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Advances in Paroxysmal Nocturnal Hemoglobinuria (PNH)

Advances in Paroxysmal Nocturnal Hemoglobinuria (PNH). Bart Scott, MD Assistant Professor of Medicine, Division of Oncology, University of Washington Director of Hematology and Hematologic Malignancies, Seattle Cancer Care Alliance Seattle, WA.

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Advances in Paroxysmal Nocturnal Hemoglobinuria (PNH)

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  1. Advances in Paroxysmal Nocturnal Hemoglobinuria (PNH)

    Bart Scott, MD Assistant Professor of Medicine, Division of Oncology, University of Washington Director of Hematology and Hematologic Malignancies, Seattle Cancer Care AllianceSeattle, WA
  2. Actuarial Survival From the Time ofDiagnosis in 80 Patients With PNH2 100 80 Age- and Gender-Matched Controls 60 Patients Surviving (%) 40 Patients With PNH 20 0 0 5 10 15 20 25 Years After Diagnosis Paroxysmal Nocturnal Hemoglobinuria (PNH):A Chronic, Systemic, and Life-Threatening Disease Prevalence: 15.9 / million1 Diagnosed at all ages Median age early 30s3,4 Progressive disease2–4 Uncontrolled complement activation underlies the morbidities and mortality Despite best supportive care 5 year mortality: 35%2 The expected survival of an age- and gender-matched control group is shown for comparison (Hillmen et al. 1995) 1. Hill A et al. Blood 2006;108:290a. Abstract 985;2. Hillmen P et al.N Engl J Med 1995;333:1253–1258;3. Nishimura JI et al.Medicine 2004;83:193–207; 4. Socié G et al. Lancet 1996;348:573–577.
  3. What is PNH? PNH is a disease of chronic complement-mediated hemolysis characterized by a somatic (acquired) mutation of the PIG-A gene in which blood cells lack key, naturally occurring terminal complement inhibitors (e.g. CD55 and CD59) on cell surfaces1-4 This mutation results in a deletion of GPI anchors, rendering proteins unable to attach to the surface of the cell PNH is a progressive and destructive disease that leads to: Thrombosis5 End-organ damage1,6 Increased mortality1,7 1. Brodsky R. Paroxysmal nocturnal hemoglobinuria. In: R Hoffman et al., eds. Hematology - Basic Principles and Practices. 4th ed. Philadelphia, PA: Elsevier Churchill Livingstone 2005;419–427; 2. Rosse WF et al.Hematology (Am SocHematolEduc Program) 2004:48–62; 3. Wiedmer T et al.Blood 1993;82:1192–1196; 4. Rother RP et al.JAMA 2005;293:1653–1662; 5. Hillmen P et al. Blood 2007;110:4123–4128; 6. Hillmen P et al.Am J Hematol 2010;85:553–559; 7. Hillmen P et al.N Engl J Med 1995;333:1253–1258.
  4. PNH: What it’s Not It is not paroxysmal1 Even in the absence of symptoms, destructive progression of hemolysis is ongoing It is not nocturnal1 Hemolysis in PNH is subtle and constant, 24 hours a day Hemoglobinuria is a less commonly seen complication ¾ patients present without hemoglobinuria2 1. RotherR et al. Nature Biotechnology 2007;25,11:1256–1264; 2. International PNH Interest Group. Blood. 2005;106:3699–3709.
  5. The Defect in PNH PNH clones are defined as PNH cells with a deficiency of proteins that require a GPI anchor for attachment to the cell membrane1 CD59 (MIRL) Forms a defensive shield for red blood cells (RBCs) from complement-mediated lysis Inhibits the assembly of the membrane attack complex CD55 (DAF) Prevents formation and augments instability of the C3 convertases, attenuating the complement cascade CD59 CD55 GPI-anchor GPI = glycerophosphatidylinositol. 1. Borowitz MJ et al.Cytometry B ClinCytom 2010;78:211–230. Adapted from: Johnson RJ et al. J ClinPathol: Mol Pathol 2002;55:145–152;Brodsky R. Paroxysmal nocturnal hemoglobinuria. In: R Hoffman et al, eds. Hematology - Basic Principles and Practices. 4th ed. Philadelphia, PA: Elsevier Churchill Livingstone; 2005;419–427.

  6. Autoreactive T Cells from Patients with PNH Specifically RecognizeGlycosyl-Phosphatidyl-Inositol (GPI)

    Abstract 647 Gargiulo et al
  7. PIG-A Etn-P GlcN glycan nucleus PIG-A Inositol-P X chr. GPI anchor + GPI protein ER Paroxysmal Nocturnal Hemoglobinuria Pathogenesis PIG-A PIG-A nucleus GPI anchor X chr. protein ER Normal cell PNH cell Hematopoietic Stem Cells
  8. Intravascular Hemolysis Absence of complement regulators Thrombosis Absence of complement regulators Bone Marrow Failure and cytopenia Mechanism? PNH Triad
  9. crippled PIG-A+ cells Noxious agent Parodoxical Expansion of PNH Clone(Escape Theory) Time PIG-A+ cells PIG-A null cells Rotoli & Luzzatto, 1989
  10. Evidence for a role of autoimmunity in PNH PNH is closely related to aplastic anemia – a T-cell-mediated autoimmune disorder: T cells are the likely agents suppressing normal hematopoiesis in PNH. The target of T cells could be either a GPI-linked protein or GPI itself. GPIhas been found within the presentation groove of CD1d(Joyce et al. Science 1998; De Silva et al.J Immunol. 2002) Identical or quasi-identical TCRβ CDR3 sequences found in CD8+CD57+ T cells in a group of HLA- disparate PNH patientssuggesting antigen not HLA -restricted(Gargiulo et al. Blood 2005) CD1d is expressed on human and murine hematopoietic stem and progenitor cells(Kotsianidis et al. Blood 2006; Broxmeyer et al. Blood 2012)
  11. Hypothesis: GPI-specific, CD1d-restricted T cells responsible for selection of PNH cells T cell T cell T cell receptor No Killing Killing GPI CD1d/b2m GPI-anchored protein GPI+ GPI- Karadimitris and Luzzatto, Leukemia 2001
  12. *p=0,0355 C1R C1R- CD1d with GPI addition 6 PNH Patients CD1d-dependent GPI-specific T cells in PNH *Wilcokson Rank Test
  13. Normal Controls PNH Patients Increased frequency of novel invariant TCRVa21 mRNA chain within the whole TCRVa21 family repertoire of PNH patients
  14. Summary CD1d-restricted GPI-specific CD8+ T cells are present and expanded in PNH patients. T cells with a novel invariant TCRa chain have been discovered in some PNH patients. These T cells could be the “noxious agent” responsible for the pathogenesis of PNH.
  15. GPI-specific, CD1d-restricted T cells are present in PNH patients and could be the responsible of the suppression of GPI+ HSC. T cell T cell No Killing T cell receptor Killing GPI CD1d/b2m GPI-anchored protein GPI+ GPI- Future work: further structural and functional characterization
  16. Expansion of the PNH Clone Is Necessary to Result in Clinical PNH Step 1 Somatic Mutation of PIG-A Step 2 Immunologic Attack Selective Damage Step 3 Growth Advantage Expansion may be due to another somatic mutation The need for both selection and expansion may explain the rarity of PNH Selected Cells Expanded Cells GPI-Deficient Cell Normal HematopoieticStem Cells GPI-Anchor Deficiency Immunologic Selection Benign Tumor- Like Expansion Adapted from: Inoue N et al.Int J Hematol2003;77:107.

