Pathogen inactivation in platelet concentrates in France

Transcription

1 Swisstransfusion: Jahrestagung 2011 Fribourg, 8-9 septembre, 2011 Pathogen inactivation in platelet concentrates in France Jean-Pierre Cazenave EFS-Alsace, UMR_S949 INSERM-Université de Strasbourg, France

2 Patients and their doctors have always feared medical risks linked to transfusion Risks of transmission of infectious agents to blood recipients are secondary to contamination of blood donors and of derived labile blood products (red blood cells, platelets, plasma) and of industrially prepared plasma derived drugs. In a recent past, emerging viruses (HBV, HIV, HCV) have been the cause of human tragedies. Implementation of preventive measures have reduced the risk of infectious diseases. These reactive measures do not take into account the occurrence of the next risk and the time to set up a reply. In France, the introduction of pathogen inactivation of labile blood products has been progressive and based on technical, microbiological, epidemiological and clinical criteria. [plasma: (100%), platelets: 2005 (4/17 regions)]

3 Epidemiological data and pathogen inactivation 1. Time interval varies between the recognition of the risk of an infectious disease and implementation of screening in the blood donor : 30 years for hepatitis B, 15 years for hepatitis C, 4 years for HIV and 4 years for WNV. 2. Following inactivation of plasma derived drugs, no infection due to these viruses has occured. 3. Emerging new pathogens transmitted by transfusion are feared : WNV, Chikungunya, dengue, XMRV, HHV-8, Q fever, Chagas disease, malaria. 4. Epidemiological modifications of populations of donors and recipients secondary to migrations (travel, war, famine) and of climate changes (mosquitos expansion and epidemies).

4 The INTERCEPT blood system 1. Photochemical method using amotosalen and UVA ( nm) 2. Inactivation of a large spectrum of pathogens : bacteria, viruses, protozoa, spirochetes and lymphocytes (no effect on bacterial spores, nvcjd) 3. Platelets (APC or BCPC) resuspended in 35 % plasma and 65 % additive solution 4. Pre-clinical (pharmacokinetics, toxicology) and 11 clinical trials completed (including eurosprite, SPRINT) 5. CE marking (Class III drug-device combination) in 2002 and marketing approval in 2005 (France, AFSSAPS), 2007 (Germany, PEI), 2009 (Swissmedic) 6. Approved claims : transfusion support of patients requiring PC according to clinical practice guidelines ( AFSSAPS: 0.5 to 0.7x10 11 platelets /7kg). INTERCEPT APC or BCPC are not clinically different from untreated PC. 7. Clinical use in Europe : > 1,000,000 transfusions units of INTERCEPT PC and PFC 8. Clinical use in 4 regions in France : EFS-Ile de la Réunion, EFS-Martinique, EFS-Guadeloupe-Guyane and EFS-Alsace (100 % use)

5 Mechanism of action of amotosalen for platelets and plasma Amotosalen (S-59) UVA Illumination Targeting Intercalation Crosslinking Helical region of single- or double-stranded DNA or RNA Multiple crosslinks block strand separation and replication

6 INTERCEPT Blood System (Amotosalen + UVA) A broad spectrum of pathogen inactivation Enveloped viruses HIV-1 HIV-2 HBV DHBV HCV BVDV HTVL-I HTLV-II CMV/EBV/HHV-8 WNV SARS Vaccinia Chikungunya Dengue Influenza virus (H1N1) Avian flu virus (H5N1) XMRV Non-enveloped viruses Bluetongue virus, type 11 Simian Adenovirus-15 Feline calicivirus Parvovirus B19 Human adenovirus 5 Gram-negative bacteria Klebsiella pneumoniae Yersinia enterocolitica Escherichia coli Pseudomonas aeruginosa Salmonella choleraesuis Enterobacter cloacae Serratia marcescens Gram-positive bacteria Staphylococcus epidermidis Staphylococcus aureus Streptococcus pyogenes Listeria monocytogenes Corynebacterium minutissimum Bacillus cereus (vegetative) Lactobacillus sp. Bifidobacterium adolescentis Propionibacterium acnes Clostridium perfringens Spirochetes Treponema pallidum Borrelia burgdorferi Protozoa Trypanosoma cruzi Plasmodium falciparum Leishmania mexicana Babesia microti Residual leukocytes T lymphocytes, cytokines Bacterial spores resistant Prions resistant In general, 5 to 6 log reduction in infectious assays In addition replaces gamma irradiation

