Pathophysiology 7/18/2012 PAROXYSMAL NOCTURNAL HEMOGLOBINURIA

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1 PAROXYSMAL NOCTURNAL HEMOGLOBINURIA OUTLINE OF DISCUSSION WHAT IS IT WHO GETS IT NATURAL HISTORY TYPES RISKS COURSE TREATMENTS SYMPTOMS PREGNANCY Pathophysiology Acquired hematopoietic stem cell disorder in which somatic mutation of the X-linked PIGA gene results in partial or absolute deficiency of all proteins normally linked to the cell membrane by a glycophosphatidylinositol (GPI) anchor. 1

2 Clonal Expansion Inoue et al Blood 2006;4232; Murakami et al ASH 52th Meeting, Poster Abs# 4242; Kelly et al. Blood 2007;110: Abs #3671 GPI Structure 2

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4 The complement cascade regulation and erythrocytes Luzzatto, L. et al. Haematologica 2010;95: Classification of PNH Category Rate of Intravascular Hemolysis** Bone Marrow Flow Cytometry Benefit from Eculizumab Classic Florid (macroscopic Cellular marrow with hemoglobinuria is erythroid hyperplasia frequent or persistent) and normal or nearnormal morphology Large population (>50%) of GPI-AP deficient PMNs Yes PNH in the setting of Mild to moderate Evidence of a another bone marrow (macroscopic concomitant bone failure syndrome hemoglobinuria is marrow failure intermittent or absent) syndrome Although variable, the Dependent on the size percentage of GPI-AP of the PNH clone deficient PMNs is usually relatively small (<30%) Subclinical No clinical or Evidence of a biochemical evidence of concomitant bone intravascular hemolysis marrow failure syndrome Small (<1%) population No of GPI-AP deficient PMNs detected by highresolution flow cytometry * Based on recommendations of the Int'l PNH Interest Group4 ** Based on macroscopic hemoglobinuria, serum LDH concentration, and reticulocyte count Karyotypic abnormalities are uncommon. Aplastic anemia and refractory anemia/mds are the most commonly associated marrow failure syndromes. Analysis of PMNs is more informative than analysis of RBCs due to selective destruction GPI-AP deficient RBCs. Ask the Hematologist: How Do I Diagnose and Treat PNH? Charles Parker, MD ASH 2008 Diagnosis Parker et al Blood

5 HEMOLYSIS Diagnosis Parker et al Blood 2005 Bone Marrow Biopsy Aplastic Anemia 5

6 APLASTIC ANEMIA Diagnosis Parker et al Blood 2005 Bone Marrow Biopsy Myelodysplasia 6

7 MYELODYSPLASIA Diagnosis Parker et al Blood 2005 FIRST CVA AT AGE 44 7

8 Chronic Uncontrolled Complement Activation Leads to Devastating Consequences Normal red blood cells are Without this protective protected from complement attack complement inhibitor by a shield of terminal shield, PNH red blood cells complement inhibitors are destroyed Complement Activation Thrombosis Renal Failure Pulmonary Hypertension Abdominal Pain Dyspnea Significant Impact on Survival Dysphagia Intact RBC Free Hemoglobin/Anemia Fatigue Hemoglobinuria Significant Impact on Morbidity NO Erectile Dysfunction 1. International PNH Interest Group. Blood. 2005;106: Brodsky R. Paroxysmal Nocturnal Hemoglobinuria. In: Hematology - Basic Principles and Practices. 4th ed. R Hoffman; EJ Benz; S Shattil et al, eds. Philadelphia, PA: Elsevier Churchill Livingstone; 2005; Rother RP et al. JAMA. 2005;293: Socie G et al. Lancet. 1996;348: Hill A et al. Br J Haematol. 2007;137: Lee JW et al. Hematologica 2010;95(s2): Abstract #505 and Hill A et al. Br J Haematol. 2010; May;149(3): Hillmen P et al. Am J Hematol. 2010;85: Signs and Symptoms 8

9 Epidemiology 1-2 cases per million persons in the USA Male to female ration ~1:1 (secondary to lyonization) Survival 65% at 10 years and 48% at 15 years of diagnosis (newer effective treatments might increase survival) Highly variable course from indolent to life threatening Thrombosis associated with poor prognosis and leading cause of death in patients with PNH Parker CJ. Historical aspects of paroxysmal nocturnal haemoglobinuria: defining the disease. Br J Haematol. 2002;117:3-22. Nguyen JS, Case discussion NEJM (10):1048 Treatment Hemolysis: Transfusions, Iron, Folic acid, Steroids, Eculizumab. Thrombosis: Warfarin prophylaxis, thrombolysis, anticoagulation therapy, eculizumab. Bone Marrow Failure: Growth factors, Immunosuppresive therapy (ATG, Cyclosporine A), Bone Marrow Transplant. 9

10 Eculizumab - Soliris Overall survival of 79 patients from initiation of eculizumab treatment compared with an ageand sex-matched normal population. Kelly R J et al. Blood 2011;117: by American Society of Hematology 10

11 Conclusion PNH is characterized by chronic hemolysis, thrombosis, anemia, bone marrow failure, disabling fatigue, poor quality of life. X-linked mutation to the PIG-A gene. Clinical trials in patients with PNH Eculizumab has proven to be an effective treatment. Hemolysis can continue to occur after initiation of Eculizumab by effectors prior to induced block in the complement pathyway. Allo-SCT continues to be the only curative therapy. 11