9/19/2012. Case study. Case study PNH: A REVIEW AND AN UPDATE

Transcription

1 PNH: A REVIEW AND AN UPDATE Jamile M. Shammo MD, FASCP, FACP Associate Professor of Medicine and Pathology Rush University Medical Center Chicago Case study A 37 year old man was referred to the hematology clinic for evaluation and management of MDS He had anemia for 7 years, and was treated with iron supplements, epo, and had a bone marrow biopsy eventually which showed low risk MDS, and absent iron stores. he had been evaluated for hematuria and was evaluated by a urologist who performed 2 cystoscopies, which were not revealing Case study At the time of his clinic visit, he complained of fatigue, and episodes of back pain He also described episodes of dark urine His iron studies were consistent with iron deficiency anemia A flow cytometry of the peripheral blood was sent for RBC/Granulocytes testing to detect a possible PNH clone. 1

2 Proximal Terminal Patients Surviving (%) 9/19/2012 Paroxysmal Nocturnal Hemoglobinuria: A Chronic Disabling and Life-Threatening Disease PNH is an acquired disorder of the hematopoietic stem cell Estimated 4,000 6,000 patients in U.S.1 5 year mortality: 35% Actuarial Survival From the Time of Diagnosis in 80 Patients With PNH2 Age- and Gender- Matched Controls Diagnosed at all Ages Median age early 30 s 20 Patients with PNH The expected survival of an age- and sex-matched control group is shown for comparison (Hillmen et al 1995). In a patient population where ½ the patients have <30% clone, 1 in 7 patients died by 5 years. de Latour et al. Blood. 2008; 112: Years After Diagnosis 1. Hill A et al. Blood. 2006;108(11): 290a. Abstract Hillmen P et al. N Engl J Med. 1995;333: Nishimura JI, et al. Medicine. 2004;83: Socié G et al. Lancet. 1996;348: Hill A et al. Br J Haematol. 2007;137: The Defect in PNH The Somatic Mutation of the X-chromosome PIG A Gene Prevents All GPI Anchored Proteins from Binding to Cell Surface CD59 Forms a defensive shield for RBCs from complement-mediated lysis Inhibits the assembly of the membrane attack complex CD55 Prevents formation and augments instability of the C3 convertases, attenuating the complement cascade CD59 GPI-anchor CD55 1. Adapted from: Johnson RJ et al. J Clin Pathol: Mol Pathol. 2002;55: 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; Overview of Complement Complement Cascade C3 C3b C3a C5 C5b C5a Membrane Attack C5b-9 Cause Complex of Hemolysis Cause in of PNH Hemolysis in PNH 2

3 Multimeric C9 Lesions on PNH Erythrocyte Membrane 7 Classification of PNH 1. Classical PNH: Manifests with florid intravascular hemolysis and episodes of visible hemoglobinuria. 2. PNH in the setting of another BM failure state: This entity is characterized by mild hemolysis and a small clone size 3. Subclinical PNH: With <1% clone, and no clinical or biochemical evidence of intravascular hemolysis PNH Clonal Expansion in an AA Representative Population n = 75 At the start of follow up PNH+ Patients At the last of follow up Transitional pattern n (%) (Classic PNH) (8) (11%) Expansion 13 (17%) Persistent 44 (59%) Newly developed 5 (4%) n = 114 Disappearance 18 (24%) PNH- Patients 109 (96%) Sugimori C et al. BJH. 2009; 147: AdBoard Master_Sept 14,

4 Peripheral Blood Abnormalities at Presentation Anemia alone Anemia and Thrombocytopenia Anemia and Neutropenia Pancytopenia % De Latour RP et al. Blood 2008;112: Paroxysmal Nocturnal Hemoglobinuria Clinical manifestations Hemolytic anemia paroxysmal Even in the absence of symptoms, destructive progression of hemolysis is ongoing nocturnal Hemolysis in PNH is subtle and constant, 24 hours a day Hemoglobinuria is a less commonly seen complication ¾ patients present without hemoglobinuria 1 Bone marrow failure/pancytopenia Thrombophilia/ Propensity for clots 1. International PNH Interest Group. Blood. 2005;106: Factors Determining Hemolysis Proportion of abnormal cells Abnormality type III vs type II Activation of complement 4

