Leukodepletion, Pathogen Inactivation, Irradiation – For some,

or everyone?

Aleksandar Mijovic

King’s College Hospital/National Health Service Blood & Transplant

London, UK

Zadar 2011

Immunologic effects AlloimmunisationFebrile non-haemolytic reactionsPlatelet refractorinessRejection of transplanted organGraft-vs-host disease

Immune modulation Increased risk of bacterial infection (?)Increased recurrence of malignancy (?)

Infectious disease transmission

CMVHTLV-IEpstein-Barr virus

vCJD?

Adverse effects of leukocytes in blood components

Modified from: McCullough 2005

vCJD

• 4 cases in UK due to transfusion of non-leukodepleted red cells from donors who later developed vCJD.

• Incubation period 6-8.5 years

Infectivity of experimental TSE’s in blood -intracerebral route

(Brown et al, Transfusion 1998:38;810)

22%

24%

54%

Buffy coat Red cells Plasma

vCJD - What’s been done to prevent transmission?

– Universal Leukodepletion (1999)– Import of plasma from USA– Donor selection – ban of donors who

received transfusions after 1980– Donor testing not yet available– Prion-reduction filters (for children and

patients with haemoglobinopathies) – 2012?

Universal Leucocyte Depletion -specification (UK SACBC)

UK France Council of Europe

WBC /unit

5 x 106 1 x 106 1 x 106

% units 99 97 90

Stats confidence

95% 95% Not stated

Effect of Leukodepletion on NH-FTRYazer et al, 2004; Pruss et al, 2004

0

0.1

0.2

0.3

0.4

0.5

Platelets Red Cells Red Cells

PrULD PoULD BC-depl. Pre-StLD Post StLD

NH-FTR rate [%]

Effects of Leukodepletion on Platelet Refractoriness

• After leukoreduction in Canada:

• Alloimmunisation reduced from 19% to 7%

• Immune refractoriness reduced from 14% to 4%

– Seftel et al 2004

TRAP study, 1997•Lymphocytotoxic antibodies

•45% controls

•17-21% in treated groups

•Platelet Refractoriness

•13% controls

• 3-5% if platelets filtered or UV light-treated

Leukodepletion for cardiac surgery

• Randomised study of: a) Buffy-coat depleted RBC; b) filtered, fresh RBC; c) filtered RBC, post storage

• Infection rates:– 23.0% : 16.9% : 17.9%

• Mortality:– 7.8 % vs 3.6% vs 3.3%

Van de Watering et al 1998

Leukodepletion in hospitalised patients Dzik W et al, Transfusion 2002

• 2780 pts randomised to receive LD or non-LD blood products.

• No difference in primary outcomes: 1) In-hospital mortality; 2) Length of hospital stay (LOS); 3) Hospital costs

• Nor in secondary outcomes: 1) LOS in ICU;

2) post-operative LOS; 3) antibiotic usage;

4) re-admission rate

Risk for CMV disease in BMT(Ljungman et al 1998)

Recipient Donor CMV disease

NEG NEG 0%

NEG POS 5.4%

POS NEG 13.7%

POS POS 11.7%

PREVENTION OF CMV INFECTION

Use of CMV Neg Blood Products

Incidence of CMV Infection reduced to 0-7% (pneumonia ~ 0%)

Leukodepletion Equally effective to donor screening

(Bowden et al 1995)

Abandonment of CMV screening premature (Nichols et al 2003)

Leukodepletion vs CMV serology to prevent CMV infection

• Both are effective

• Neither is perfect

• Not possible to decide if one is better than the other

• Benefit of using both is unknown

Canadian Consensus Conference 2001

Pathogen Inactivation:in search of Zero-risk?

SHOT report 2010

SHOT report 2010

Estimated risk of viral transmission by transfusion in the UK [per million donations]

(2009)

Virus HBV HCV HIV HTLV-1

Trans-

Missions

1.5 0.01 0.20 0.06

www.hpa.org.uk

414 blood donors in 2005340 blood donors in 20061500 clinical cases with 9 deaths 2006

PATHOGEN INACTIVATION/REDUCTION

key issues

1. Effective inactivation of a range of agents; no evidence of toxicity. Compare with current alternatives.

2. Underlying residual risk in a given country.

3. ?Threat from new (or newly identified) microbial agents.

