the need for individualized procedures in ecp, the ... · 2015 britsh guidelines on the clinical...
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The Need for Individualized Procedures in ECP, the European
Perspective!
Volker Witt, MD
St. Anna Kinderspital, Vienna, Austria
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ECP = extrcorporeal photopheresis
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4 15.01.2015 2
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What is ECP?
STEPS OF THE PROCESS
• Harvesting Leukocytes
• Preparing a buffy coat
• Adding a Photosensitizer
• Transferring in a irradiation disposable
• Irradiating a “buffy coat”
• Retransfusion to the patient
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What is ECP?
STEPS OF THE PROCESS
• Harvesting Leukocytes
• Preparing a buffy coat
• Adding a Photosensitizer
• Transferring in a irradiation disposable
• Irradiating a “buffy coat”
• Retransfusion to the patient
• Apheresis • Inline systems
• Offline systems
• To draw peripheral blood
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What is ECP?
STEPS OF THE PROCESS
• Harvesting Leukocytes
• Preparing a buffy coat
• Adding a Photosensitizer
• Transferring in a irradiation disposable
• Irradiating a “buffy coat”
• Retransfusion to the patient
• Directly from the Apheresis device
• Diluted by plasma
• Diluted by saline solution
• Hematocrit
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What is ECP?
STEPS OF THE PROCESS
• Harvesting Leukocytes
• Preparing a buffy coat
• Adding a Photosensitizer
• Transferring in a irradiation disposable
• Irradiating a “buffy coat”
• Retransfusion to the patient
• 8-MOP
• Final concentration (?)
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What is ECP?
STEPS OF THE PROCESS
• Harvesting Leukocytes
• Preparing a buffy coat
• Adding a Photosensitizer
• Transferring in a irradiation disposable
• Irradiating a “buffy coat”
• Retransfusion to the patient
• Chamber
• Bag
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What is ECP?
STEPS OF THE PROCESS
• Harvesting Leukocytes
• Preparing a buffy coat
• Adding a Photosensitizer
• Transferring in a irradiation disposable
• Irradiating a “buffy coat”
• Retransfusion to the patient
• In a pivoting a bag
• By flowing through a chamber
• Constantly
• Inconstantly
• Time
• Hematocrit
• Measuring the dose
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What is ECP?
STEPS OF THE PROCESS
• Harvesting Leukocytes
• Preparing a buffy coat
• Adding a Photosensitizer
• Transferring in a irradiation disposable
• Irradiating a “buffy coat”
• Retransfusion to the patient
• Immediately
• After incubating
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As often happened in the past, ECP was invoked as a last resort in front of patients with highly unsatisfactory therapeutic proposals. In fact, that was the case of acute and chronic GvHD when ECP was even borrowed from the treatment of cutaneous T cell lymphoma.
Extracorporeal photopheresis for bronchiolitis obliterans syndrome after allogeneic stem cell transplant: An emerging therapeutic approach?
Claudia Del Fante∗, Cesare Perotti Transfusion and Apheresis Science 56 (2017) 17–19
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A possible explanation of the positive impact on BOS after ECP intensification may be the higher number of cells treated over time and consequently the more intense and long lasting immunomodulation.
Extracorporeal photopheresis for bronchiolitis obliterans syndrome after allogeneic stem cell transplant: An emerging therapeutic approach?
Claudia Del Fante∗, Cesare Perotti Transfusion and Apheresis Science 56 (2017) 17–19
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Moreover, differently from others, we are convinced that in this setting of patients response to ECP must be considered also stabilization or even slowing of lung function decline over time, considering that nearly all patients meet a rapid and dramatic evolution.
Extracorporeal photopheresis for bronchiolitis obliterans syndrome after allogeneic stem cell transplant: An emerging therapeutic approach?
Claudia Del Fante∗, Cesare Perotti Transfusion and Apheresis Science 56 (2017) 17–19
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Extracorporeal Photochemotherapy published guidelines:
2007 French guidelines (Kanold J. , Transfusion) acute and chronic GvHD, children
2012 Italian guidelines (Pierielli L. , Transfusion)
acute and chronic GvHD, adults and children 2014 European Academy of Dermatology and Venerology (Knobler R. , JEADV) Guidelines on the use of ECP (aGVHD, cGVHD included) 2014 COCHRAN Review (Weitz M.)
acute and chronic GvHD, children
2015 Britsh Guidelines on the clinical use of apheresis procedures … (Howell C, Transfusion) 2016 US ASFA guidelines (Schwartz J. J Clin Apheresis)
acute and chronic GvHD, adults and children
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The current methods for delivery of ECP use ‘closed’ or ‘open’ systems. Open ECP necessitates collection of a buffy coat on a cell separator, separation of the buffy coat from the system and subsequent UVA irradiation in a separate device, before reinfusion to the patient. By contrast the closed system incorporates an internal UVA source in the apheresis device with no separation of the buffy coat from the device, before return to the patient.