5 Definition of PNH type RBCs Type I cells Normal RBC s with normal CD59 expression Circulating survival: days 1,2 Type III cells PNH clone with complete CD59 deficiency Circulating survival: 20 days 1,2 Type II cells PNH clone with complete deficiency (Type III cells) and partial CD59 deficiency Circulating survival: 45 days 1,2 1. Rosse WR Reviews in Molecular Medicine 1997; 76: Rosse WF Blood 1971; 37:556 Things That Activate Complement in Vivo Tick-over spontaneous activation Alternative pathway Chronic hemolysis Exposure to endotoxin from GI tract leads to increased risk of massive hemolysis Other infections, surgery, trauma, pregnancy Mastellos D et al. Immunologic Res. 2003; 3: ; Mergenhagen STE et al. J of Inf Dis. 1973; 128:S86. Chenoweth DE et al. N Engl J Med. 1981; 304: Girardi G. Am J Reprod Immunol. 2008; 59: Chronic Kidney Disease Common Symptoms of PNH Common Symptoms in Patients With PNH PNH Symptom Incidence Rate (%) 41% Dysphagia1 47% Pulmonary Hypertension2 66% Dyspnea1 57% Abdominal Pain1 64% Chronic Renal Insufficiency3 47% Erectile dysfunction1 26% Hemoglobinuria4 40% 5 89% Anemia6 96% Fatigue, Impaired QoL1 1. Meyers G et al. Blood. 2007;110(11):Abstract Hill A et al. Br. J. Hematol. 2010;149(3): Hillmen P et al. Am. J. Hematol. 2010; 85: International PNH Interest Group. Blood. 2005;106(12): Hillmen P et al. N Engl J Med. 1995;333: Nishimura J et al. Medicine. 2004;83(3):

6 PNH and Hemolysis Normal red blood cells are protected from complement attack by a shield of terminal complement inhibitors Without this protective complement inhibitor shield, PNH red blood cells are destroyed Complement Activation Intact RBC Reduced Red Cell Mass Free Hemoglobin Anemia 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: Consequences of Chronic Hemolysis and Free Hemoglobin Normal red blood cells are protected from complement attack by a shield of terminal complement inhibitors Without this protective complement inhibitor shield, PNH red blood cells are destroyed Renal Failure Pulmonary Hypertension Significant Impact on Survival Complement Activation Abdominal Pain Dyspnea Dysphagia Intact RBC Free Hgb/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: Chronic Kidney Disease in PNH: Common Symptoms of PNH 40% of patients experience clinical thrombotic events 1 Leading cause of death 2 Accounts for 40-67% of deaths 1 First thrombotic event can be fatal 1,3 Median time to TE was years from diagnosis 4 First TE increases risk for death 5- to 10-fold 1 1. Hillmen et al. Blood. 2007;110: International PNH Group et al. Blood. 2005;106(12): Audebert HJ et al. J Neurol. 2005;252: De Latour. Blood. 2008;112:

7 Chronic Kidney Disease Common Symptoms of PNH Common Sites of Occur Frequently in PNH TE Type Hillmen P et al (N=80) Hillmen P et al (N=195) DVT or PE 33% 40% CVA/MI 16% 15% Typical VTE most common VTE in PNH Atypical VTE more common in PNH than in the general population 3 Higher proportion of PE and/or DVT sites of thrombosis consistently found in PNH patients Socie et al (29%)4 and Nishimura and Rosse (27%)5 1. Hillmen P et al. N Engl J Med. 1995;333: Hillmen P et al. Blood. 2007; 100: Fowkes FJI et al. Eur J Vasc Endovasc Surg. 2003;25: Socie G et al. Lancet. 1996;348: Nishimura J et al. Medicine. 2004;83(3): Chronic Kidney Disease Common Symptoms of PNH Clinical Symptoms Predictive of TE South Korean National Registry. Lee JW et al. Hematologica (s2):Abstract #505 and 506. Chronic Kidney Disease Common Symptoms of PNH Potential Assessments to Identify Risk in PNH Baseline Platelet Count Proportion with History of TE 1 Thrombocytopenic <100,000 X 10 9 /L 45% Non-Thrombocytopenic 100,000 X 10 9 /L 27% Patients with thrombocytopenia have elevated incidence of TE 1 Evidence of platelet consumption in PNH 1,2 Platelet consumption may result from microthrombi 1,3 D-dimer and other markers of elevated inflammatory response 3,4 61% and 82% of PNH patients in French and US studies demonstrated an elevated risk for TE as indicated by increased D-dimer levels Chronic terminal complement activation leads to systemic inflammatory and hypercoagulable state in PNH 1. Socie G et al. Blood. 2009;114:Abstract Hill A et al. Br J Haematol. 2007;137: Weitz I et al. Research. 2010;125:S Helley D et al. Hematologica.2010;95(4):

