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Current Status of Pathogen Reduction Methods

Current Status of Pathogen Reduction Methods. James P. AuBuchon, MD President & Chief Executive Officer Puget Sound Blood Center Professor of Medicine and of Laboratory Medicine University of Washington Seattle, Washington. E. E. T. R. N. U. D. L. O. O. N. O. V. R. A. R. T.

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Current Status of Pathogen Reduction Methods

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  1. Current Status of Pathogen Reduction Methods James P. AuBuchon, MD President & Chief Executive Officer Puget Sound Blood Center Professor of Medicine and of Laboratory Medicine University of Washington Seattle, Washington

  2. E E T R N U D L O O N O V R A R T T O N N I N E A G C O T H I T V A A S I E N T T P G I O D E U N C O I N O D Transfusion safety is like an onion… SAFETY

  3. “Emerging” Pathogens Ocean virus Chikungunya virus; Dengue fever Modified from: Morens DM et al. Nature 2004;430:242-9.

  4. Pathogen Inactivation Methods Currently Under Investigation or in Use Chemicals: Physical disruption Solvent/detergent technology Photoactive compounds: Genomic disruption Psoralen derivatives (amotosalen) Riboflavin Methylene blue Chemicals: Short-term activation  Genomic disruption S-303 (FRALE: Frangible Anchor Linker Extender) Direct radiation effect  Genomic disruption UVC

  5. Methods: Available or Approaching Plasma Quarantined plasma Solvent/detergent treatment Methylene blue + light Amotosalen + UV Riboflavin + UV UVC alone Platelets Amotosalen + UV Riboflavin + UV UVC alone Red cells/Whole blood S-303 Riboflavin + UV

  6. PI Plasma: The Similarities Reduction in procoagulant activity: 10-20% Effect of implementation: Clinical utility Rock G. Vox Sang 2011;100;169-78.

  7. PI Plasma: The Differences SD Plasma ↓Allergic reactions (1/50,000 units) ↓TRALI [0 ?] NAT for non-enveloped viruses (HAV, B19) Reduction in HMW vWF + ADAMTS-13 retention Reduction in anticoagulant proteins  thrombosis [?] MB Plasma Slightly greater fibrinogen + F VIII reduction

  8. Evaluation MB Plasma Clots by Thromboelastometry Slower MAXIMUM CLOT FIRMNESS Strength OK Less thrombin THROMBIN GENERATION CLOT FORMATION Cardigan R et al. Transfusion 2009;49:696-703.

  9. PI Plasma: The Differences SD Plasma ↓Allergic reactions (1/50,000 units) ↓TRALI [0 ?] NAT for non-enveloped viruses (HAV, B19) Reduction in HMW vWF + ADAMTS-13 retention Reduction in anticoagulant proteins  thrombosis [?] MB Plasma Slightly greater fibrinogen + F VIII reduction Implementation  Increased use [?]  Reduced TTP response France: 11 severe allergic reactions (1 death) UV ± Photosensitizer Plasma UVC alone: ↓ F XI (no clinical trials) Nubret K et al. Transfusion 2011;51:125-8.

  10. PI Platelets: The Similarities Some loss of platelets through process (small; manageable) UV light  Identifiable platelet damage Increased metabolic rate Increased activation during storage (↓mt DNA transcription)

  11. Using UVC to Inactivate ControlTreated Platelets 9.4±1.6 9.1±1.3 x 108/mL HSR 68±1 61±8% pH 7.29±0.12 7.09±0.05 Aggr: Collagen 62±7 69±7% Glucose 63±9 41±8 mg/dL Lactate 12.5±0.9 15.2±1.0 mM Illumination: 0.4J/cm2 Testing: Day 8 Walker WH et al. Vox Sang 2007;93(suppl 2):69.

  12. In vitro Assessment of Functional Properties Intercept 12 Mirasol 10 Control 8 Fibrinogen receptor expression, MFI 6 4 2 0 Control TRAP-6 aggregation response,, % Mirasol Intercept Picker SM et al. Transfusion 2009;49:1224-32.

