Transcript Slide 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
Transfusion safety is like an onion…
I
T
D
SAFETY
“Emerging” Pathogens
Ocean virus
Chikungunya virus; Dengue fever
Modified from: Morens DM et al. Nature 2004;430:242-9.
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
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
PI Plasma: The Similarities
Reduction in procoagulant activity:
Effect of implementation:
10-20%
Clinical utility
Rock G. Vox Sang 2011;100;169-78.
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
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.
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.
PI Platelets: The Similarities
Some loss of platelets through process (small; manageable)
UV light  Identifiable platelet damage (↓mt DNA transcription)
Increased metabolic rate
Increased activation during storage
Using UVC to Inactivate
Control
Platelets
HSR
pH
Aggr: Collagen
Glucose
Lactate
9.4±1.6
68±1
7.29±0.12
62±7
63±9
12.5±0.9
Treated
9.1±1.3 x 108/mL
61±8%
7.09±0.05
69±7%
41±8 mg/dL
15.2±1.0 mM
Illumination: 0.4J/cm2
Testing: Day 8
Walker WH et al. Vox Sang 2007;93(suppl 2):69.
Fibrinogen receptor expression, MFI
In vitro Assessment of Functional Properties
12
Intercept
10
Mirasol
8
Control
6
4
2
TRAP-6 aggregation response,, %
0
Control
Mirasol
Intercept
Picker SM et al. Transfusion 2009;49:1224-32.
Treatment Effect: Metabolic Changes
14
Lactate, mM
12
10
Control
Intercept
Mirasol
8
6
4
2
0
1
5
7
8
Storage time, days
Picker SM et al. Vox Sang 2009;97:26-33.
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 15-25%
Reduced survival
Clinical Trial: Amotosalen-Treated Platelets
The euroSPRITE Trial
Treated
Control
Units transfused/patient
7.5+5.8
5.6+5.5
p > 0.05
Count increment (109/L):
1h post-transfusion
24h post-transfusion
27.6+13.3
16.4+9.5
35.8+23.3
24.7+17.6
p < 0.02
p = 0.004
14,900+6200
10,600+7100
p = 0.11
p = 0.02
Corrected count increments:
1h post-transfusion
13,100+5400
24h post-transfusion
7300+5400
Van Rhenen D et al. Blood 2000;96:819a.
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.
Clinical Trial: Riboflavin-Treated Platelets
The MIRACLE Trial
n = 110
CCI1h: 31% decrease (primary outcome measure)
MAX
75%
50,000
CCI1h
CCI24h
40,000
MEAN
50%
25%
MIN
CCI
30,000
20,000
10,000
0
-10,000
Mirasol
Control
Mirasol
Control
Transfusion 2010;50:2362-75.
Clinical Trial: Riboflavin-Treated Platelets
The MIRACLE Trial
n = 110
CCI1h: 31% decrease (primary outcome measure)
No differences observed
Clinical bleeding assessment
Inter-transfusion interval
Transfusion 2010;50:2362-75.
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)
Patients
Transfusions
Transfusions/patient
Before
690
6829
9.9
After
756
7538
10.0
Platelets collected/unit
6.6x1011
6.7x1011
Storage period
Outdating
5d
9.1%
7d
1.2%
Osselaer JC et al. Transfusion 2007;47:19A.
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
Prevention of Alloimmunization
MECHANISM INHIBITED BY
PHOTINACTIVATED PI
MECHANISM NOT INHIBITED
BY PHOTINACTIVATED PI
Marschner S et al. Transfusion 2010;50:2489-98.
Prevention of Graft versus Host Disease
Adducts:
Amotosalen + UV
Gamma irradiation
1/83 base pairs
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.
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.
PI Platelets: Concerns
HOVON Trial
Heme/Onc pts (n=295)
Expected: ≥ 2 plt transfusions
Plasma (n=99)
PAS III (n=94)
PR – PAS III (n=85)
357 transfusion events
292 per protocol
381 transfusion events
278 per protocol
391 transfusion events
257 per protocol
Early cessation:
Lower CCI1hr
Increased bleeding
Primary endpoint:
CCI1hr
Secondary endpoints: CCI24hr, bleeding, transfusion needs
and intervals, reactions
Kerkoffs J-LH et al. BJH 2010150:209-17.