8 Chronic Kidney Disease Common Symptoms of PNH Kidney Pathology in PNH Chronic hemolysis and cell-free plasma hemoglobin lead to chronic kidney disease in PNH 1-4 Repetitive exposure of tissue to cell-free hemoglobin may lead to renal damage in PNH 3,4 80% of PNH patients (median age of 31.5 years) had MRI evidence of significant renal hemosiderosis 1,5 Marked hemosiderin deposits in the proximal renal tubule are a common feature in all autopsy and biopsy reports dealing with PNH Demonstrable by MRI even when no overt hemoglobinuria is seen Autopsy and biopsy often show interstitial nephritis and fibrosis 3,4 1. Brodsky R. Hematology: Basic Principles and Practice. Churchill Livingstone; 2005: Rother R et al. JAMA. 2005;293: Clark DA et al. Blood. 1981;Jan;57(1): Hillmen P et al. Am. J. Hematol. 2010; 85: Hill A et al. Blood. 2006;108:Abstract 979. Chronic Kidney Disease Common Symptoms of PNH 64% of Patients Exhibit Clinical Chronic Kidney Disease (CKD) 59% of patients with minimal (0-1) transfusion history had CKD (n=22) Hillmen P et al. Am. J. Hematol. 2010;85: Chronic Kidney Disease Common Symptoms of PNH Impact of PNH on Quality of Life ~75% of Patients Reported Symptoms as Moderate to Very Severe 59% patients were transfusion-free for at least 12 mo or had never been transfused 76% were forced to modify their daily activities to manage their PNH 17% were unemployed due to PNH *Moderate to severe; N=29. Meyers G et al. Blood. 2007;110 (11): Abstract

9 Two Independent International Groups Recommend Testing High Risk Patient for PNH Guidelines for the diagnosis and monitoring of paroxysmal nocturnal hemoglobinuria and related disorders by flow cytometry Michael J. Borowitz *, Fiona E. Craig, Joseph A. DiGiuseppe, Andrea J. Illingworth, Wendell Rosse, D. Robert Sutherland, Carl T. Wittwer, Stephen J. Richards, On behalf of the Clinical Cytometry Society Borowitz MJ et al. International Clinical Cytometry Society. Part B Clin Cytometry. 2010;78B: ; International PNH Interest Group. Blood. 2005;106(12): Standard Diagnostic Test for PNH Flow cytometry performed on peripheral blood Granulocytes and at least one additional cell line should be evaluated Red blood cells (RBCs) Monocytes Quantitative results Optimal-High sensitivity analysis: 0.01% Routine analysis: 1% Easy to understand PNH reports Use more than one reagent against GPI-anchored proteins Borowitz MJ et al. for International Clinical Cytometry Society. Part B Clin Cytometry. 2010;78B: Testing for PNH in Red Blood Cells Normal RBC s with normal CD59 expression (Type I cells) PNH clone with complete CD59 deficiency (Type III cells) Gating on GPA+ RBC s PNH clone with complete CD59 deficiency (Type III cells) and partial CD59 deficiency (Type II cells) GPA = glycophorin A. Data Source - Dahl-Chase Diagnostic Services. 9

10 CD24- Granulocytes 9/19/2012 Testing for PNH: RBC s and Granulocytes WBC RBC FLAER- GPI Anchor Binding Marker CD59 GPI Anchored Protein 80.1 % of Granulocytes lack GPI proteins 31.4% RBCs are Type III PNH cells Data Source - Dahl-Chase Diagnostic Services. Historical Management of PNH Transfusions Risk of iron overload Transient treatment of anemia Anticoagulants Risk of hemorrhage Ineffective in many patients 2 Red cell supplements ESAs may expand clones and elevate hemolysis Folic acid, iron, erythropoiesis-stimulating agents Steroids/androgen hormones No controlled clinical trials AE s ESA = erythropoietin stimulating agents. 1. International PNH Interest Group. Blood. 2005;106: Hillmen P et al. Blood. 2007;110: PNH Bone Marrow Transplant - BMT is the only potentially curative therapy for PNH 1, - Indications for transplant include 1. uncontrollable hemolysis 2.thrombosis 3. Bone marrow failure state There is considerable morbidity and mortality associated with BMT for PNH. Patient selection and timing of transplant are important variables in making the decision. 1. Santarone S et al. Haematologica. 2010;Jun;95(6): De Latour PF et al. Abstract #316. EBMT Bieri S et al. Bone Marrow Transplantation. 2008; Fraser CJ et al. Blood. 2006;108: Brodsky RA. Blood. 2009;113:

11 August 12_10_2010Gbl 9/19/2012 PNH Bone Marrow Transplant In a recent retrospective study in France examining PNH patients 2 54% had GVHD In another study examining PNH patients (n=23) 1 50% chronic GVHD; 42% acute GVHD BMT has a significant impact on quality of life post transplant 3,4 Allogeneic BMT recommended for PNH patients with lifethreatening cytopenias or possibly the rare patient with disabling hemolysis or thrombosis not controlled with existing therapy 5 1. Santarone S et al. Haematologica. 2010;Jun;95(6): De Latour PF et al. Abstract #316. EBMT Bieri S et al. Bone Marrow Transplantation. 2008; Fraser CJ et al. Blood. 2006;108: Brodsky RA. Blood. 2009;113: BMT In PNH Study Year Pub (N) Age Median (range) Study Population Mortality GVHD Cause of Death Risk of Death or GVHD Santarone S et al PNH patients; 23 42% ov erall n=10 of 20 ev aluable N=11: infections n=4, agvhd n=1, Hematologica + EBMT (20-59) HLA matched patients (50%) cgvhd cgvhd n=2, multiorgan failure [34% at 6 mo abstract (22 identical n=2, EBV lymphoma n=1 (from abstract)] N=11 agvhd (42%) sib), 3 unmatched At least 42% De Latour et al. EBMT, Abstract # N=83 (54%) 31% treated v s. (23-38) BMF; 17% controls at N=69 (45%) PNH 5 years N=100 (54%) N=53 deaths 28 from infections 13 from GVHD At least 31% Ruggeri et al. EBMT, Abstract #O SAA 7 PNH 53% 2 years (projected) 28 +/- 6% agvhd N=14 of 44 at risk (32%) cgvhd NA At least ~28% de Latour et al. Blood % (n=22) NA NA 42% (death) de Latour et al. ASH abstract N=75 (54%) ~30% at 5 yrs vs. (23-36) BMF; 32.2% at 10 N=62 (45%)PNH years for controls (n=401; ) n=45 (32%) cgvhd N=39 (28%) Main causes: n=35 (25%) agvhd Infection (n=19) Gv HD (n=9) Hemorrhage (n=4) At least 25% Witherspoon et al (19-42) Hemolytic PNH 43% < 6 months 50% N=6: GVHD n=2, infections n=2, other n=2 At least 43% 9 20 (14-38) Non-Hemolytic PNH 33% 44% N=3: infections n=2, other n=1 At least 33% Parker PNH Patients 44% (10 yr) NA NA 44% (death) Hegenbart et al Hemolytic PNH; (25-49) 2 BMF 43% n=5 (71%) n=3: Infection n=1; GVHD n=1; Organ failure n=1 At least 43% Saso et al (10-47) 32% SAA 44% at 2 yr n=16 (34%) agvhd 19/48 (40%) died in HLA identical 21d engraftment; cohort n=13/39 cgvhd with Gv HD (n=3) 90d engraftment At least 33% Considerations for Managing the PNH/AA Patient PNH PNH with hemolysis PNH Intermediate + hemolysis AA/PNH Moderate AA with hemolysis Moderate AA without hemolysis Severe AA without hemolysis Eculizumab? Prophylactic Anticoagulaion IST BMT De Latour RP, Amoura Z, and Socie G. La revue de medecine interne. 2010;

12 Proximal Terminal 9/19/2012 Eculizumab ( Soliris) Complement Cascade SOLIRIS C3 C3b C3a SOLIRIS binds with high affinity to C5 Terminal complement - C5a and C5b-9 activity blocked C5 C5b C5a C5b-9 Cause of Hemolysis in PNH Proximal functions of complement remain intact Weak anaphylatoxin Immune complex clearance Microbial opsonization 1. Figueroa JE, Densen P. Clin Microbiol Rev. 1991;4(3): Walport MJ. N Engl J Med. 2001;344(14): SOLIRIS (eculizumab) [package insert]. Alexion Pharmaceuticals; Rother RP et al. Nature Biotech. 2007;25(11): Eculizumab Clinical Trials in PNH Pilot Study NEJM N = 11 Primary endpoint: reduction of hemolysis TRIUMPH NEJM Pivotal Phase III, Double-Blind, Placebo-Controlled Trial, N = 87 SHEPHERD Blood Broader patient population, including those receiving minimal transfusions or with thrombocytopenia, N = 97 Long-Term Extension Trial Hillmen Blood Evaluated long-term safety, efficacy and effect on thrombosis; Placebo patients switched to SOLIRIS N = 187 Dosing Schedule Pretreatment Induction Phase Maintenance Phase 2 weeks before induction Week and every 2 weeks thereafter Neisseria meningitidis vaccination SOLIRIS dose, mg X 900 X 900 In clinical trials all patients received a meningococcal vaccination SOLIRIS should be administered via IV infusion over 35 minutes every 7 days during induction and every 14 days during maintenance SOLIRIS dose adjustment to every 12 days may be necessary for some patients to maintain LDH reduction Concomitant medications allowed Steroids, immunosuppressant drugs, anti-clotting agents and hematinics 1 SOLIRIS (eculizumab) [package insert]. Alexion Pharmaceuticals; Hillmen P et al. N Engl J Med. 2004;350(6):