  13. Treatment Effect: Metabolic Changes Lactate, mM Storage time, days Picker SM et al. Vox Sang 2009;97:26-33.

  14. PI Platelets: The Similarities Some loss of platelets through process (small; manageable) UV light  Identifiable platelet damage Increased metabolic rate Increased activation during storage Reduced recovery Reduced survival 15-25%

  15. Clinical Trial: Amotosalen-Treated Platelets The euroSPRITE Trial TreatedControl Units transfused/patient 7.5+5.8 5.6+5.5 p > 0.05 Count increment (109/L): 1h post-transfusion 27.6+13.3 35.8+23.3 p < 0.02 24h post-transfusion 16.4+9.5 24.7+17.6 p = 0.004 Corrected count increments: 1h post-transfusion 13,100+5400 14,900+6200 p = 0.11 24h post-transfusion 7300+5400 10,600+7100 p = 0.02 Van Rhenen D et al. Blood 2000;96:819a.

  16. Clinical Trial: Amotosalen-Treated Platelets The SPRINT Trial WHO Grade 2, 3 or 4 bleeding: No difference between groups Platelet content of treated units: 7.5% less Post-transfusion counts: 22-26% lower in treated group Comparison by dose: Equivalent effect from similar dose French/Belgian experience: No increase in usage Loss: 8% McCullough J et al. Blood 2001;98:450a. Murphy S et al. Transfusion 2006;46:24-33.

  17. Clinical Trial: Riboflavin-Treated Platelets The MIRACLE Trial n = 110 CCI1h: 31% decrease (primary outcome measure) MAX 75% CCI1h CCI24h 50,000 MEAN 50% 25% 40,000 MIN CCI 30,000 20,000 10,000 0 -10,000 Mirasol Control Mirasol Control Transfusion 2010;50:2362-75.

  18. Clinical Trial: Riboflavin-Treated Platelets The MIRACLE Trial n = 110 CCI1h: 31% decrease (primary outcome measure) CCI1h: 31% decrease (primary outcome measure) No differences observed Clinical bleeding assessment Inter-transfusion interval Transfusion 2010;50:2362-75.

  19. Pathogen-Inactivated Platelets in Routine Use 3 yr before  3 yr after adoption of INTERCEPT platelets (Used in place of bacterial detection and gamma irradiation) BeforeAfter Patients 690 756 Transfusions 6829 7538 Transfusions/patient 9.9 10.0 Platelets collected/unit 6.6x1011 6.7x1011 Storage period 5d 7d Outdating 9.1% 1.2% Osselaer JC et al. Transfusion 2007;47:19A.

  20. PI Platelets: The Similarities Some loss of platelets through process (small; manageable) UV light  Identifiable platelet damage Increased metabolic rate Increased activation during storage Reduced recovery Reduced survival Interaction with leukocytes’ DNA  Reduction in alloimmunization Consideration of replacement of γ-irradiation

  21. Prevention of Alloimmunization MECHANISM INHIBITED BY PHOTINACTIVATED PI MECHANISM NOT INHIBITED BY PHOTINACTIVATED PI Marschner S et al. Transfusion 2010;50:2489-98.

  22. Prevention of Graft versus Host Disease Adducts: Amotosalen + UV 1/83 base pairs Gamma irradiation 1/37,000 base pairs Prevention of GvHD in murine model Inhibition of APC function Inhibition of cytokine production R Dodd Vox Sang 2002;83(Suppl 1):267-70. Osselaer JC et al. Blood 2007;110:849a.

  23. PI Platelets: Concerns SPRINT Trial (FDA) Respiratory distress: 5 test vs. 0 control (n=671) Independent, blinded review of all (148) pulmonary events  No association with PI platelets Corash L et al. Blood 2011;117:1014-20.

  24. Heme/Onc pts (n=295) Expected: ≥ 2 plt transfusions Plasma (n=99) 357 transfusion events 292 per protocol PAS III (n=94) 381 transfusion events 278 per protocol PR – PAS III (n=85) 391 transfusion events 257 per protocol Early cessation: Lower CCI1hr Increased bleeding PI Platelets: Concerns HOVON Trial Primary endpoint: CCI1hr Secondary endpoints: CCI24hr, bleeding, transfusion needs and intervals, reactions Kerkoffs J-LH et al. BJH 2010150:209-17.

  25. Heme/Onc pts (n=295) Expected: ≥ 2 plt transfusions Plasma (n=99) 357 transfusion events 292 per protocol PAS III (n=94) 381 transfusion events 278 per protocol PR – PAS III (n=85) 391 transfusion events 257 per protocol PI Platelets: Concerns HOVON Trial SPONTANEOUSLY REPORTED; UNBLINDED TRIAL Primary endpoint: CCI1hr Secondary endpoints: CCI24hr, bleeding, transfusion needs and intervals, reactions Kerkoffs J-LH et al. BJH 2010150:209-17.

