab for treating patients with paroxysmal nocturnal hemoglobinuria. Cochrane Database Syst Rev 2014; 10:CD010340.
- Hillmen P, Muus P, Dührsen U, et al. Effect of the complement inhibitor eculizumab on thromboembolism in patients with paroxysmal nocturnal hemoglobinuria. Blood 2007; 110:4123.
- Nishimura J, Yamamoto M, Hayashi S, et al. Genetic variants in C5 and poor response to eculizumab. N Engl J Med 2014; 370:632.
- Rondelli T, Risitano AM, Peffault de Latour R, et al. Polymorphism of the complement receptor 1 gene correlates with the hematologic response to eculizumab in patients with paroxysmal nocturnal hemoglobinuria. Haematologica 2014; 99:262.
- http://soliris.net/sites/default/files/assets/soliris_pi.pdf (Accessed on August 07, 2014).
- DeZern AE, Uknis M, Yuan X, et al. Complement blockade with a C1 esterase inhibitor in paroxysmal nocturnal hemoglobinuria. Exp Hematol 2014; 42:857.
- Risitano AM. Anti-Complement Treatment in Paroxysmal Nocturnal Hemoglobinuria: Where we Stand and Where we are Going. Transl Med UniSa 2014; 8:43.
- Risitano AM, Ricklin D, Huang Y, et al. Peptide inhibitors of C3 activation as a novel strategy of complement inhibition for the treatment of paroxysmal nocturnal hemoglobinuria. Blood 2014; 123:2094.
- Hill A, Ridley SH, Esser D, et al. Protection of erythrocytes from human complement-mediated lysis by membrane-targeted recombinant soluble CD59: a new approach to PNH therapy. Blood 2006; 107:2131.
- Ricklin D, Lambris JD. Complement-targeted therapeutics. Nat Biotechnol 2007; 25:1265.
- Peffault de Latour R, Schrezenmeier H, Bacigalupo A, et al. Allogeneic stem cell transplantation in paroxysmal nocturnal hemoglobinuria. Haematologica 2012; 97:1666.
- Saso R, Marsh J, Cevreska L, et al. Bone marrow transplants for paroxysmal nocturnal haemoglobinuria. Br J Haematol 1999; 104:392.
- Pantin J, Tian X, Geller N, et al. Long-term outcome of fludarabine-based reduced-intensity allogeneic hematopoietic cell transplantation for debilitating paroxysmal nocturnal hemoglobinuria. Biol Blood Marrow Transplant 2014; 20:1435.
- Taniguchi K, Okada M, Yoshihara S, et al. Strategy for bone marrow transplantation in eculizumab-treated paroxysmal nocturnal hemoglobinuria. Int J Hematol 2011; 94:403.
- Matos-Fernandez NA, Abou Mourad YR, Caceres W, Kharfan-Dabaja MA. Current status of allogeneic hematopoietic stem cell transplantation for paroxysmal nocturnal hemoglobinuria. Biol Blood Marrow Transplant 2009; 15:656.
- Brodsky RA, Luznik L, Bolaños-Meade J, et al. Reduced intensity HLA-haploidentical BMT with post transplantation cyclophosphamide in nonmalignant hematologic diseases. Bone Marrow Transplant 2008; 42:523.
- Srinivasan R, Takahashi Y, McCoy JP, et al. Overcoming graft rejection in heavily transfused and allo-immunised patients with bone marrow failure syndromes using fludarabine-based haematopoietic cell transplantation. Br J Haematol 2006; 133:305.
- Tian H, Liu L, Chen J, et al. Haploidentical hematopoietic stem cell transplant in paroxysmal nocturnal hemoglobinuria. Leuk Lymphoma 2016; 57:835.
- Reiss UM, Schwartz J, Sakamoto KM, et al. Efficacy and safety of eculizumab in children and adolescents with paroxysmal nocturnal hemoglobinuria. Pediatr Blood Cancer 2014; 61:1544.
- Danilov AV, Brodsky RA, Craigo S, et al. Managing a pregnant patient with paroxysmal nocturnal hemoglobinuria in the era of eculizumab. Leuk Res 2010; 34:566.
- Kelly RJ, Höchsmann B, Szer J, et al. Eculizumab in Pregnant Patients with Paroxysmal Nocturnal Hemoglobinuria. N Engl J Med 2015; 373:1032.
- Kelly R, Arnold L, Richards S, et al. The management of pregnancy in paroxysmal nocturnal haemoglobinuria on long term eculizumab. Br J Haematol 2010; 149:446.
- Marasca R, Coluccio V, Santachiara R, et al. Pregnancy in PNH: another eculizumab baby. Br J Haematol 2010; 150:707.
- Tichelli A, Socié G, Marsh J, et al. Outcome of pregnancy and disease course among women with aplastic anemia treated with immunosuppression. Ann Intern Med 2002; 137:164.
- de Guibert S, Peffault de Latour R, Varoqueaux N, et al. Paroxysmal nocturnal hemoglobinuria and pregnancy before the eculizumab era: the French experience. Haematologica 2011; 96:1276.
- Bjørge L, Ernst P, Haram KO. Paroxysmal nocturnal hemoglobinuria in pregnancy. Acta Obstet Gynecol Scand 2003; 82:1067.
- Kelly RJ, Hill A, Arnold LM, et al. Long-term treatment with eculizumab in paroxysmal nocturnal hemoglobinuria: sustained efficacy and improved survival. Blood 2011; 117:6786.
- Nishimura J, Kanakura Y, Ware RE, et al. Clinical course and flow cytometric analysis of paroxysmal nocturnal hemoglobinuria in the United States and Japan. Medicine (Baltimore) 2004; 83:193.
- Socié G, Mary JY, de Gramont A, et al. Paroxysmal nocturnal haemoglobinuria: long-term follow-up and prognostic factors. French Society of Haematology. Lancet 1996; 348:573.
- INITIAL EVALUATION AND MONITORING
- Baseline evaluations of the newly diagnosed patient
- Monitoring of the established patient
- OVERVIEW OF APPROACH TO THERAPY
- PAIN FROM SMOOTH MUSCLE DYSTONIA
- Evaluation for thrombosis
- Management of thrombosis
- Prevention of thrombosis
- ANTI-COMPLEMENT THERAPY
- Indications for anti-complement therapy
- Available anticomplement therapies
- - Eculizumab
- Toxicities and cost
- Anti-complement therapies in development
- HEMATOPOIETIC CELL TRANSPLANTATION
- Conditioning regimen and stem cell product
- SPECIAL POPULATIONS
- Oral contraceptives
- SUMMARY AND RECOMMENDATIONS