Klinische Erfahrungen mit der Pathogeninaktivierung von ... · Klinische Erfahrungen mit der Pathogeninaktivierung von Thrombozytenkonzentraten (Interceptverfahren) Department for

Klinische Erfahrungen mit der Pathogeninaktivierung von Thrombozytenkonzentraten

(Interceptverfahren)

Department for Blood Group Serology and Transfusion Medicine

(Interceptverfahren)

G. Leitner Klinik für Blutgruppenserologie und

Transfusionsmedizin

5. LeukocytesAdverse immune responses

and transfusion reactions

1. BacteriaIntroduced during

collection

2. Emerging/UnknownViruses

Residual risk

NAT


4. Known PathogensFor which no assay

is available

3. Window PeriodLimits of detection of

current assays(e.g. false negatives)

Patient

Window period

Ab/Ag(d)

NAT(d)

gain(d)

HIV 22 11 11


HCV 70 11 59

HBV 56 31 22

Bacterial contamination• PC (pool, apherese) 1: 2-3000*

– reaction 1: 25.000 (1:50.000)– mortality 25% (Sepsis)**

• RBC 0.03-0.3% (DL), 17,5% Ghana– reaction 1: 100 000 bis 1:1 000 000


– reaction 1: 100 000 bis 1:1 000 000– mortality 20% (Sepsis)**

• FFP < 0.04% (storage < minus 30°C)*Blajchman et al, 2001 **Bacterial Contamination of Blood Components: Risks, Strategies, and Regulation, Christopher D. Hillyer et al , 2003

Pathogen-inactivation• Pasteurisation (human albumin)• Heat inactivation• pH 4 inactivation• nanofiltration• solvent/detergent (SD) (plasma)• methylenblue/light (plasma)


• methylenblue/light (plasma)• UV-C 100 - 280 nm• mirasol (vitamin B2)/Caridian BCT

– plasma and platelets• intercept (psoralen) / Cerus

– Plasma and platelets

Helinx Compounds


• Amotosalen HCl platelet and plasma inactivation (S-59)

• S-303 für RBC

Naturally occurring psoralens

•The average daily dietary

intake of natural

psoralens is ~1300 µg

•The amount of 8-

methoxypsoralen in an


Average human psoralen intake = 1–2 mg/day

methoxypsoralen in an

average stalk of celery

(90 g) is ~60 µg compared with 50 µg in a platelet transfusion

Highly specific mechanism of Action

Amotosalen

(S-59)

UVA Illumination


Targeting

Intercalation Crosslinking

Helical region of single- or

double-stranded

DNA or RNA

Multiple crosslinks block

strand separation no

replication,

no transcriptionWollowitz Seminars in Hematology 2001;38:4-11

INTERCEPT Platelet System


• 7

Amotosalen Chemistry During Processing

After UVA


After CAD

Efficacy and Safety for Platelets Evaluated in 11 Clinical Studies (1,108 Patients)

EU Studies

Buffy Coat

Count Increments

(n=103)

Thrombocytopenic Patients (n=1074)

Bleeding Time

(n=32)

Grade 2 Bleeding

US Studies

Healthy Subjects (n=34)

Recovery and Survival

Without CAD

(n=24)

Safety, Tolerability &

PK With CAD

(n=10)


Buffy Coat

7-Day Storage Pilot

Count Increments

(n=20)

Apheresis

Count Increments

Integrated Set

(n=43)

Buffy Coat

Count Increments

Integrated Set

(n=20)

Grade 2 Bleeding

(n=645)


γγγγ-Irradiation - With CAD

(n=15)


With CAD

(n=16)

Buffy Coat

7-Day Storage

Count Increments

(n=211)

Van Rhenen et al: Blood 2003;101:2426-2433

McCullough et al: Blood 2004; 104:1534-1541

Lozano et al: Br J Haematol, e-pub, 2011

11

# of Patients

Receiving

INTERCEPT

Alsace 36 Month HV

Study# INTERCEPT

Transfusions

Study Design /

Endpoints

~6000~42,000 Routine Use, unblinded, AE

HV 1 327416,631 Routine Use, unblinded, AE

Mont Godinne 36 Month HV 7958030 Routine Use, unblinded, AE

SPRINT 3182678 Randomized,

Blinded, Bleeding

Gent -Pediatric 83500 Open label,

unblinded, ATR/AE

INTERCEPT Clinical Study Experience


Pediatric 83500 unblinded, ATR/AE

Lubeck 52560 Open label, unblinded, ATR/AE

Basel 46551 Open label, unblinded, ATR/AE

Euro-SPRITE 52390 Randomized,

blinded, CCI

HOVON ~67*~350* Randomized, unblinded, CCI

TESSI 101101 Randomized,

blinded, 7 day CCI

* Based upon interim analysis of HOVON Study.