  17. The Role of Complement

  18. The Complement System: Always on, Strongly Amplified, Dependent on Natural Regulators The complement system is a vital component of the natural (innate) protective immune system1 Complement is activated by three mechanisms (classical, alternative, and lectin) which allow the system to respond to inflammatory, infectious, ischemic, necrotic, as well as foreign and self antigens Always ‘on’ to allow rapid immune response1 Rapid amplification leads to powerful and destructive immune reactions2 Natural inhibitors of complement keep amplification in check and prevent uncontrolled complement activation2 1. Holers VM et al. ImmunolRev 2008;223:300–316; 2. Zipfel PF et al.CurrOpinNephrolHypertens2010;4:372–378.
  19. Factors That Amplify Complement Activation Glovsky MM et al.Ann Allergy Asthma Immunol2004;93:513–523; Rubio MT et al.Bone Marrow Transplant 2008;41(Suppl. 1):S220. Abstract P766; Mastellos D et al. Immunologic Res 2003;3:367–385; Mergenhagen STE et al. J Infect Dis 1973;128:S86; Chenoweth DE et al.N Engl J Med 1981;304:497–503; Giradi G. Am J ReprodImmunol2008;59:183–192.
  20. Chronic Uncontrolled Complement ActivationLeads to Devastating Consequences in PNH Lectin pathway Classical pathway Alternative pathway Immune complex clearanceMicrobial Opsonization C3 C3 + H2O: always active (chronic) Proximal Amplification Weak anaphylatoxin C3a Natural inhibitor: CD59 - Natural inhibitors: CD55 - C3b iC3b C5-convertase C5 Terminal C5b C6 C7 C8 C9 C5a Potent anaphylatoxin Chemotaxis Pro-inflammatory Leucocyte activation Endothelial activation Pro-thrombotic C5b-9Membrane attack complex Cell lysis Pro-inflammatory Platelet activation Leucocyte activation Endothelial activation Pro-thrombotic Anaphylaxis Inflammation Thrombosis Cell destruction Inflammation Thrombosis Consequences Consequences 1. Zipfel PF et al. Vaccine. 2008;26(Suppl 8):I67-74; 2. Figueroa JE, Densen P. ClinMicrobiolRev. 1991;4:359-95; 3. Walport MJ. N Engl J Med. 2001;344:1058-66; 4. Rother RP et al. Nat Biotechnol. 2007;25:1256-64; 5. Meyers G et al. Blood. 2007;110:abs 3683; 6. Hill A et al. Br J Haematol. 2010;149:414-25; 7. Hillmen P et al. Am J Hematol. 2010;85:553-9; 8. Parker C et al. Blood.2005;106:3699-709; 9. Hillmen P et al. N Engl J Med. 1995;333:1253-8; 10. Nishimura J et al. Medicine (Baltimore). 2004;83:193-207; 11. Caprioli J et al. Blood. 2006;108:1267-79; 12. Noris M et al. Clin J Am Soc Nephrol. 2010;5:1844-59; 13. George JN. Blood. 2010;116:4060-9; 14. Loirat C et al. PediatrNephrol. 2008;23:1957-72; 15. Ståhl AL et al. Blood. 2008;111:5307-15; 16. Hosler GA et al. Arch Pathol Lab Med. 2003;127;834-9; 17. Ariceta G et al. PediatrNephrol.2009;24:687-96.
  21. AdBoard Master_Sept 14, 2010 Absence of CD59 Allows Terminal Complement Complex Formation C5a C8 C6 C6 C6 C6 C6 C5 CD59 CD59 C7 C7 C7 C7 C7 C5b C5b C5b C5b C5b C9 C9 x 12 - 15 C8 X X C5 convertase C5 convertase C9 C8 C8 C5b-9 C5b,6,7 C5b-8 Adapted from: Cellular and Molecular Immunology AK Abbas, AH Litchman and JS Pober, 3rd Edition. 1991 WB Saunders; Philadelphia.
  22. Chronic Uncontrolled Complement Activation Leads to Tissue and End Organ Damage Strict regulation is needed to avoid unnecessary damage to self due to overt or mistargeted activation1,2 Tight control needed especially for the alternative pathway which is continuously turned on Membrane Attack Complex (MAC) on PNH Erythrocyte Photo: W Rosse. Reprinted with Permission. Endothelial Cells Damaged by Complement Attack Photo: S. Meri, Univ. of Helsinki. Reprinted with Permission. 1. HolersVM et al. ImmunolRev 2008;223:300–316; 2. ZipfelPF et al. CurrOpinNephrolHypertens 2010;4:372–378.
  23. Historically Viewed as a Hemolytic Anemia Normal red blood cells (RBCs) are protected from complement attack by a shield of terminal complement inhibitors Without this protective complement inhibitor shield, PNH RBCs are destroyed ComplementActivation Lack of Bound CD55, CD59 Leads to Uncontrolled Complement Activation Intact RBC Reduced Red Cell Mass Anemia Free Hemoglobin 1. International PNH Interest Group. Blood 2005;106:3699–3709. 2. Brodsky R Paroxysmal Nocturnal Hemoglobinuria. In: Hematology - Basic Principles and Practices. 4th ed. R Hoffman; EJ Benz; S Shattilet al.eds. Philadelphia, PA: Elsevier Churchill Livingstone;2005;419–427. 3.Rother RP et al.JAMA 2005;293:1653–1662. 4. Socie G et al. Lancet 1996;348:573–577. 5. Hill A et al.Br J Haematol 2007;137:181–192.
  24. Hemolysis Leads to NO Consumption in PNH Patients R=0.5094, P<0.001 R=0.9529, P<0.0001 NO consumption assay: NO chemiluminescence 100 100 Plasma Free Hb (µmol/l) Plasma Free Hb (µmol/l) 10 10 1 1 1 100 10 1000 10000 LDH (u/l) NO Consumption (µmol/l) LDH significantly correlates with free hemoglobin (Hgb)1 Confirms LDH as a biomarker for hemolysis LDH ≥1.5x at diagnosis had a 4.8-fold greater mortality2 Free Hgb significantly correlates with NO consumption Hgb is in reduced state and reactive with NO 1. Hill A et al. Br J Haematol 2010;149:414–425; 2. Lee JW et al. ASH 2011. Abstract 3166.
  25. Consequences of Nitric Oxide (NO) Depletion Reduced Nitric Oxide Can Cause Smooth muscle dystonias1 Vascular constriction – pulmonary and systemic hypertension, erectile dysfunction2 Gastrointestinal contractions – dysphagia, abdominal pain Platelet activation and aggregation1–4 Platelet hyperreactivity Hypercoagulability 1. Rother R et al. JAMA 2005;293:1653–1662; 2. Hill A et al.Br J Haematol 2010;149:414–425; 3. Weitz I. Thrombosis Res 2010;125:S106–S107; 4. Helley D et al.Haematologica2010;95:574–581.
  26. Chronic Uncontrolled Complement Activation Leads to Devastating Consequences Thrombosis Renal Failure Significant Impact on Survival Pulmonary Hypertension Abdominal Pain ComplementActivation Chest Pain Dyspnea Elevated LDH Dysphagia Free Hemoglobin Significant Impact on Morbidity Fatigue Decreased NO Hemoglobinuria Erectile Dysfunction LDH = lactate dehydrogenase. 1. International PNH Interest Group. Blood 2005;106:3699–3709; 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;419–427; 3. Rother RP et al.JAMA. 2005;293:1653–1662; 4. Socie G et al.Lancet 1996;348:573–577; 5. Hill A et al. Br J Haematol 2007;137:181–192; 6. Lee JW et al.Hematologica2010;95(s2): Abstracts 505 and 506; 7. Hill A et al.Br J Haematol 2010;149:414–425;8. Hillmen P et al.Am J Hematol 2010;85:553–559.
  27. Historical Management of PNH Supportive care options do not impact progression and risk for severe morbidities and mortality1 Transfusions1 – risk of iron overload Anticoagulants1 – ineffective in many patients Red cell supplements1 – may expand clone and elevate hemolysis Steroids/androgen hormones1 – adverse events Although BMT is the only potentially curative therapy for PNH, BMT is associated with significant morbidities and mortality2,3 In a study examining PNH patients (n=23)2 50% chronic GVHD; 42% acute GVHD3 Transplant-related mortality was 42% BMT has a significant impact on quality of life (QoL) post-transplant4,5 1. International PNH Interest Group. Blood 2005;106:3699–3709; 2. Santaraone S et al. Haematologica2010;95:983–988; 3. de Latour PF et al.EBMT 2009:Abstract 316; 4. Bieri S et al.Bone Marow Transplant 2008;42:819–827; 5. Fraser CJ et al. Blood 2006;108:2867–2873.