4. ?How to measure safety increment from PI.

5. Logistics; process control. Separate PI steps needed for each blood component

6. ?Cost-benefit.

Inactivation of Pathogens in platelets by S-59 (Log)

• HIV >6.2• HBV >5.5• HCV >4.5• CMV >5.9• West Nile >6.0• HTLV I/II 4.7-

5.1• ParvoB19 4.0-4.9

• E.Coli >6.4 • S.Aureus 6.6• P.Aeruginosa 4.5• B.Cereus >6.0• Yersinia E. >5.9

• P.Falciparum 7.0• T.Cruzi >5.3

Photochemical Treatment of Platelets – euroSPRITE trial

• Randomised study (52 v 51 pts) of Amotosalen (S-59) treated BC platelets.

• Average dose: 3.9 vs 4.3 x 1011 (p<.001)

• 1-h increment: 27.5 vs 35.8 x 109 /L. Difference 8.3 (95% CI, 0.9 – 15.8) (p=.03)

• 1-h CCI: 13.1 vs 14.9 x 103 (p=.11)

• Bleeding/adverse events not different

Van Rhenen et al 2003

Photochemical Treatment of Platelets – SPRINT trial

• Randomised study (318 v 327 pts) of Amotosalen (S-59) treated apheresis platelets.

• Average dose: 3.7 vs 4.0 x 1011 (p<.001)

• Grade 2 bleeding: 58.5% vs 57.5% (NInf)

• Grade ¾ bleeding: 4.1% vs 6.1% (Ninf)

• 1-h CCI: 11.1 vs 16.0 x 103 (p<.001)

• Units received: 8.4 vs 6.2 (p<.001)

McCullough et al 2004

MIRASOL randomised trialMirasol Clinical Evaluation Group 2010

• Mirasol: Riboflavin (vitamin B2) + UV light• RCT: 56 pts (303 transf.) received PR-

platelets, 54 pts (238 transf.) received reference platelets.

• Primary outcome: 1-hour CCI• PR-P vs REF-P: 11725 : 16939 (criteria for

non-INF not met).• PLT/RC utilisation not significantly different;

Safety profile similar.

Plasma - Spoiled for Choice?

• Fresh Frozen Plasma

• Solvent/Detergent treated plasma

• Methylene Blue/UV light treated plasma

FFP vs S/D vs MB Plasma: risk of disease transmission

STANDARD FFP S/D PLASMA (OCTAPLAS)

METHYLENE BLUE PLASMA

Viral disease Current estimated risks in UK*:

HBV 1:0.6 million

HCV 1:100 million

HIV 1:20 million

Very low - S/D treatment effectively kills all lipid envelope viruses (but NOT HAV and Parvovirus B19)

1 possible HCV transmission.

vCJD Not known.

Four cases of transmission via blood transfusion reported in the UK.

Not known.

Pooling could have adverse effect unless estimated infectivity in the source was 200-fold less than in UK

Not known.

TRALI 1 in 15 - 20,000 transfused

units.

Male donor plasma reduces risk.

? 1 possible case; expected to be less because of dilution of HLA-antibodies by pooling.

As for FFP

•Risks per donated unit estimated for All

BloodProducts

STANDARD FFP S/D PLASMA (OCTAPLAS)

METHYLENE BLUE PLASMA

Coagulation Factors

> 75% > 0.7 iu/mL 2 antiplasmin ~ 0- 23%•Protein S 50-64%•Loss of HMW Von Willebrand factor multimers

75% > 0.5 iu/mL

Fibrinogen recovery 65-83%

Clinical efficacy

& Risks

Cryosupernatant preferred in TTP

Preferred in TTP

Liver transplants – increased risk of bleeding ?

Risk of VTE/PE?