INTERCEPT(n=318)

Control(n=327)

p-Value

Primary Endpoint

Patients with Grade 2 bleeding (%) 58.5 57.5 P<0.001

SPRINT : controlled, randomized, double-blindHemostasis Endpoints

McCullough J, et al. Blood. 2004;104:1534–41.


Secondary Hemostasis Endpoints

Patients with Grade 3 or 4 bleeding (%) 4.1 6.1 P<0.001

Number of bleeding sites with Grade 2 bleeding

1.1 1.0 NS

Proportion of patients with maximum Grade 2 bleeding (%)

54 52 NS

INTERCEPTControl

0.6

0.8

1.0P

ropo

rtio

n of

pat

ient

s w

ithG

rade

2 b

leed

ing

McCullough et al. Blood. 2004;104:1534.

SPRINT Phase III Platelet Trial:Time to Onset of Grade 2 Bleeding


Similar median time to onset = 8 days (p=0.78)

0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 320.0

0.2

0.4

Pro

port

ion

of p

atie

nts

with

Gra

de 2

ble

edin

g

Study day

INTERCEPT Platelet Hemovigilance

Study No. Transfusions

No. Countries

No. Sites

Location

HV1 5,106 4 5 Montgodinne, Madrid RC, Bergen, Tronheim, Pescara

HV2 7,437 3 7 Montgodinne, Erasme, St Jan Brugge, Strasbourg, St Etienne, Rennes, Valladolid


HV3 (closed) 6,632 9 13 Lübeck, La Reunion, Uppsala, Rennes, St Etienne, Prague, Barcelona, Madrid BTC, Bergen, Iceland BTC, Basel, Lisbon, Rome, Ljubjana

France HV-system(2006-2011)

104,148 1 national

CHKV epidemic 1,950* 1 1 Ile de La Reunion

Total: 125,273

No Unexpected Adverse Events

Transfusion Patient

Total 18,641 3,861

Any AE 181 (0.97%) 136 (3.5%)


Related AE (ATR) 125 (0.67%) 94 (2.4%)

Any SAE 19 (0.10%) 18 (0.5%)

SAE (probably related ATR)

1 (0.005%) 1 (0.03%)

16

INTERCEPT treatment has effectively replaced gamma-irradiationfor prevention of TA-GVHD

StudyNumber of

Transfusions

% Non-gamma

irradiated

Total Number of Patients

Hem-Onc Patients

HSCT Patients

Incidence of TA-GVHD

Phase III Trials 4 575 100% 87 82 28 0

HV1 5 5,106 97.3% 1 651 378 47 0

HV2 6 7,437 98.9% 2 1,400 748 121 0

Lin et al. Vox Sanguinis, 2011, (sup) Poster

Department for Blood Group Serology and Transfusion Medicine 17

HV3 6,991 95% 3 2,062 974 310 0

Mt. Godinne 7 3,645 100% 186 186 186 0

Pediatric 8 500 100% 83 48 10 0

Basel 9 551 100% 46 38 15 0

Lübeck 10 560 100% 52 52 17 0

Strasbourg 11 55,104 100% ~8,000 ~4,400 not available 0

1. Volume loss: 5%, platelet loss: 9-12% (16%)

during INTERCEPT treatment

2. pH loss due to treatment (> 6.4)

3. pH stable during storage

Summary / Validation 2010


3. pH stable during storage

4. Swirling is seen in all PCs during storage

5. Glucose runs out in some PCs from day 5

6. 100% sterility

Amicus Crescendo Fenwal

Software

Trima AccelTerumo(BCT)

Software


Software 2.51, 2.52, 3.1

Software 5.1; 5.2; 6.0

Start: 29.3.2012

Spenden 3126

Hergestellte TK 6443

Doppel TK (Plt ≥ 5.0 x10^11) 54%


Doppel TK (Plt ≥ 5.0 x10^11) 54%

Triple TK (Plt ≥7.2 ≤ 8.0 x 10^11 ) 27%

Außerhalb der Spezifikation 0,62% = 20

Außerhalb der Spezifikationen (aSZF)