7 Clinical experience with INTERCEPT platelets and plasma in France since 2005 Pilot center 100% INTERCEPT platelets and plasma 100 % INTERCEPT platelets Epidemy of : Chikungunya Dengue Chagas 275,779 platelet doses (France. 2010) 380,707 FFP doses (France. 2010) Alsace : 2 millions inhabitants 3 hospitals : Strasbourg Colmar Mulhouse > 81,000 PC INTERCEPT > 88,000 plasma INTERCEPT

8 3 periods of transfusion of PC prepared in plasma, T-Sol, Intersol + Intercept

9 Platelet concentrates (PC) transfused* to all patients in Alsace PC (100% plasma) PC-T-sol (35% plasma) PC INTERCEPT (35% plasma) Patients (n) 2,050 1,678 2,069 Age (yrs) (median, min-max) 64 (3 97) 63 (<1 99) 63 (<1 106) PC transfused (n) 10,629 9,151 13,241 Platelet content per unit 5.2 x x x PC mean / patient PC mean dose plt x10 11 / patient RBCC median / patient ATR (% / patient) 2.9 % 2 % 1.7 % Cazenave JP et al. Transfusion 2010; 51:

10 Distribution of the number of PC prepared in plasma, T-Sol, Intersol + INTERCEPT transfused during the 3 periods in Alsace (%) PERIOD 1 PLASMA PERIOD 2 T SOL PERIOD 3 INTERCEPT [3-5] [6-10] [11-20] [21-50] [51-100] >100 Number of PC transfused per patient

11 Platelet concentrates (PC) transfused to hematology-oncology patients in Alsace PC (100% plasma) Patients (n) PC unit tranfused (n) 5,816 7,675 PC-INTERCEPT (35% plasma) p Platelet content per unit 5.2 x x PC unit transfused x10 11 /patient 8.7 ± ± Platelet total dose x10 11 /patient 45.3 ± ± Total RBCC units 15.2 ± ± Cazenave JP et al. Transfusion 2010;51:

12 PC transfused to hematology-oncology pediatric and adult patients in Alsace C-P * 1/1/2003 1/2/2004 I-P ** 1/9/2006 1/8/2007 Age (years) > 0.1 < 3 > 2 <17 > 16 > 0.1 < 3 > 2 <17 > 16 Patients (n) PC unit transfused (n) Mean / patient 7.0 ± ± ± ± ± ± 20.6 Median / patient Platelet total dose x10 11 Mean / patient 30.3± ± ± ± ± ± 89.0 Median / patient Total RBCC units Mean / patient 7.7 ± ± ± ± ± ± 18.9 Median / patient * C-P unit : 5.2 x plt; ** I-P unit : 4.2 x plt

13 Demography of platelet concentrates (PC) transfused to oncohematology patients in Strasbourg, only, during period 1 (129/671) and during period 3 (330/699) Pathology Period 1 n (%) PC(100%plasma) Period 3 n (%) PC-INTERCEPT Solid tumors 22 (17) 77 (23.3) AML 31 (24) 82 (24.8) ALL 9 (6.9) 14 (4.2) Non Hodgkin lymphomas 16 (12.4) 60 (18.2) Multiple myeloma 15 (11.6) 39 (11.8) Myelodysplasia 3 (2.3) 15 (4.5) CML 1 (0.8) 9 (2.7) CLL 10 (7.7) 10 (3) Hodgkin 3 (2.3) 4 (1.2) Other or unknown 19 (14.7) 20 (6.1)

14 Platelet concentrates (PC) transfused to hematology-oncology patients in Strasbourg, only Pathology Period 1 (n=129) PC (100% plasma) Total dose/plt (x10 11 ) Period 3 (n=330) PC-INTERCEPT Total dose/plt (x10 11 ) All patients (Alsace) 45.3 (n=671) 46.1 (n=699) Solid tumors AML ALL Non Hodgkin lymphoma Multiple myeloma Myelodysplasia CLL Hodgkin