  28. Morbidities and Mortality in PNH

  29. Thrombosis Thrombosis Is the Leading Cause of Death in PNH1 Accounts for 40–67% of deaths2 First thrombotic event (TE) can be fatal2,3 First TE increases risk for death 5- to 10-fold2 Up to 44% of patients experience clinical thrombotic events2 Occurs in typical and atypical sites4 Is not adequately managed with anticoagulation2 All patients with PNH are at risk for thrombosis2 1. International PNH Group et al.Blood 2005;106:3699–3709; 2. Hillmenet al. Blood 2007;110:4123–4128; 3. AudebertHJ et al.J Neurol 2005;252:1379–1386; 4. Lee JW et al.Hematologica2010;95(s2): Abstract 506.
  30. Thrombosis Multifactorial Pathogenesis of Thrombosis in PNH Pathogenesis of thrombosis in PNH is a result of uncontrolled complement activation1 Activation of complement C5b–9 Hemolysis leads to reduced nitric oxide levels and vasoconstriction2–4 Platelets undergo morphological changes, release microparticles, and aggregate2,4 Activation of complement C5a Leukocytes release tissue factor and inflammatory cytokines (IL-6) to initiate coagulation2,3,5 Leukocytes decrease expression of plasminogen activator receptor (PAR) leading to impaired fibrinolysis4 1. McKeage K. Drugs 2011;71:2327–2345; 2. Hill A et al.Br J Haematol 2007;137:181–192; 3. Weitz I. Thrombosis Res 2010;125:S106–S107; 4. Helley D et al.Hematologica.2010;95:574–581; 5. Markiewski MM et al.Trends Immunol 2007;28:184–192.
  31. Thrombosis Chronic Uncontrolled Complement Activation Leads to Vasoconstriction and Thrombosis Impaired regulation of smooth muscles Local vasoconstriction Pro-inflammatory effect on endothelial cells Chronic hemolysis Platelet activation Local vasoconstriction Chronic Hemolysis Chronic UncontrolledComplementActivation [NO] C5b-9 C5b-9 C5a CLOT Inflammation Endothelial cell injury Systemic thrombosis Platelet Activation Inflammation Platelet Aggregation Leukocyte Activation Adapted from: Gladwin MT et al.Free Rad Biol & Med 2004;36:707–717; Rother RP et al. JAMA 2005;293:1653–1662.
  32. Thrombosis The Incidence of TE is Increased in Patients with Elevated LDH at Diagnosis P<0.001 Univariate analysis showed that the incidence of TE was significantly increased in patients with LDH ≥1.5x ULN at diagnosis (43/171; 25.1%) compared with patients with LDH <1.5x ULN (2/53; 3.8%; OR 8.57) Data from South Korean National Registry. Lee JW et al. Presented at the 54th Annual Meeting of the American Society of Hematology; December 8–11, 2012; Atlanta, GA. Abstract 1273.
  33. Thrombosis Risk of First Ever Ischemic Stroke (FEIS) Elevated in PNH Age of FEIS in PNH patients is markedly less than in the general population1 2,3 1 2,3 1 1. Gostynski M et al.J Neurol 2006;253:86–91; 2.Hillmen P et al. Blood 2007;110:4123–4281; 3. Data on file. Alexion Pharmaceuticals, Inc.
  34. Thrombosis Thrombosis is Associated With Risk of Early Mortality TE increases risk of death 15-fold over patients with no TE TE was an independent prognostic factor related to poor survival (HR 15.4; 95% CI 9.3–25.4; P<0.001) in a large cohort of French PNH patients (n=415) de Latour RP et al.Blood 2008;112:3099–3106.
  35. Thrombosis HillmenP et al.Blood 2007;110:4123–4128. Thrombosis Occurs in Both Typical and Atypical Sites* Myocardial Infarction/ unstable angina ARTERIAL Superficial vein thrombosis Cerebrovascular accident/ transient ischemic attack Cerebral/internal jugular thrombosis Pulmonary embolus Deep vein thrombosis* Hepatic/portal vein thrombosis VENOUS Mesenteric/splenic vein thrombosis *124 events, 63 patients *Includes 18.5% lower extremity and 14.5% other (inferior vena cava, bilateral lower extremity, pelvic, ureter, axillary, subclavian, and brachiocephalic veins).
  36. Thrombosis PNH Patients are at Risk of Thrombosis Despite Anticoagulation or Minimal Transfusion Requirements (n=91) (n=22) HillmenP et al. Blood 2007;110:4123–4128.
  37. Thrombosis Thrombosis Can Occur Regardless of Clone Size (n=43) Data from South Korean National Registry. Lee JW et al.Hematologica 2010;95(s2): Abstract 505.
  38. Thrombosis Thrombosis in PNH Conclusions 40–67% mortality in PNH results from thrombosis1 Thrombosis is the leading cause of death in PNH2 First TE increases risk for death 5- to 10-fold1 LDH 1.5× ULN at diagnosis is associated with TE and mortality3 DVT or PE most common clinical presentation1 Arterial thromboses are also common1 Anticoagulant therapy may not be adequate to control thrombosis in PNH1 Clinical thrombosis evident in PNH patients: No transfusion history1 Smaller clone size4 1. Hillmen P et al.Blood 2007;110:12:4123–4128; 2. International PNH Group et al.Blood 2005;106:3699–3709; 3. Lee JW et al. Blood (ASH Annual Meeting Abstracts) Nov 2011;118:3166; 4. Lee JW et al.Hematologica2010;95(s2): Abstract 506.
  39. Chronic Kidney Disease 1. Brodsky R. Hematology: Paroxysmal nocturnal hemoglobinuria. In: R Hoffman et al, eds. Hematology - Basic Principles and Practices. 4th ed. Philadelphia, PA: Elsevier Churchill Livingstone 2005;419–427; 2. Rother R et al.JAMA 2005;293:1653–1662; 3. Clark DA et al.Blood 1981;57:83–89; 4. Hillmen P et al.Am J Hematol 2010;85:553–559; 5. McKeage K. Drugs 2011;71:2327–2345. Kidney Pathology in PNH Complement-mediated hemolysis and cell-free plasma hemoglobin lead to chronic kidney disease in PNH1–5 Repetitive exposure of tissue to cell-free hemoglobin may lead to renal damage in PNH3,4 Micrograph of a Renal Biopsy from a PNH Patient, Indicative of Vascular Damage Normal tissue on the right Interstitial scarring on the left Clark DA, et al. Blood. 1981;57:83-89. Reprinted with Permission.
  40. Chronic Kidney Disease 1.Hillmen P, et al. Am J Hematol 2010;85:553–559; 2. Brodsky R. Hematology: Paroxysmal nocturnal hemoglobinuria. In: R Hoffman et al, eds. Hematology - Basic Principles and Practices. 4th ed. Philadelphia, PA: Elsevier Churchill Livingstone 2005;419–427. 3. Hill A. et al. Blood 2006;108: Abstract 979. Chronic Kidney Disease: Morbidity and Mortality in PNH Kidney failure is the cause of 8–18% of PNH-related deaths1 80% of PNH patients (median age of 31.5 years) had MRI evidence of significant renal hemosiderosis2,3 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
  41. Chronic Kidney Disease 64% of PNH Patients Exhibit Clinical Chronic Kidney Disease (CKD) 1. HillmenP et al. AmJ Hematol 2010;85:553–559.
  42. Chronic Kidney Disease Kidney Disease in PNH: Conclusions Kidney failure is the cause of 8–18% of PNH-related deaths1 Kidney disease in PNH is caused by complement-mediated hemolysis2,3 64% of patients with PNH exhibit chronic kidney disease at any one time4 Kidney disease is underappreciated in PNH4 1. Nishimura JI et al. Medicine 2004;83:193–207; 2. Clark DA et al.Blood 1981;57:83–89; 3. McKeage K. Drugs 2011;71:2327–2345; 4. Hillmen P et al.Am J Hematol 2010;85:553–559; 5. Kim JSet al.Hematologica 2011;96(s2): Abstract 271.
  43. Common Symptoms of PNH Clone Size Does Not Correlate to Symptom Severity 1. Urbano-Ispizua A et al. Hematologica 2010;95(s2): Abstract 1022.
  44. Common Symptoms of PNH Common PNH Symptoms are Associated With TE P=0.0004 P=0.024 P=0.015 Elevated LDH (≥1.5× ULN) in combination with abdominal pain, chest pain, and dyspnea are associated with a higher risk of TE Study description: a retrospective analysis of the medical charts of 286 PNH patients in a South Korean National Registry. Lee JW et al. Hematologica2010;95(s2): Abstracts 505 and 506.
  45. Common Symptoms of PNH Data from South Korean National Registry. Lee JW et al. Presented at the 54th Annual Meeting of the American Society of Hematology; December 8–11, 2012; Atlanta, GA. Abstract 1273. Chronic Complement-Mediated Hemolysis in Combination With Clinical Symptoms Increase the Risk of Thrombosis Odds Ratio for TE (Multivariate Analysis) The risk of TE in patients with LDH ≥1.5× ULN was 7.01 times greater than in patients with LDH <1.5× ULN (P=0.013).
  46. Common Symptoms of PNH Common Symptoms of PNH: Conclusions Common symptoms in PNH associated with TE should be considered as part of a comprehensive clinical assessment Abdominal pain, chest pain, dyspnea, hemoglobinura Abdominal pain and dyspnea are linked by underlying hemolysis and the threat of thrombosis2 66% of patients report shortness of breath3 59% of patients report abdominal pain4 97% of patients report fatigue1 Fatigue and severe dyspnea are prominent clinical features that can be associated with pulmonary hypertension and cardiac dysfunction 76% of patients with PNH have disruptions in daily activities1 Clone size does not correlate to symptom severity5 1. Weitz I et al. Intern Med J. 2012; 2. Lee JW et al. Hematologica 2010;95(s2): Abstract 506. 3. Meyers G et al. Blood 2007;110: Abstract 3683; 4. Lee JW et al. Hematologica 2010;95(s2): Abstract 505; 5. Urbano-Ispizua A et al. Hematologica 2010;95(s2): Abstract 1022.