13 Lactate Dehydrogenase (U/L) Standard Effect Size (SES) Median Units Transfused Cognitive* Pain* Insomnia* Constipation Nausea Diarrhea 9/19/2012 TRIUMPH and SHEPHERD: Response TRIUMPH Placebo/Extension TRIUMPH SOLIRIS /Extension SHEPHERD SOLIRIS % response after the first dose Time, Weeks TRIUMPH placebo patients switched to SOLIRIS after week 26. All TRIUMPH patients entered the long-term extension study. P<0.001 at all measured time points. Hillmen P et al. Blood. 2007;110(12): % Reduction in Mean Units Transfused Across all Subgroups: TRIUMPH Patients not on SOLIRIS (n=44) SOLIRIS (n=43) * * (n=87) (n=30) (n=35) (n=22) Overall >25 Pre-treatment Transfusion Strata * * 51% of SOLIRIS patients achieved transfusion independence vs 0% of patients not on SOLIRIS 1 Patients with concomitant bone marrow dysfunction may continue to require minimal transfusions *P< Transfusion data obtained during 12 months before treatment; values were normalized for a 6-month period. 1. Hillmen P et al. N Engl J Med. 2006;355; Schubert J. Br. J Haematol. 2008;142(2): Patients Report Rapid and Sustained Improvement Across Broad Range of 1.2 Measures Large Impact Moderate Impact Small Impact *P<0.05. P< FACIT-Fatigue EORTC Fatigue Global Health Physical Role Dyspnea EORTC Functioning EORTC Symptoms 1. Brodsky R et al. Blood. 2006;108(11): Abstract Data on file. Alexion Pharmaceuticals. 13

14 Proportion of Patients (%) Thrombotic Events (#) 9/19/2012 Eculizumab therapy and Thrombotic Events Pre-SOLIRIS Treatment N=195 P= SOLIRIS Treatment 63% of patients received concomitant anticoagulants 1 The effect of anticoagulant withdrawal was not studied 2 Events observed in both venous and arterial sites 3 PI: There were fewer thrombotic events with SOLIRIS treatment than during the same period of time prior to treatment. 1. Brodsky R et al. Blood. 2008;111(4): SOLIRIS (eculizumab) [package insert]. Alexion Pharmaceuticals; Hillmen P, et al. Blood. 2007;110: Chronic Kidney Disease Common Symptoms of PNH Renal Function change with eculizumab At 6 Months P< P< P= Overall (n=189) Stage 1 2 (n=81) Stage 3-5 (n=40) Segment of PNH Population No Change Improvement Worsening Hillmen P et al. Am. J. Hematol. 2010; 85: Eculizumab has a Major Impact on Survival in PNH Survival is comparable to age and sex matched control population 96% (76/79) patient survival. There was no difference in mortality between patients on eculizumab and the normal population (P=0.46) 2 patients over 70 years of age had worse survival (P=0.0042). No patients under the age of 50 years died Kelly R et al. Blood. 2010;116(21) Abstract #