Less efficacious in TTP?

Mutagenicity?

Volume 250-300 ml 200 ml 275 ml

Cost (per unit) 2011

£ 30.16

£ 52.53 £ 171.46

0

20

40

60

80

100

120

140

160

180

200

0

2

4

6

8

10

12

14

16

= SD/Cryopoor plasma exchange

Prednisolone

R Fem Vascath L Fem Vascath

PulmonaryEmbolism

A.S., 18 y, TTP

22 Plasma exchanges

COMPARATIVE STUDY OF TWO TYPES OF PLASMA IN LIVER

TRANSPLANTATIONRETROSPECTIVE, SINGLE CENTRE STUDY OF ADULT

ORTHOTOPIC LIVER TRANSPLANT PATIENTS:

200 S/D FFP OCTAPLAS (1998-2001)

199 SINGLE DONOR FFP (after March 2001)

ENDPOINTSPRIMARY:

AMOUNT OF BLOOD PRODUCTS USEDESTIMATED BLOOD LOSS USE OF OTHER HAEMOSTATIC PRODUCTS

SECONDARY48HRS MORTALITY

RESULTS

FFP Octaplas Difference

(95% CI)

P

Wilcoxon

Overall

Blood loss

5005 5717 694

(-330 – 1739)

0.17

Intra-op

Plasma

2560 2430 -74

(-521 – 257)

0.57

Post-op

Plasma

225 700 149

(0 – 381)

0.02

Intra-op

Red Cells

2091 2440 300

(0 – 658)

0.063

Post-Op

Red Cells

1925 1925 0 1.0

Overall

Platelets

838 1043 252

(0 – 570)

0.019

Viral safety

Reduced risk of TRALI

Reduced risk of vCJD?

Increased blood usage in OLT

Increased VTE risk

Cost

S/D plasma or FFP ?

Conclusions

Use S/D PLASMA in:- Below age 16- Young patient with good immediate and long-

term prognosis, anticipated to receive few blood products.

- Thrombotic Thrombocytopenic Purpura

Acute GVHD

Transfusion related• onset 2-30 days• pancytopenia/BM

aplasia• No response to Th• Mortality >90%

Post BMT/PBPCT• onset 35-70 days• rare BM aplasia• Incidence 20-70%• 80-90% respond to

Th• mortality 10-15%

Graft-versus-host disease of the skin

Leukodepletion – does it prevent TA-GVHD? - No case since 2001 in UK

Pathogen Inactivation for Cellular Components

Gamma/ X-ray Irradiation 25Gy

Transfusion-associated Graft-vs-Host disease: Prevention

Indications for irradiation of blood components in the UK

A. Indication by patient condition

• Intrauterine transfusions

• Neonatal exchange transfusions

• Congenital immune deficiencies

• Allogeneic HSC transplant patients

• Autologous HSC patients

• Hodgkin’s disease

• Purine analogue treatment

• Aplastic anaemia treated with ATG or Alemtuzumab

B. Indication by component type

• Granulocyte transfusions

• HLA-matched blood components

• Blood components from relatives

Frequency of Homozygous HLA donors to recipients heterozygous for the same haplotype

[1 : x]

Population Parent/child Sibling Unrelated

Japan 102 193 874

Canada (Cauc.) 154 294 1664

Germany 220 424 3144

USA (Cauc.) 475 902 7174

France 762 2685 16835

Survey of Blood Use in France (1997)

175 Hospitals, 3206 Transfused Patients

57% of transfusion recipients were > 65 years

Mathoulin-Pelissier et al, Transfusion 40:1140, 2000

“Greying” of the Population

• Life Expectancy in UK (2001)

• 80 y for Women

• 75 y for Men

• In 2007, people ≥ 60 were 21.8% of UK population.

• The same year, people aged 65+ outnumbered those under 16 y for the first time ever.

UN Dept. of Economic & Social Affairs

Who should we irradiate blood products for?

• According to national guidelines

• All recipients with malignant disease

• Recipients > age 65 yr

• Everyone