15 Demography of platelet concentrates transfused to 781 hematology-oncology patients in Alsace in 2010 Pathology Patients (n) Patients (%) Solid tumors % Acute leukemias % Non Hodgkin lymphoma % Multiple myeloma 55 7% Myelodysplasia % Chronic leukemia % HSC allograft % Hodgkin 5 0.6% Other or unknown %

16 Quantities of platelet concentrates transfused to 781 hematology-oncology patients in Alsace in 2010 Pathology Transfusion /pt (n) Dose of platelets(x10 11 ) /transfusion Dose of platelets (x10 11 /7kg) /transfusion Total dose/plt (x10 11 )/patient /year All patients Solid tumors Acute leukemias Non Hodgkinlymphomas Multiple myeloma Myelodysplasias Chronic leukemias HSC allograft Hodgkin

17 Comparison of platelet concentrates transfused to all patients and onco-hematology (OH) patients in Alsace in 2007 (period 3) and in 2010 Patients (n) Transfusion /pt (n) Dose of platelets(x10 11 ) /transfusion Dose of platelets (x10 11 /7kg) /transfusion Total dose/plt (x10 11 )/patient /year All patients (2,069) 2010.All patients (2,362) OH patients (699) 2010.OH patients (781)

18 Transfusion of INTERCEPT platelets and surgery during major hereditary thrombopathies 1. Glanzmann thrombasthenia type I with the Gypsy mutation Patient 1 : 21 year old woman with ovarian cyst resection - Total dose (D10) : x platelets - 3 RBCC + 1 FPC Intercept Patient 2 : cesarean section in a 22 year old woman - presence of anti-hla and anti-hpa1a antibodies - Total dose (D11) : x platelets - no RBCC Patient 3 : avulsion of 2 molar teeth in a 6 year old boy - Total dose (D6) : 12 x platelets 2. Thrombopenia with absent radius : 2 year old boy - Born on 23/09/2006 and transfused during his first year in Nancy - Since 18/05/2007, transfused in Strasbourg : 1 APC Intercept / week, total dose : 91 x platelets - No ATR (24/06/2008)

19 Platelets and plasma treated with INTERCEPT and transfused at EFS-Alsace ( ) 0-3 years N patients /N units transfused 3-17 years N patients /N units transfused 17 years N patients /N units transfused MCPSD-IA 20/33 95/ /40,104 CPAD-IA 313/1, /3, /20,045 PFC-IA 449/1, /1, /40,259 Total patients ( %) Total units ( %) 782/2,755 (4.0%/2,6%) 524/5,033 (2,7%/4.6%) 18,381/100,408 (93,3%/92.8%)

20 Significant Reduction of AcuteTransfusion Reactions 1 episode of TRALI due to high titer HLA 1 and 2 antibodies in a multiparous apheresis donor.

21 Frequency of Transfusion Transmitted Bacterial Infections (TTBI) of conventional platelet concentrates (PC) and of INTERCEPT inactivated PC Conventional PC INTERCEPT-PC Year PC (n) TTBI TTBI / 10 4 PC PC (n) TTBI TTBI / 10 4 PC ,853 4 (0) , ,708 9 (3) , ,349 6 (1) , ,634 9 (0) , ,149 2 (1) , Total 1,198,691 30(5) , AFSSAPS annual hemovigilance reports from 2006 to 2009 (gravity 1-4, imputability 3 and 4) 5 deaths (4 LR-APC / 1 LR-BCPC conventional)

22 Conclusions 1. Inactivation of PC (later plasma) by INTERCEPT was introduced in 2006 for all patients transfused in Alsace to increase transfusion safety by a proactive rather than passive approach 2. Avoid bacterial detection and prevent sepsis due bacterial contamination 3. Replace gamma irradiation for TA-GvHD 4. Avoid CMV serology for allogeneic transplants 5. Prevent transfusion-transmitted viral diseases (closing the window period, small copy numbers, mutants ) and protect emerging pathogens from entering the blood supply 6. Reduce acute adverse events 7. Inactivation of PC is efficient to prevent bleeding due to thrombocytopenia or thrombopathy 8. Hemostatic efficiency does not require to transfuse more platelets (total dose) or red cells 9. Final safety in PSL transfusion when plasma, platelets and RBC are inactivated

23 Thank you for your attention