  47. Early Identification of Patients at High Risk for PNH

  48. Advancements in Treatment Options Warrant Early Diagnosis and Intervention Early diagnosis is essential for improved patient prognosis: PNH Bone marrow failure1 International PNH Registry Provides evidence to inform clinical decision making Over 2100 patients from 26 countries are currently enrolled in the PNH registry 1. Sugimori C et al. Blood 2006;107:1308–1314.
  49. Two Independent International Groups Recommend Testing High-Risk Patients 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:211–230; International PNH Interest Group. Blood 2005;106:3699–3709.
  50. Suggestions for PNH Testing by ICCS PNH Guidelines Borowitz MJ et al; Clinical Cytometry Society. Cytom B Clin Cytom 2010;78B:211–230
  51. Incidence of PNH Clones by Diagnostic Code in the Clinical Setting Utilizing High-Sensitivity Flow Cytometry (HSFC) Objective: To use multi-parameter HSFC to analyze the incidence of PNH clones in patients recommended for testing in the clinical setting Key Results: 6987 individuals were screened for PNH clones utilizing HSFC 421 of 6987 patients (6.1%) across all high-risk populations recommended for testing were found to be PNH positive PNH clinical clone (>1%) detection rate was 3.8% Subclinical clone (<1%) detection rate was 2.3% Movalia MK et al. Presented at the American Society of Hematology 53rd Annual Meeting; December 10–13, 2011; San Diego, CA. Abstract 1033.
  52. Incidence of PNH Clones in High-Risk Patient Populations ICD-9 = International Classification of Diseases, 9th revision. *Includes patients already diagnosed as having PNH. Patients with PNH clone ≥ 0.01% High-risk patients may be included in more than 1 ICD-9 category. MovaliaMK et al.Presented at the American Society of Hematology 53rd Annual Meeting; December 10–13, 2011; San Diego, CA. Abstract 1033.
  53. PNH Clonal Expansion in an AA Representative Population At the Last ofFollow Up At the Start ofFollow Up Transitional pattern n (%) n=75 (Classic PNH) (8) (11%) Expansion 13 (17%) PNH+Patients Persistent 44 (59%) Newly developed 5 (4%) Disappearance 18 (24%) n=114 109 (96%) PNH-Patients Sugimori C et al. BJH. 2009;147:102-112.
  54. AA Immunosuppressive Therapy (IST) Has Increased Efficacy in AA Patients With PNH Cells * The presence of PNH cells was the only significant predictor of response to IST in 140 AA patients (P<0.01) in multivariate analysis2 * Patients With Response Complete response (CR) was defined as hemoglobin normal for age, neutrophil count more than 1.5 × 109/L, and platelet count more than 150 × 109/L; Partial response (PR) was defined as transfusion independent and no longer meeting criteria for severe disease in patients with severe AA.1 Overall response = CR + PR *P value = complete response, P=0.03; Overall response, P<0.001. 1. Sugimori C et al. Blood 2006;107:1308–1314; 2. Sugimori C et al.ExpHematol 2007;35:13–20.
  55. AdBoard Master_Sept 14, 2010 Considerations for Managing the PNH/AA Patient PNH AA/PNH PNH with hemolysis PNH Intermediate + hemolysis Severe AA without hemolysis Moderate AA with hemolysis Moderate AA without hemolysis ? IST BMT ProphylacticAnticoagulaion Eculizumab De Latour RP, Amoura Z, and Socie G. La revue de medecine interne. 2010; 200-207.
  56. RA-MDS Evidence of PNH Cells in RA-MDS Interim Results from EXPLORE, a Multi-center Prevalence Study of PNH Clone Size in Patients with AA, MDS, and other BMF Galili N et al. Poster presentation at: American Society of Clinical Oncology 45th Annual Meeting; May 29–June 2, 2009; Orlando, FL..
  57. Unexplained Cytopenias Patients With Unexplained Cytopeniasare at High Risk for PNH1 Test the Following Cytopenic Patients for PNH5,6 Unexplained Cytopenia Cytopenia and Evidence of Hemolysis Cytopenia With Any of These Coexisting Findings After thorough work-up LDH Haptoglobin Reticulocyte count(with or without anemia) Thrombosis Anemia Coombs-negative hemolytic anemia Bone marrow failure disorder Hemoglobinuria(dark colored urine) *0.01% PNH cell threshold. 1. Movalia MK et al. Blood 2011;118: Abstract 1033; 2. Barzi A, Sekeres MA. ClevClin J Med 2010;77:37–44; 3. Jordan MB et al. Blood 2011;118:4041–4052; 4. Moreno C et al.Blood 2010;116:4771–4776; 5. Borowitz MJ et al;Clinical Cytometry Society. Cytom BClinCytom2010;78B:211–230; 6. Brodsky RA. Blood 2009;113:6522–6527.
  58. Unexplained Cytopenias 93% of Patients With PNH Have Peripheral Blood Abnormalities No concomitant cytopenias Other combinations* Anemia and neutropenia Anemia and thrombocytopenia Anemia: hemoglobin <12.0 g/L . Neutropenia: ANC <1.5×109/L. Thrombocytopenia: platelet count <1.5×1011/L. *Other combinations: thrombocytopenia alone, neutropenia alone, both thrombocytopenia and neutropenia. Socieet al. Lancet 1996;348:573–577.