Grenze - Volumen Erlaubte Abweichung Erlaubtes Volumen

255 ml - 6,37 ml 248 ml

420 ml + 10,5 ml 431 ml

Abweichungsregel minus 2.5%; plus 2.5%


420 ml + 10,5 ml 431 ml

Grenze - Yield Erlaubte Abweichung Erlaubter Yield

2.5 x 1011 - 0,06 2.44 x 1011 = 2.4 x1011

8.0 x 1011 + 0.2 8.2 x 1011

Konsequenzen

Intercept Tks

• 7 Tage Lagerung• kein CMV

a SZF (n = 20)

• 5 Tage Lagerung• CMV nach bestimmt


• kein CMV• kein

• CMV nach bestimmt• gamma

Ergebnisse der Qualitätskontrolle

• n = 235 Tk

• Volumen vor/nach IBS• Zellzahl vor/nach IBS


• Zellzahl vor/nach IBS

Vor ICB- nach ICB

5

6

7

8

9

vor


0

1

2

3

4

5vornach

7

8

Vor – und Nachwert% 13.8 (4.5)

Hist 9-12%16%

15

20

25%

6

X 1

011


Amicus Trima

3

4

5

Amicus Trima

5

10

24.02.2013 14:54:35 PI.WST

X 1

0

mL 28.8 (9.3)

% 6.5 (2.6)

400

450

Verlust - Volumen

13% plt


vor nach

250

300

350 13% plt

20,00

25,00

30,00

35,00

Threshold 20% Verlust


0,00

5,00

10,00

15,00

20,00

0 50 100 150 200 250

Reihe1

7.2%

Verlust (n = 235)

yield Plt 0.87 x 1011

(± 0.82)

% 13.8 (± 4.5)

Thrombozyten


(± 4.5)

n>threshold 17 (7.2%)

historisch 9-12% (16%)

ausgangswert

Thrombozytenbedarf 2003 - 2012

5000

6000

7000

8000


0

1000

2000

3000

4000

1 2 3 4 5 6 7 8 9 10

Reihe1

TransfusionserfolgSA

n = 30

AKHn = 30

Plt G/L vor 16.9 (6.1) 15.4 (9.6)

Plt G/L nach 50.4 (21.1) 31.1 (20.4)


Plt G/L nach 50.4 (21.1) 31.1 (20.4)

Anstieg errechnet 68.1 (32.9) 45.6 (12.4)

Anstieg gemessen 33.5 (21.0) 15.7 (12.4)

% Anstieg 51.4 (27.7) 36.4 (30.0)

CCI 15.0 CCI 10.4

CCI nach IBS

10

15

20

25

30

20

25

AKH


0

5

10

0

5

10

15

20

SA

CCIp < 0.0001; U-Test (Mann-Whitney)

30

40

2005 Dr.Witt/SA

-20

-10

0

10

20

0 1

ICB J=1 N=0

CC

I (G

/l)

14,27 ± 10,77

Non Intercept

8,96 ± 8,54

Intercept

15±7.4

ROTEM• inactivated • normal

19 Plt

Thrombo 36 G/l

19 Plt 22 Plt

36 Plt 100 Plt

Hämovigilanz Transfusionsbedarf6 AE /6000 Tk (0.1%) Transfusionsintervall

Vor IBS (n=48) 2.1(±2)Related AE

(ATR)125 (0.67%)


Nach IBS (n=68) 3.4 (±2)SAE

(probably related ATR)

1 (0.005%)

18.641Transfusionen

Studiendaten

300

350

4000

1

ICB J=1 N=0

0

50

100

150

200

250

J N

Unerwünschte Transfusionsnebenw irkung (J/N)

Häu

figke

it

EuroSprite Sprint

ICB n=103

Contr1n=103

ICB n=645

Contr n=645

Plt x 10^11 (mean) 3.7 4.0 3.9 4.3

• POOL • Apherese

Plt x 10^11 (mean) 3.7 4.0 3.9 4.3

Total plt dose 22.3 21.2 29.4 24.1

n transf 7.5 5.6 8.4 6.2

interval 3 3.4 1.9 2.4

1 (24) h CCI 28 (16) 36 (25) 12 (13) 34 (22)

Ich danke für Ihre Aufmerksamkeit


Documents

Klinische Erfahrungen mit der Pathogeninaktivierung von ... · Klinische Erfahrungen mit der Pathogeninaktivierung von Thrombozytenkonzentraten (Interceptverfahren) Department for