PI Platelets: Concerns
HOVON Trial
Heme/Onc pts (n=295)
Expected: ≥ 2 plt transfusions
Plasma (n=99)
PAS III (n=94)
PR – PAS III (n=85)
357 transfusion events
292 per protocol
381 transfusion events
278 per protocol
391 transfusion events
257 per protocol
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.
PI Platelets: Concerns
Maximum grade of bleeding (%)
Grade 1
Grade 2
Grade 3
Plasma
12%
6%
1%
PAS III
11%
4%
0
PR – PAS III
19%
7%
6%
APPROPRIATE
CLINICAL TO
SIGNIFICANCE?
COMBINE?
Kerkoffs J-LH et al. BJH 2010.
6-7d Storage of Amotosalen-Treated Platelets
Untreated
PI Platelets
100
101
Patients
HSCT: 67%
CCI1hr
9,383
p < 0.05
Δ = 17% (<30%)
CI1hr
21,600
NS
CI24hr
15,200
p < 0.05
2.3
NS
Interval
6d: 20%
8,163
19,400/μL
11,100
2.2d
7d: 80%
Lozano M et al. ISBT 2010.
Bacterial Reduction by Antimicrobial Peptides
Antimicrobial Peptides Studied
Mohan KVK et al. Transfusion 2010;50:166-73.
Bacterial Reduction by Antimicrobial Peptides
Mohan KVK et al. Transfusion 2010;50:166-73.
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
S-303 Mechanism of Action
pH ACIDIC
t1/2 = 25 min
NEUTRAL
 ACTIVATION
S-300NO NUCELIC ACID
INTERACTIONS
Similar to amotosalen but no UV activation required
Effect of S-303 on RBC Recovery and Survival
35d storage
Treated
Control
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.
Problems with RBC Pathogen Inactivation
NEOANTIGEN
No Monocyte Mononuclear Assay activity.
North A et al. Vox Sang 2007; 93(suppl 1):167-8.
Problems with RBC Pathogen Inactivation
Modified S-303 Process: Glutathione: 2  20mM at neutral pH
S-303 Treatment and Immunogenicity
Augmented Rabbit Model
UNTREATED RBCs
RBC
Recovery
(log scale)
Recently completed: Blinded
crossover autologous reinfusion trial
mS-303
TRMT
Rabbits immunized with S-303 + KLH
S-303
TRMT
Time
North A et al. Vox Sang 2007; 93(suppl 1):168.
Riboflavin Treatment and Immunogenicity
Baboon Model
90
Unlabeled infusions: Days 0, 21, 42, 49
51Cr infusion: Day 56
RBC 80
Recovery
(%) 70
Control RBCs
60
50
40
No Ab demonstrated
Riboflavin + UV
20
10
Quinacrine
mustard trmt
Ab demonstrated
100
200
300
400
500
Time (h)
Goodrich RP et al. Transfusion 2009;49:64-74.
Current Status of
Pathogen Reduction Methods
Yes, PI works.
But can the system accommodate?
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.
“If someone says it’s not about the money,
it’s about money!”
Intercept Platelet conversion experience - Strasbourg
Kit cost:
Personnel time:
75€/apheresis unit
3€
Costs avoided:
Bacterial detection:
Per new test:
30€
10€
For France: Cost neutral with apheresis proportion
85%  55%
Cazenave JP et al. Vox Sang 2007; 93(suppl 1):51-2.
Reduction of Economic Impact
APHERESIS
TREATED
APHERESIS
PLATELET
PLATELET
TREATED
APHERESIS
APHERESIS
PLATELET
PLATELET
Plt
Plt
Plt
WHOLE
BLOOD
TREATED
POOLED
PLTS
Plt
Plt
Plt
Plt
Plt
DOUBLE
POOL
Plt
Plt
Plt
Plt
Plt
TREATED
POOLED
PLTS
Pathogen Inactivation Technologies
An opportunity to improve patient safety
and
simplify blood banking.