  59. How Do You Test for PNH?

  60. Standard Diagnostic Test for PNH Flow cytometry performed on peripheral blood Granulocytes and at least one additional cell line should be evaluated 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.; Clinical Cytometry Society. Cytom B Clin Cytom 2010;78B:211–230.
  61. Patient 1: Normal RBCs with normal CD59 expression (Type I cells) Patient 2: PNH clone with complete CD59 deficiency (Type III cells) Patient 3: PNH clone with complete CD59 deficiency (Type III cells) and partial CD59 deficiency (Type II cells) Testing for PNH in RBCs Gating on GPA+ RBCs GPA = glycophorin A. Data Source: Dahl-Chase Diagnostic Services..
  62. Why Look Beyond RBCs for PNH? Granulocytes provide more accurate representation of PNH clone size1 Percentages of PNH RBCs may be affected by: Hemolysis Blood transfusion PNH reports should provide quantitative results expressing clone size on both granulocytes and RBCs 1. Borowitz MJ et al; Clinical Cytometry Society. Cytom B Clin Cytom 2010;78B:211–230.
  63. PNH Patient With an 80% WBC Clone Size and 31% RBC Clone Size Indicating Hemolysis WBC RBC CD24- Granulocytes 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.
  64. ICCS Recommendations for Follow-Up Testing of Patients With an Identified PNH Clone Annual monitoring1 Stable patients Patients with aplastic anemia and small PNH clone Patients with refractory cytopenia with unilineage dysplasia (RCUD) and small PNH clone More frequent monitoring to evaluate for expanding clones Patients with changing symptoms or lab values Patients in early stages of treatment 1. Borowitz MJ et al.; Clinical Cytometry Society. Cytom BClinCytom2010;78B:211–230.
  65. December 2008 May 2009 March 2009 CD14-Granulocytes CD24-Granulocytes CD24-Granulocytes CD24-Granulocytes FLAER-GPI Anchor Marker FLAER-GPI Anchor Marker FLAER-GPI Anchor Marker Gran clone: 7.6% RBC clone: 1.6% Gran clone: 23.3% RBC clone: 2.4% Gran clone: 14.2% RBC clone: 1.8% CD59 –GPI Anchor Protein CD59 –GPI Anchor Protein CD59 –GPI Anchor Protein 6 Months 3 Months 9 Months Importance of Monitoring Granulocytes and RBCs Over Time September 2008 CD24-Granulocytes FLAER-GPI Anchor Marker Gran clone: 3.8% RBC clone: 0.8% CD59 –GPI Anchor Protein PNH Clone Expanded in <1 Year Data Source: Dahl-Chase Diagnostic Services.
  66. Global, observational, non-interventional study to collect real-world safety, effectiveness, and QoL data Open to all physicians treating patients with PNH regardless of therapy Objectives Database for publications to enhance understanding of disease and improve outcomes Promote evidence-based medicine Current enrollment Over 2000 patients enrolled Participation in 24 countries, including Argentina, Australia, Belgium, Canada, Denmark, Finland, France, Germany, The Netherlands, New Zealand, Russia, South Korea, Spain, Sweden, Switzerland, Taiwan, United Kingdom, United States Enrollment information: www.pnhsource.com
  67. SOLIRIS® (eculizumab) Humanized First in Class Anti - C5 Antibody Human Framework Regions No mutations Germline Complementarity Determining Regions (murine origin) Human IgG4 Heavy Chain Constant Regions 2 and 3 (Eliminates complement activation) Human IgG2 Heavy Chain Constant Region 1 and Hinge (Eliminates Fc receptor binding) Hinge CH1 CL CH2 CH3 Rother R et al. Nat Biotech 2007;25:1256
  68. Eculizumab Blocks Terminal Complement1,2 Complement Cascade2,3 Soliris Eculizumab binds with high affinity to C51,2 C3 C3a Proximal Terminal complement - C5a and C5b-9 formation blocked1,2 C3b Proximal functions of complement remain intact1,2 Weak anaphylatoxin2,4 Immune complex clearance2 Microbial opsonization2 C5 C5a Terminal C5b C5b-9 Please see full prescribing information for Soliris® (eculizumab). 1. Soliris® (eculizumab) Summary of Product Characteristics. Alexion Europe SAS; 2012;2. Rother RP et al. Nature Biotech 2007;25:1256–1264; 3. Walport MJ. N Engl J Med 2001;344:1058–1066; 4. Figueroa JE, Densen P. Clin MicrobiolRev 1991;4:359–395.
  69. Therapeutic Indications and Usage Eculizumab is a Complement Inhibitor Indicated for: The treatment of patients with paroxysmal nocturnal hemoglobinuria(PNH) to reduce hemolysis The treatment of patients with atypical hemolytic uremic syndrome (aHUS) to inhibit complement-mediated thrombotic microangiopathy The effectiveness of Eculizumabin aHUS is based on the effects on thrombotic microangiopathy (TMA) and renal function Prospective clinical trials in additional patients are ongoing to confirm the benefit of Eculizumabin patients with aHUS Please see full prescribing information for Soliris® (eculizumab). Soliris® (eculizumab) Summary of Product Characteristics. Alexion Europe SAS; 2012.
  70. WARNING: SERIOUS MENINGOCOCCAL INFECTIONS Eculizumab increases the patient’s susceptibility to meningococcal infection due to its mechanism of action To reduce the risk of infection, a tetravalent vaccine against serotypes A, C, Y and W135 (preferably conjugate), is strongly recommended to vaccinate patients at least 14 days prior to receiving the first dose of eculizumab Patients less than 2 years of age or not vaccinated at least 14 days before starting treatment with eculizumab must receive treatment with appropriate prophylactic antibiotics until 14 days after vaccination. Revaccinate according to current medical guidelines for vaccine use Vaccination may not be sufficient to prevent meningococcal infection and the use of antibacterial agents may need to be considered Monitor patients for early signs of meningococcal infection; evaluate immediately if infection is suspected and treat with antibiotics if necessary Please see full prescribing information for Soliris® (eculizumab). Soliris® (eculizumab) Summary of Product Characteristics. Alexion Europe SAS; 2012.
  71. What is the Long-Term Experience With Eculizumab? Pilot Study – NEJM2004 N=11 Primary endpoint: reduction of hemolysis Long-Term Extension Trial HillmenBlood2007 Evaluated long-term safety, efficacy and effect on thrombosis; Placebo patients switched to eculizumab N=187 TRIUMPH – NEJM2006 Pivotal Phase III, Double-Blind, Placebo-Controlled Trial, N=87 SHEPHERD – Blood2008 Broader patient population, including those receiving minimal transfusions or with thrombocytopenia, N = 97 Please see full prescribing information for Soliris® (eculizumab). Soliris® (eculizumab) Summary of Product Characteristics. Alexion Europe SAS; 2012.
  72. In clinical trials all patients were vaccinated against Neisseria meningitidis¹ Concomitant medications allowed: Steroids, immunosuppressant drugs, anti-clotting agents and hematinics² Eculizumab should be administered via IV infusion within 25-45 minutes every 7 days during induction and every 14 days during maintenance¹ Eculizumabdose adjustment to every 12 days may be necessary for some patients to maintain LDH reduction¹ Eculizumab is a Chronic Treatment for a Chronic Disease q14d Dose within ±2 days. Please see full prescribing information for Soliris® (eculizumab). 1. Soliris® (eculizumab) Summary of Product Characteristics. Alexion Europe SAS; 2012. 2. Hillmen P et al. N Engl J Med 2004;350:552–559.
  73. TRIUMPH – Placebo/Extension TRIUMPH – Soliris/Extension SHEPHERD – Eculizumab 0 4 8 12 16 20 24 28 32 36 40 44 48 52 Time, Weeks 86% Reduction in LDH: TRIUMPH and SHEPHERD 3000 2500 2000 1500 100% response after the first dose LDH (U/L) 1000 500 0 TRIUMPH placebo patients switched to Eculizumabafter Week 26 All TRIUMPH patients entered the long-term extension study P<0.001 at all measured time points. Please see full prescribing information for Soliris® (eculizumab). Soliris® (eculizumab) Summary of Product Characteristics. Alexion Europe SAS; 2012. Hillmen P et al. Blood 2007;110:4123–4128.
  74. 45 39 40 35 30 N=195 25 Thrombotic Events (#) 20 15 P=0.0001 10 3 5 0 EculizumabTreatment Pre-EculizumabTreatment 92% Reduction in Thrombotic Events 63% of patients received concomitant anticoagulants1 The effect of anticoagulant withdrawal was not studied2 Events observed in both venous and arterial sites3 There were fewer thrombotic events with Eculizumab treatment than during the same period of time prior to treatment2 Please see full prescribing information for Soliris® (eculizumab). 1. Brodsky R et al.Blood 2008;111:1840–1847; 2. Soliris® (eculizumab) Summary of Product Characteristics. Alexion Europe SAS; 2012; 3. HillmenP et al.Blood 2007;110:4123–4128.
  75. 94% reduction in event rate with Eculizumab Eculizumab Reduced Thrombosis in Patients Treated with Anticoagulants1 P<0.001 N=91 *Excludes patients on antiplatelet agents. Please see full prescribing information for Soliris® (eculizumab). Soliris® (eculizumab) Summary of Product Characteristics. Alexion Europe SAS; 2012.1. Hillmen P et al. Blood 2007;110:4123–4128.
  76. Effect of Eculizumab on Chronic Kidney Disease in PNH
  77. 59% of patients with minimal (0–1) transfusion history had CKD (n=22) 64% of Patients Exhibit Chronic Kidney Disease (CKD)1 1. Hillmen P et al. Am J Hematol 2010;85:553–559.
  78. Renal Function With Eculizuamb in Different Baseline PNH Populations – 6 Months1 80 75.0 70 64.2 60.3 60 P<0.001 P=0.05 50 Proportion of Patients (%) 40 31.7 30 24.7 20.0 20 11.1 7.9 5.0 10 0 Overall(n=189) Stage 1–2(n=81) Stage 3–5(n=40) Segment of PNH Population No Change Improvement Worsening Please see full prescribing information for Soliris® (eculizumab). Soliris® (eculizumab) Summary of Product Characteristics. Alexion Europe SAS; 2012. 1. Hillmen P et al. Am J Hematol 2010;85:553–559.
  79. Renal Function With Eculizumabin Different Baseline PNH Populations – 18 Months1 80 71.4 67.1 70 60.2 60 P<0.001 P<0.001 P=0.05 50 Proportion of Patients (%) 40 34.3 30.1 30 22.9 20 5.4 5.7 10 2.7 0 Overall(n=189) Stage 1–2(n=81) Stage 3–5(n=40) Segment of PNH Population No Change Improvement Worsening Please see full prescribing information for Soliris® (eculizumab). Soliris® (eculizumab) Summary of Product Characteristics. Alexion Europe SAS; 2012. 1. Hillmen P et al. Am J Hematol 2010;85:553–559.
  80. Chronic Kidney Disease in PNH: Summary Early intervention with eculizumab has shown a time-dependent improvement in renal function in protecting against progression of renal damage1 Please see full prescribing information for Soliris® (eculizumab). Soliris® (eculizumab) Summary of Product Characteristics. Alexion Europe SAS; 2012. 1. Hillmen P et al. Am J Hematol 2010;85:553–559.

