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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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slide1

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

slide2

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Transfusion safety is like an onion…

SAFETY

slide3

“Emerging” Pathogens

Ocean virus

Chikungunya virus; Dengue fever

Modified from: Morens DM et al. Nature 2004;430:242-9.

slide4

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

slide5

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

slide6

PI Plasma: The Similarities

Reduction in procoagulant activity: 10-20%

Effect of implementation: Clinical utility

Rock G. Vox Sang 2011;100;169-78.

slide7

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

slide8

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.

slide9

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.

slide10

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)

slide11

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.

slide12

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.

slide13

Treatment Effect: Metabolic Changes

Lactate, mM

Storage time, days

Picker SM et al. Vox Sang 2009;97:26-33.

slide14

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%

slide15

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.

slide16

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.

slide17

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.

slide18

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.

slide19

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.

slide20

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

slide21

Prevention of Alloimmunization

MECHANISM INHIBITED BY PHOTINACTIVATED PI

MECHANISM NOT INHIBITED BY PHOTINACTIVATED PI

Marschner S et al. Transfusion 2010;50:2489-98.

slide22

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.

slide23

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.

slide24

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.

slide25

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.

slide26

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.

slide27

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.

slide28

Bacterial Reduction by Antimicrobial Peptides

Antimicrobial Peptides Studied

Mohan KVK et al. Transfusion 2010;50:166-73.

slide29

Bacterial Reduction by Antimicrobial Peptides

Mohan KVK et al. Transfusion 2010;50:166-73.

slide30

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

slide31

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

slide32

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.

slide33

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.

slide34

Y

ANTI-ACRIDINE

Problems with RBC Pathogen Inactivation

Modified S-303 Process: Glutathione: 2  20mM at neutral pH

slide35

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.

slide36

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.

slide37

Current Status of

Pathogen Reduction Methods

Yes, PI works.

But can the system accommodate?

slide38

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.

slide39

“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.

slide40

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

slide41

Pathogen Inactivation Technologies

An opportunity to improve patient safety

and

simplify blood banking.