  26. PI Platelets: Concerns Maximum grade of bleeding (%) PlasmaPAS IIIPR – PAS III Grade 1 12% 11% 19% Grade 2 6% 4% 7% Grade 3 1% 0 6% CLINICAL SIGNIFICANCE? APPROPRIATE TO COMBINE? Kerkoffs J-LH et al. BJH 2010.

  27. NS p < 0.05 NS 6-7d Storage of Amotosalen-Treated Platelets UntreatedPI Platelets Patients 100 101 CCI1hr 9,383 8,163 CI1hr 21,600 19,400/μL CI24hr 15,200 11,100 Interval 2.3 2.2d HSCT: 67% p < 0.05 Δ = 17% (<30%) 6d: 20% 7d: 80% Lozano M et al. ISBT 2010.

  28. Bacterial Reduction by Antimicrobial Peptides Antimicrobial Peptides Studied Mohan KVK et al. Transfusion 2010;50:166-73.

  29. Bacterial Reduction by Antimicrobial Peptides Mohan KVK et al. Transfusion 2010;50:166-73.

  30. Methods: Available or Approaching Plasma Quarantined plasma Solvent/detergent treatment Methylene blue + light Amotosalen + UV Riboflavin + UV Platelets Amotosalen + UV Riboflavin + UV UV alone Red cells S-303 Riboflavin + UV

  31. NEUTRAL S-303 Mechanism of Action t1/2 = 25 min pH ACIDIC  ACTIVATION S-300- NO NUCELIC ACID INTERACTIONS Similar to amotosalen but no UV activation required

  32. Effect of S-303 on RBC Recovery and Survival 35d storage TreatedControl 24h Recovery 81.7+6.3% 84.5+6.2% p = 0.048 Survival 37.4+8.9d 37.6+6.7d p > 0.05 n = 29, paired 11 full-unit reinfusions Rios et al. Transfusion 2006;46:1778-86.

  33. Y ACRIDINE ACRIDINE Problems with RBC Pathogen Inactivation NEOANTIGEN Y No Monocyte Mononuclear Assay activity. North A et al. Vox Sang 2007; 93(suppl 1):167-8.

  34. Y ANTI-ACRIDINE Problems with RBC Pathogen Inactivation Modified S-303 Process: Glutathione: 2  20mM at neutral pH

  35. UNTREATED RBCs mS-303 TRMT S-303 TRMT S-303 Treatment and Immunogenicity Augmented Rabbit Model Recently completed: Blinded crossover autologous reinfusion trial RBC Recovery (log scale) Rabbits immunized with S-303 + KLH Time North A et al. Vox Sang 2007; 93(suppl 1):168.

  36. Control RBCs No Ab demonstrated Riboflavin + UV Quinacrine mustard trmt Ab demonstrated Riboflavin Treatment and Immunogenicity Baboon Model 90 Unlabeled infusions: Days 0, 21, 42, 49 51Cr infusion: Day 56 RBC Recovery (%) 80 70 60 50 40 30 20 10 100 200 300 400 500 Time (h) Goodrich RP et al. Transfusion 2009;49:64-74.

  37. Current Status of Pathogen Reduction Methods Yes, PI works. But can the system accommodate?

  38. Impact of Conversion to PI Platelets All Patients Hematology Patients Before PI After PI Platelet Transfusions Required Osselaer JC et al. Transfusion 2009;49:1412-22.

  39. “If someone says it’s not about the money, it’s about money!” Intercept Platelet conversion experience - Strasbourg Kit cost: 75€/apheresis unit Personnel time: 3€ Costs avoided: Bacterial detection: 30€ Per new test: 10€ For France: Cost neutral with apheresis proportion 85%  55% Cazenave JP et al. Vox Sang 2007; 93(suppl 1):51-2.

  40. APHERESIS PLATELET APHERESIS PLATELET TREATED POOLED PLTS TREATED POOLED PLTS Plt Plt Plt Plt Plt Plt Plt Plt Plt Plt Plt Plt Plt Plt Plt Plt Plt Plt Plt Plt Plt Plt Plt Plt Plt Plt Plt Plt Plt Plt Plt Plt Plt Plt Plt Plt Plt Plt Plt Plt Plt Plt Plt WHOLE BLOOD Reduction of Economic Impact TREATED APHERESIS PLATELET TREATED APHERESIS PLATELET DOUBLE POOL

  41. Pathogen Inactivation Technologies An opportunity to improve patient safety and simplify blood banking.

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