  81. Is the Primary Cause of Fatigue in PNH Anemia or Hemolysis?

  82. 12.0 8 11.5 6 Ecu(n=43) Patients not on Ecu(n=44) EcuHgb Placebo Hgb 11.0 4 10.5 2 Change From Baseline FACIT-Fatigue Score Hemoglobin, g/dL 0 10.0 –2 9.5 –4 9.0 –6 8.5 0 2 4 6 8 10 12 14 16 18 20 22 24 26 Time, Weeks TRIUMPH Demonstrated That Improvement in Fatigue Occurred Independent of Hemoglobin Response P<0.001 FACIT-Fatigue Score ≥3 or more points denotes a clinically significant improvement Hgb Level FACIT-Fatigue Score Hgb Placebo In SHEPHERD, 78% of patients reported a significant improvement in fatigue1 FACIT = Functional Assessment of Chronic Illness Therapy. Please see full prescribing information for Soliris® (eculizumab). Soliris® (eculizumab) Summary of Product Characteristics. Alexion Europe SAS; 2012. Adapted from: Hillmen P et al. N Engl J Med 2006;355:1233–1243;Brodsky R et al. Blood Rev 2008;22:65–74; Hill A et al.Haematologica 2008;93(Suppl. 1):359. Abstract 0904; Brodsky R et al.Blood 2008;111:1840–1847; Schubert J, et al. Br J Haematol2008;142(2):263-72.
  83. Patients not on Ecu(n=44) Ecu(n=43) 73% Reduction in Mean Units Transfused Across All Subgroups: TRIUMPH 18 16 14 12 10 Median Units Transfused 8 6 4 * * 2 * * 0 (n=87) (n=30) (n=35) (n=22) Overall 4–14 15–25 >25 Pre-treatment Transfusion Strata† 51% of Ecupatients achieved transfusion independence vs 0% of patients not on Ecu1 Patients with concomitant bone marrow dysfunction may continue to require transfusions2 *P<0.001. †Transfusion data obtained during 12 months before treatment; values were normalized for a 6-month period. Please see full prescribing information for Soliris® (eculizumab). Soliris® (eculizumab) Summary of Product Characteristics. Alexion Europe SAS; 2012. 1. Hillmen P et al. N Engl J Med 2006;355;1233–1243; 2. Schubert J. Br J Haematol2008;142:263–272.
  84. Eculizumab Treatment Results in Large and Clinically Meaningful Improvements in Patient-Reported Outcomes 1.2 1.13 1.12 Large Clinical Impact 1 0.8 0.69 Moderate Clinical Impact 0.65 0.6 Standard Effect Size (SES) Small Clinical Impact 0.4 0.2 0 FACIT-Fatigue* EORTC Fatigue* Dyspnea* Pain† (P<0.001) (P<0.001) (P=0.002) (P<0.001) Please see full prescribing information for Soliris® (eculizumab). Soliris® (eculizumab) Summary of Product Characteristics. Alexion Europe SAS; 2012. 1. Brodsky R et al. Blood 2006;108: Abstract 3770; 2. Data on file. Alexion Pharmaceuticals. 3. Weitz I, et al. Internal Medicine Journal2012.Accepted Article; doi: 10.1111/j.1445-5994.2012.02924.x
  85. Eculizumab Reduces Hemolysis and Improves Fatigue in IST-Treated Patients IST IST: Severe hemolysis Ecu: Significant and sustained reduction in hemolysis IST: Severe fatigue Ecu: Significant and sustained reduction in fatigue Demonstrates effectiveness of treatment with Eculizumab to reduce hemolysis and fatigue in AA patients despite concomitant IST treatment Mean LDH (U/IL) LDH * * * N=12 Months of Eculizumab ¥ ¥ ¥ FACIT-Fatigue Mean FACIT Fatigue N=10 Months of Eculizumab * P<0.01 when prior and post months compared. . P<0.05 when prior and post months compared. Schrezenmieier et al Blood 2009
  86. How Does Eculizumab Impact Pulmonary Hypertension and Dyspnea in PNH?
  87. Reduction of Pulmonary Hypertension With Eculizumab as Measured by NT-ProBNP Solirisvs Placebo (P<0.001) 50% Reduction 60 52.5 50 P<0.037 43.8 39.4 40 Proportion of Patients With Evidence of Pulmonary Hypertension 30 26.3 20 10 0 Baseline Week 26 Baseline Week 26 Placebo Eculizumab Treatment Group - TRIUMPH (n=73)1 Pulmonary Hypertension Defined as NT-proBNP ≥160 pg/mL2 Please see full prescribing information for Soliris® (eculizumab). Soliris® (eculizumab) Summary of Product Characteristics. Alexion Europe SAS; 2012. 1. Hill A et al. Br J Haematol2012;158:409–414. 2. Machadaet al.JAMA. 2006.
  88. What is the Long-Term Experience With Eculizumab? Pilot Study – NEJM2004 N=11 Primary endpoint: reduction of hemolysis Long-Term Extension Trial HillmenBlood2007 Evaluated long-term safety, efficacy and effect on thrombosis; Placebo patients switched to Eculizumab N=187 TRIUMPH – NEJM2006 Pivotal Phase III, Double-Blind, Placebo-Controlled Trial, N=87 SHEPHERD – Blood2008 Broader patient population, including those receiving minimal transfusions or with thrombocytopenia, N = 97 Please see full prescribing information for Soliris® (eculizumab). Soliris® (eculizumab) Summary of Product Characteristics. Alexion Europe SAS; 2012.
  89. 86% Reduction in LDH Sustained Over Entire Course of 36 Month Treatment Period *P<0.0000001 * * * * * * * * Dashed line represents the upper limit of the normal range (103–223 U/L) Please see full prescribing information for Soliris® (eculizumab). Soliris® (eculizumab) Summary of Product Characteristics. Alexion Europe SAS; 2012. Brodsky R et al. Blood 2010;116: Abstract 4237.
  90. What is the Clinical Data on the Long-term Outcome of Treatment with Eculizumab in Patients with PNH?
  91. Eculizumab in PNH: 10-Year Multicenter ExperiencePatient Characteristics at Baseline *Normal <430 IU/L. IU=international units. Please see full prescribing information for Soliris® (eculizumab). Soliris® (eculizumab) Summary of Product Characteristics. Alexion Europe SAS; 2012. Hill A et al. Presented at the 54th Annual Meeting of the American Society of Hematology (ASH). December 8–11, 2012, Atlanta, GA. Abstract #3472. Appears in Blood 2012;120(21).
  92. Eculizumab in PNH: 10-Year Multicenter ExperienceReduction in TE with Long-term Eculizumab Therapy P<0.05 * *Patients received eculizumab treatment from May 2002 to April 2012 Please see full prescribing information for Soliris® (eculizumab). Soliris® (eculizumab) Summary of Product Characteristics. Alexion Europe SAS; 2012. Hill A et al. Presented at the 54th Annual Meeting of the American Society of Hematology (ASH). December 8–11, 2012, Atlanta, GA. Abstract #3472. Appears in Blood 2012;120(21).
