Living with PNH 7/3/2013. Paroxysmal Nocturnal Hemoglobinuria (PNH): A Chronic, Systemic, and Life- Threatening Disease

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1 Living with PNH Laurence A. Boxer, MD University of Michigan Case Study 15 year old awakened in the morning with chest pain and a sore throat. She experienced chest pain all day accompanied with coughing up blood. CXR was negative in the ER but her CBC revealed a WBC of 3.2, HCT 32%, platelets 20,000, D-Dimers were elevated. PHX of abdominal pain for past 5 years, urinalysis was positive in the past for blood or hemoglobin. Lab Tests: Hemoglobinuria, PNH screen was positive on red cells 39%, flaer test on neutrophils and monocytes was 39%. Bone marrow biopsy revealed normal number of precursors. The diagnosis was PNH presenting with pancytopenia. Therapy: Solaris Paroxysmal Nocturnal Hemoglobinuria (PNH): A Chronic, Systemic, and Life- Threatening Disease What is PNH? PNH: What it s Not 1

2 The Defect in PNH The Role of Complement The Complement System: Always on, Strongly Amplified, Dependent on Natural Regulators Factors That Accelerate Complement Activation Testing for PNH in RBCs Patient 1: Normal RBCs with normal CD59 expression (Type I cells) Why Look Beyond RBCsfor PNH? Patient 2: PNH clone with complete CD59 deficiency (Type III cells) GPA = glycophorina. Gating on GPA+ RBCs Data Source: Dahl-Chase Diagnostic Services.. Patient 3: PNH clone with complete CD59 deficiency (Type III cells) and partial CD59 deficiency (Type II cells) 2

3 ICCS Recommendations for Follow-Up Testing of Patients With an Identified PNH Clone Importance of Monitoring Granulocytes and RBCs Over Time September 2008 December 2008 CD14-Granulocytes March 2009 May 2009 Gran clone: 3.8% RBC clone: 0.8% Gran clone: 7.6% RBC clone: 1.6% Gran clone: 14.2% RBC clone: 1.8% Gran clone: 23.3% RBC clone: 2.4% 3 Months 6 Months 9 Months PNH Clone Expanded in <1 Year Data Source: Dahl-Chase Diagnostic Services. Chronic Uncontrolled Complement Activation Thrombosis Leads to Devastating Consequences Renal Failure Incidence of PNH Clones in High-Risk Patient Populations Complement Activation Elevated LDH Pulmonary Hypertension Abdominal Pain Chest Pain Dyspnea Significant Impact on Survival Free Hemoglobin Decreased NO Dysphagia Fatigue Hemoglobinuria Significant Impact on Morbidity Erectile Dysfunction LDH = lactate dehydrogenase. 1. International PNH Interest Group. Blood 2005;106: ; 2. Brodsky R.Paroxysmal nocturnal hemoglobinuria. In: R Hoffman et al,eds. Hematology -Basic Principles and Practices. 4th ed. Philadelphia, PA: Elsevier Churchill Livingstone; 2005; ; 3. RotherRP et al.jama. 2005;293: ; 4. SocieG et al.lancet 1996;348: ; 5. Hill A et al. Br J Haematol2007;137: ; 6. Lee JW et al. Hematologica2010;95(s2): Abstracts 505 and 506; 7. Hill A et al. Br J Haematol 2010;149: ; 8. HillmenP et al. Am J Hematol2010;85: Standard Diagnostic Test for PNH Basic Evaluation for PNH Flow cytometric evidence of partial or complete absence of multiple glycosyl phosphatidylinositol - anchored proteins on red cells and granulocytes. CBC retic count, LDH, bilirubin, haptoglobin, iron stores, D-Dimers Marrow aspirate and biopsy, cytogenetics 3

4 Classification of PNH* Category Rate of intravascular Hemolysis Marrow Flow Cytometry Benefit from Eculizumab Classic Florid (macroscopic hemoglobin- Cellular marrow Large population Yes with erythroid (>50%) of uriais frequent or persistent) hyperplasia and normal or near- GPI-AP deficient PMNs** normal morphology PNH in Mild to moderate (macroscopic Evidence of a concomitant Although variable, the the the setting of Dependent on size another marrow hemoglobinuriais intermittent marrow failure syndrome^ percentage of GPI-AP of the PNH clone failure syndrome^ or absent) deficient PMNs is usually relatively small (<30%) Subclinical No clinical or biochemical Evidence of a concomitant Small (<1%) population of No evidence of intravascular hemolysis marrow failure syndrome GPI-AP deficient PMNs detected by high resolution flow cytometry Thrombosis Is the Leading Cause of Death in PNH 1 *Based on recommendations of the International PNH Interest Group (Blood106:3699, 2005) Parker CJ, Williams Hematology, 8th Edition, 2010, pg. 526 MultifactorialPathogenesis of Thrombosis in PNH Chronic Uncontrolled Complement Activation Leads to Vasoconstriction and Thrombosis Thrombosis Occurs in Both Typical and Atypical Sites* Hematopoietic Stem Cell Transplantation for PNH Indications for transplantation Marrow failure- approach to management depends primarily on the underlying marrow abnormality (e.g., aplastic anemia) but the treatment regimen must be sufficient to eradicate the PNH clone Major complications of PNH Refractory, transfusion-dependent hemolytic anemia Recurrent, life-threatening thromboembolic complications Outcomes There are no PNH-specific adverse events. Severe, acute graft-versus host disease occurs in approximately 33% of patients and the incidence of chronic graft-versus host disease is roughly 35% Overall survival for unselected PNH patients who undergo transplantation using an HLA-matched sibling donor is in the range of 50-60% Parker, CJ, Williams Hematology, 8th Edition, 2010, pg

5 Soliris: Humanized, First-in-Class, Anti- C5 Antibody Human Framework Regions No mutations Germline SolirisBlocks Terminal Complement 1,2 Complement Cascade 2,3 Soliris Human IgG 2 Heavy Chain Constant Region 1 and Hinge (eliminates Fc receptor binding) Hinge CH2 CH3 Complementarity Determining Regions (murine origin) Human IgG 4 Heavy Chain Constant Regions 2 and 3 (eliminates complement activation) Proximal Terminal C3 C3b C5 C5b C3a C5a C5b-9 Soliris binds with high affinity to C5 1,2 Terminal complement - C5a and C5b-9 formation blocked 1,2 Proximal functions of complement remain intact 1,2 Weak anaphylatoxin 2,4 Immune complex clearance 2 Microbial opsonization 2 Please see full prescribing information for Soliris (eculizumab). RotherR et al. Nat Biotech2007;25:1256. Please see full prescribing information for Soliris (eculizumab). 1. Soliris (eculizumab) [package insert]. AlexionPharmaceuticals; Revised 03/ Rother RP et al. Nature Biotech. 2007;25(11): Walport MJ. N Engl J Med. 2001;344(14): Figueroa JE, Densen P. Clin Microbiol Rev. 1991;4(3): % Reduction in LDH Sustained Over Entire Course of 36 Month Treatment Period Summary of Clinical Efficacy Immunosuppressive Therapy (IST) Has Increased Efficacy in AA Patients With PNH Cells Key labs and tests involved in management Flow cytometry Annual bone marrow CBC, retic count LDH, D-Dimers Bilirubin, creatinine 5

6 Self Management Patient Safety Information Card Folic acid and oral iron for ongoing hemolysis Carry identity card Vaccinate against meningococcus 6