15 Warning WARNING: SERIOUS MENINGOCOCCAL INFECTION SOLIRIS increases the risk of meningococcal infections. Meningococcal infection may become rapidly lifethreatening or fatal if not recognized and treated early. Vaccinate patients with a meningococcal vaccine at least 2 weeks prior to receiving the first dose of SOLIRIS Revaccinate according to current medical guidelines for vaccine use Monitor patients for early signs of meningococcal infections, evaluate immediately if infection is suspected, and treat with antibiotics if necessary SOLIRIS (eculizumab) [package insert]. Alexion Pharmaceuticals; Safety: Warnings and Precautions The effect of withdrawal of anticoagulant therapy during SOLIRIS treatment has not been established. Therefore, treatment with SOLIRIS should not alter anticoagulant management Patients who discontinue SOLIRIS must be monitored closely for signs of serious hemolysis If serious hemolysis occurs after SOLIRIS discontinuation, consider the following procedures/treatments: blood transfusion (packed RBCs), or exchange transfusion if the PNH RBCs are >50% of the total RBCs by flow cytometry; anticoagulation; corticosteroids; or reinstitution of SOLIRIS In clinical trials, 16 of 196 PNH patients discontinued SOLIRIS treatment; no serious hemolysis was observed SOLIRIS (eculizumab) [package insert]. Alexion Pharmaceuticals; Serious Adverse Events: Clinical Trial Experience Meningococcal infections are the most important adverse events that may be experienced by patients receiving SOLIRIS In clinical studies, 2 out of 196 patients developed serious meningococcal infections while receiving treatment with SOLIRIS Both patients had been vaccinated In clinical studies among non-pnh patients, meningococcal meningitis occurred in one patient, who was unvaccinated In post-marketing experience, cases of serious or fatal meningococcal infections have been reported SOLIRIS (eculizumab) [package insert]. Alexion Pharmaceuticals;

16 Adverse Reactions Reported in 5% of SOLIRIS Treated Patients in TRIUMPH Reaction SOLIRIS (n=43) Patients, n (%) Placebo (n=44) Headache 19 (44) 12 (27) Nasopharyngitis 10 (23) 8 (18) Back pain 8 (19) 4 (9) Nausea 7 (16) 5 (11) Fatigue 5 (12) 1 (2) Cough 5 (12) 4 (9) Herpes simplex virus infections 3 (7) 0 Sinusitis 3 (7) 0 Respiratory tract infection 3 (7) 1 (2) Constipation 3 (7) 2 (5) Myalgia 3 (7) 1 (2) Pain in extremity 3 (7) 1 (2) Influenza-like illness 2 (5) 1 (2) SOLIRIS (eculizumab) [package insert]. Alexion Pharmaceuticals; Patient Safety Card Patients should be informed that they will be provided with a Patient Safety Card Patients should carry the card with them at all times The card describes symptoms, which if experienced, should prompt the patient to seek immediate medical attention Instruct patients to show the card to all health care providers involved in their care SOLIRIS (eculizumab) [package insert]. Alexion Pharmaceuticals; PNH Registry Overview The PNH Registry is an ongoing global, observational, non-interventional study collecting safety, effectiveness, clinical characteristic and quality of life data on patients with PNH irrespective of clone size or treatment. The PNH Registry has been established in order to describe the real world outcomes of PNH, capturing a wide range of patients from all over the world. 16

17 PNH Registry Data Collection Physician-Reported Data Data collected at study enrollment and every six months thereafter Data entry minimally includes: demographics, medical history, PNH diagnosis, flow cytometry results, symptoms, and clinical outcomes All necessary information can be gathered from patient medical records Patient Reported Outcomes Patients complete questionnaires at study enrollment and every six months thereafter EORTC QLQ-30* FACIT-F-fatigue scale* Overall health status Symptom frequency and bother Healthcare utilization Work Status *validated quality-of-life instruments in other disease states PNH Registry: Future Research Topics PNH and Thrombotic Events PNH and Renal Dysfunction PNH in the Pediatric Setting Association of Clinical & Patient Characteristics with PNH Treatment Evolution of PNH Clones Survival / Mortality Correlation of PNH with Laboratory Markers PNH: Conclusions PNH is a rare and life threatening disease Delays in diagnosis range from 1 to more than 10 years 1 high-risk patients should be identified and tested for PNH 2 Reliable testing and reporting procedures matter 2 Granulocyte analysis in all cases PNH testing on RBCs alone is not adequate Adding quantitative results to report forms is essential With the advent of treatment options for PNH, there is a compelling reason to identify patients 3 1. Hillmen P et al. N Engl J Med. 1995;333: Borowitz MJ et al. for International Clinical Cytometry Society. Part B Clin Cytometry. 2010;78B: Brodsky R et al. Blood. 2008;111(4):

18 PNH: CONCLUSIONS The commercial availability of Eculizumab has certainly made a positive impact on patients quality of life, and survival Bone marrow transplantation is the only curative modality for bone marrow failure states. Other therapeutic options for PNH are being currently evaluated in clinical trials (TT30) 18