  93. Paroxysmal Nocturnal Hemoglobinuria:Compelling Long Term Clinical Benefits in PNH Patients Pre-Soliris from Time ofDiagnosis in 80 Patients With PNH1 PNH Patients on Eculizumab Compared with Age- and Gender-Matched Controls2* 100 100 80 80 Age- and gender-matched controls Age- and Gender-Matched Normal Population 60 60 Patients Surviving (%) Ecu-treated PNH Population 40 40 Patients with PNH 20 20 Patients at Risk: 153 93 45 43 12 0 0 0 2 4 6 8 10 0 5 10 15 20 25 Years After Diagnosis Time (Years) Despite best supportive care - 5 year mortality: 35%1 Hazard Ratio = 2.24 (P=0.013) *Survival after 10-years is slightly inferior to controls with causes of death related to bone marrow failure and not hemolysis or thrombosis. Please see full prescribing information for Soliris® (eculizumab). Soliris® (eculizumab) Summary of Product Characteristics. Alexion Europe SAS; 2012. 1. Hillmen P et al. N Engl J Med1995;333:1253–1258. 2. Hill A et al. Presented at the 54th Annual Meeting of the American Society of Hematology (ASH). December 8-11, 2012, Atlanta, GA. Abstract #3472. Appears in Blood 2012;120(21).
  94. Long-Term Experience with Eculizumab in PNH Up to 10 year multicenter experience of eculizumab shows: Improved survival with a well-tolerated safety profile Persistent and significant improvement in symptoms and quality of life Significant reduction in the number of thrombotic events Significant reduction in transfusion requirements Long-term use of eculizumabdemonstrates the impact on quality of life and reduction in complications, thereby improving long-term outcomes for patients with PNH Please see full prescribing information for Soliris® (eculizumab). Soliris® (eculizumab) Summary of Product Characteristics. Alexion Europe SAS; 2012. Hill A et al. Presented at the 54th Annual Meeting of the American Society of Hematology (ASH). December 8–11, 2012, Atlanta, GA. Abstract #3472. Appears in Blood 2012;120(21).
  95. Treatment Expectations: What is the Benefit of Eculizumab Therapy in PNH Patients?
  96. Eculizumab Treatment ExpectationsPNH Patients in Clinical Trials Showed a Benefit from Eculizumab Therapy In 1 Week Reduction in hemolysis(as measured by LDH)3 Reduction in fatigue3 Between 2 and 3 Weeks Improvement in quality of life1 Improvement in dyspnea4 Between 2 and 6 Months Reduction in frequency of transfusions5 Stabilization of hemoglobin levels5 Reduction in Thrombotic Event Rate2 >6 Months Continued improvement in quality of life3,6 LDH levels maintained at upper limit of normal3,6 Continued improvement in fatigue3,6 Continued reduction in frequency of transfusions3,6 Continued stabilization of hemoglobin levels5 Treatment with Eculizumabshould not alter anticoagulant management.1 At 36 Months and Up to 10 Years Reduction in hemolysis (as measured by LDH) was sustained1,7,8 Improvement in TE was maintained1,7,8 Most commonly reported adverse events were mild or moderate in severity1 Please see full prescribing information for Soliris® (eculizumab). 1. Soliris® (eculizumab) Summary of Product Characteristics. Alexion Europe SAS; 2012. 2. HillmenP et al.Blood 2007;110:4123–4128. 3. Brodsky R et al. Blood 2008;111:1840–1847. 4. Hill A et al. Br J Haematol2012;158:409–414. 5. HillmenP et al. N Engl J Med 2006;355:1233–1243. 6. SociéG et al. Blood(ASH Annual Meeting Abstracts) 2007;110: Abstract 3672. 7. Brodsky RA et al. In: Abstracts of the 52nd ASH Annual Meeting and Exposition; December 4–7, 2010; Orlando, FL. Abstract 4237. 8. Hill A et al. In: Abstracts of the 54thAnnual Meeting of the American Society of Hematology (ASH). December 8–11, 2012, Atlanta, GA. Abstract #3472. Appears in Blood 2012;120(21). 9. Szer J et al. In: Abstracts of the 54th Annual Meeting of the American Society of Hematology (ASH). December 8–11, 2012, Atlanta, GA. Abstract #1260. Appears in Blood 2012;120(21).
  97. Adverse Reactions Reported in ≥ 5% of Eculizumab Treated Patients in TRIUMPH Hillmen P, et al. NEJM. 2006;355:1233-1243. Please see full prescribing information for Soliris® (eculizumab). Soliris®SmPC: Soliris® (eculizumab) summary of product characteristics. Alexion Europe SAS 2012.
  98. Summary of Clinical Efficacy1–5 86% sustained reduction in hemolysis as measured by LDH Maintained over a 36 month treatment period1–3 92% reduction in thrombotic events 73% reduction in transfusion requirements across all patient populations 78% clinically meaningful improvement in fatigue Sustained improvement in overall quality of life Patients treated with eculizumabexperienced improvement in CKD and pulmonary hypertension Eculizumabprovided a rapid and durable effect on dyspnea, a key marker of hemolysis-induced PHT Please see full prescribing information for Soliris® (eculizumab). 1. Soliris® (eculizumab) Summary of Product Characteristics. Alexion Europe SAS; 2012 . 2. Hillmen P et al. N Engl J Med 2006;355:1233–1243; 3. Brodsky R et al.Blood 2010;116: Abstract 4237; 4. HillmenP et al.Blood 2007;110:4123–4128; 5. Socie G et al. Blood 2007;110: Abstract 3672. 4. SzerJ et al.In: Abstracts of the 54th Annual Meeting of the American Society of Hematology (ASH). December 8–11, 2012, Atlanta, GA; Abstract #1260. Appears in Blood 2012;120(21).
  99. Summary of Clinical Efficacy and Safety1–5 In a multicenter analysis eculizumabshowed a major impact on survivalin PNH; survival is comparable to age- and gender- matched controls Eculizumab significantly reduced hemolysis, the underlying cause of morbidity and mortality in PNH Significant reductions in AEs were observed suggesting good tolerability and a favorable risk/benefit ratio over the long term Please see full prescribing information for Soliris® (eculizumab). 1. Soliris® (eculizumab) Summary of Product Characteristics. Alexion Europe SAS; 2012 . 2. Hillmen P et al. N Engl J Med 2006;355:1233–1243; 3. Brodsky R et al.Blood 2010;116: Abstract 4237; 4. HillmenP et al.Blood 2007;110:4123–4128; 5. Socie G et al. Blood 2007;110: Abstract 3672. 4. SzerJ et al.In: Abstracts of the 54th Annual Meeting of the American Society of Hematology (ASH). December 8–11, 2012, Atlanta, GA; Abstract #1260. Appears in Blood 2012;120(21).
  100. Conclusions Chronic complement-mediated hemolysis is the underlying cause of progressive morbidities and mortality in PNH Thrombosis is the leading cause of death in PNH1 Renal failure has been identified as the cause of death in approximately 8–18% of PNH patients2,3 PNH may be more common than you think Delays in diagnosis range from 1 to more than 10 years4 High sensitivity flow cytometry, performed on peripheral blood, is the gold standard test Advancements in treatment options warrant early diagnosis and intervention 1. Hillmen P et al. Blood 2007;110:4123–4128; 2. Nishimura JI et al. Medicine 2004;83:193–207; 3. Hillmen P et al.Am J Hematol 2010;85:553–559;4. HillmenP et al.N Engl J Med 1995;333:1253–1258.
  101. Long Term Experience with Soliris in PNH Bart L. Scott, MD Assistant Professor of Medicine, Division of Oncology, University of Washington Director of Hematology and Hematologic Malignancies, Seattle Cancer Care AllianceSeattle, WA
  102. What is the Impact of Long-term Soliris Treatment on Clinical Outcomes and Survival? Uncontrolled Complement Activation Soliris Decreased Mortality ? Hemolysis End Organ Damage TE Renal Gastrointestinal Pulmonary Cardiac Hepatic Increased Mortality ComplicationsAssociated With ElevatedHemolysis(LDH)
  103. Long-term Treatment With Soliris in PNH: Sustained Efficacy and Improved Survival 153 consecutive patients with PNH treated with Soliris May 2002 – April 2012 Duration mean of treatment 3.5 years (range <1.0 - 9.9 years) Mortality and disease symptoms were evaluated
  104. Patient Characteristics (n=153) Hill A. ASH 2012.
  105. 74 Thrombotic Events in 50 Patients Prior to Soliris Treatment 28 thrombotic episodes in 15 patients anticoagulated prior to initiation of Soliris therapy Hill A. ASH 2012.
  106. Thrombotic Events in Equivalent Time Periods 12 months prior to initiating Soliris 36 thrombotic episodes in 22 (14.3%) patients In the most recent 12 months on therapy 3 thromboses in 3 (2.0%) patients 1 Budd-Chiari during complement blockade breakthrough caused by infection 1 CVA during reversal of warfarin overanticoagulation 1 TIA/lacunar infarct thought to be due to diabetic small vessel disease Hill A. ASH 2012.
  107. Discontinuing Anticoagulation Primary prophylaxis with warfarin has been safely stopped in 43/50 (86%) patients Secondary prophylaxis discontinued in 4 (<10%)  due to haemorrhages, risk of bleeding from varices and/ or thrombocytopenia With no thromboticsequelae Hill A. ASH 2012.
  108. Reduction in Intravascular Haemolysis All patients had a rapid reduction in LDH P < 0.0001 Hill A. ASH 2012.
  109. Median Transfusion Requirements in the 12 Months Prior to Soliris and Most Recent 12 Months on Soliris 66% of transfused patients become transfusion independent Hill A. ASH 2012.
  110. 25 patients still requiring transfusions: The mean number of transfusions fell significantly from 24.6 units (range 4-44) to 11.4 units (range 2-45), P=0.0002 Reasons for Transfusion in the 25 Patients in Leeds Not Transfusion Independent Aplasia Breakthrough haemolysis (required higher dosing) Myelodysplasia Breakthrough haemolysis (minimally transfused, maximum of 3 units in 12 months) Cause unclear Extravascular haemolysis
  111. Outcomes (n=153 patients) 137 patients on treatment as of April 2012 7 discontinued eculizumab therapy 1 predominant AA 2 spontaneous remissions of PNH clone 3 treated for indication of pregnancy alone 1 successfully transplanted for VSAA 9 patients died Hill A. ASH 2012.
  112. Outcomes 9 patients died 3 due to progression of their underlying bone marrow failure to MDS/AML One died immediately after BMT (veno-occlusive disease) 27 yrs old 2000 AA 2009 PNH Mar 2011 AML May 2011 Ecu Oct 2011 transplant; VOD Remaining 5 not directly related to PNH Hill A. ASH 2012.
  113. Causes of Death 1 1 4 1 1 1
  114. Actuarial Survival from the Time ofDiagnosis in 80 Patients with PNH1 100 80 Age-matched and gender-matched controls 60 Patients Surviving, % 40 Patients with PNH 20 0 0 5 10 15 20 25 Years after Diagnosis Mortality With Best Supportive Care 5 year mortality of 35% recently confirmed2 1. Hillmen P et al. N Engl J Med. 1995;333(19):1253-1258; 2. Kelly RJ et al. Blood. 2011;117:6786-6792.
  115. Paroxysmal Nocturnal Hemoglobinuria:Compelling Long Term Clinical Benefits in PNH Patients Survival of PNH Patients TreatedWith Soliris Compared With the Normal UK Population2 Pre-Soliris from Time ofDiagnosis in 80 Patients With PNH1 100 100 80 80 N= 153 Age- and gender-matched controls 60 60 Age- and gender-matched normal population Cumulative Surviving, % Patients Surviving, % 40 Soliris Treated PNH Population 40 Patients with PNH 20 Numbers at Risk: 153 93 45 43 12 20 0 0 5 10 15 20 25 Years After Diagnosis 0 Despite best supportive care - 5 year mortality: 35%1 0 2 4 6 8 10 Time (years) 1. Hillmen P et al. N Engl J Med. 1995;333:1253-1258. 2. Hill A. ASH 2012.
  116. Sustained Complement Inhibition Leads to Reduced Hemolysis, Thrombosis and Improvements in Survival Uncontrolled Complement Activation Decreased Mortality Soliris Reduction in LDH (P<0.0001) 100% response rate in pivotal clinical trial programs (As measured by reduction in LDH) 92% (P<0.0001) reduction in TE Hemolysis End Organ Damage Significant reduction in abdominal pain Improvement in dyspnea, dysphagia, fatigue, hemoglobinuria Thrombosis Renal Gastrointestinal Pulmonary Cardiac Hepatic Increased Mortality ComplicationsAssociated With ElevatedHemolysis(LDH) 4 fold improvement in CKD over placebo (P<0.04) Soliris appears to normalize survival in patients with PNH 1. Hillmen P et al. Blood. 2007;110(12):4123-4128. 2. Brodsky R et al. Blood. 2010;116(21): Abstract #4237. 3. Hill A et al. Blood. 2004;104:772: Abstract #2823. 4. Data on file. Alexion Pharmaceuticals, Inc. 5. Hillmen et al. N Engl J Med. 2004;350 552. 6. Brodsky et al. Blood. 2008;111:1840-1847. 7. Hillmen et al. Blood. 2007;110:4123-4128. 8. Hill A et al. Br J Haematol. 2010; May;149(3):414-425. 9. Hillmen P et al. Am J Hematol. 2010;85:553-559. 10. Hill et al. Blood. 2008;112: Abstract A486.
  117. Global, observational, non-interventional study to collect real world safety, effectiveness and QoL data Open to all physicians treating patients with PNH regardless of therapy Objectives Database for publications to enhance understanding of disease and improve outcomes Promote evidence-based medicine Current enrollment Over 2000 patients enrolled Participation in 24 countries, including Argentina, Australia, Belgium, Canada, Denmark, Finland, France, Germany, Japan, Luxembourg, Netherlands, New Zealand, Norway, Russia, South Korea, Spain, Sweden, Switzerland, Taiwan, United Kingdom, United States Enrollment information: www.pnhsource.com
  118. Discussion How does this data impact your motivation to more closely monitor patients with PNH?
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