While the open system has the potential advantages of increased cell dose and the ability to manipulate the cells further, there is an increased risk of microbial contamination with this technology.
The closed system devices have integrated mononuclear cell collection and 8-methoxypsoralen/UVA irradiation, and regulatory approval for treating patients (Wong, 2012).
Howell, Transfusion Medicine, 2015
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Atopic (neuro-) dermatitis (atopic eczema), recalcitrant
ECP IA TPE
III III III
2C 2C 2C
Cardiac transplantation ECP ECP TPE TPE
Cellular/recurrent rejection Rejection prophylaxis Desensitization Antibody mediated rejection
II II II III
1B 2A 1C 2C
Cutaneous T-cell lymphoma; mycosis fungoides; Sezary syndrome
ECP ECP
Erythrodermic Non-erythrodermic
I III
1B 2C
Dermatomyositis/polymyositis TPE ECP IV IV
2B 2C
Graft-versus-host disease ECP ECP ECP ECP
Skin (chronic) Non-skin (chronic) Skin (acute) Non-skin(acute)
II II II II
IB IB 1C 1C
Inflammatory bowel disease Adsorptive cytapheresis Adsorptive cytapheresis ECP
Ulcerative colitis Crohn’s Disease Crohn’s Disease
III/II III III
1B/2B 1B 2C
Schwartz, JCA 2016
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Lung transplantation ECP TPE TPE
Bronchiolitis obliterans syndrome Antibody mediated rejection Desensitization
II III III
1C 2C 2C
Nephrogenic systemic fibrosis ECP TPE
III III
2C 2C
Cutaneous T-cell lymphoma; mycosis fungoides; Sezary syndrome
ECP ECP
Erythrodermic Non-erythrodermic
I III
1B 2C
Pemphigus vulgaris TPE ECP IA
Severe Severe Severe
III III III
2B 2C 2C
Psoriasis ECP Ads.cytaph. Lymphocyt TPE
Disseminated pustular
III III III IV
2B 2C 2C 2C
Scleroderma (systemic sclerosis) TPE ECP
III III
2C 2A
Schwartz, JCA 2016
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Why we use ECP in GVHD?
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main complications of immunosuppressive therapies
infections
endocrine dysfunction
avascolar necrosis
multiorgan failure
secondary malignancies
quality of life ?
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+ Corticoid and IS therapy sparing
effect needed(!?)
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Immunological benefits
• Maeda A et al. (2005) Intravenous infusion of syngeneic apoptotic cells by photopheresis induces antigen-specific regulatory T cells. • J Immunol 174: 5968–5976
• Patients receiving ECP respond normally to new immune challenges and do not lose their immunity against infections, gained either from previous exposure to the pathogen or through vaccination. • Suchin KR et al. (1999)
• Extracorporeal photochemotherapy does not suppress T- or B-cell responses to novel or recall antigens. • J Am Acad Dermatol 41: 980–986
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ECP in children
• Advantages: • Selective downregulation of GVHD
without increasing infection or malignancy relapse
• Possibility to reduce general immunosuppression
• Minimal acute side effects
• No reported long-term side effects
• Problems: • Time consuming
• Venous access
• Circulating extracorporeal blood volume
• Priming with blood
• Unvalidated procedures
• Few randomized trials
• Experienced staff necessary
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Why ECP in paediatric practice merits attention ?
A substantial number of children undergo HSCT for non-malignant disorders and will not benefit from the GvHD.
The toxicities of systemic treatment in a growing child should be considered.
Therefore, addition of an effective pharmacologic-immunosuppression-sparing agent is of crucial
importance for long-term outcome of these patients.
Excellent safety profile of ECP
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Luca Pierelli RECOMMENDATIONS FOR ECP IN GVHD Transfusion 2013
Studies of Photopheresis for Treatment of Acute Graft-vs-Host Disease in Children and Adult
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15.01.2015 26 Messina et,al. BMT 2003
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The National Institutes of Health global score predicts the risk of non relapse mortality and disease-free survival in children with chronic graft-versus-host disease
Children with severe chronic graft-versus-host disease had significantly higher non relapse mortality and lower disease-free survival
Probability of continuing chronic graft-versus-host disease 8 years after onset of severe chronic graft-versus-host disease was 36%
Among survivors of more than 5 years, 22% had a performance score below 70%
Efforts to lower the risk of severe chronic graft-versus-host disease are necessary in pediatric hematopoietic stem cell transplantation
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When we could use it in GVHD?
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15.01.2015 31 Bone Marrow Transplantation (2010) 45, 1068–1076
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These preliminary data may indicate a potential survival advantage with ECP for transplant recipients undergoing standard myeloablative hematopoietic cell transplantation.
Bone Marrow Transplantation (2010) 45, 1068–1076
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How to use ECP in GVHD?
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acute and chronic GvHD
1. not responding to steroid
2. responding with intolerable side effects
(ECP combined with 2nd line treatment )
chronic GvHD
3. unsuccessfully treatment with > 3 lines of therapy (resistant, dependent, late-stage disease)
4. limited, regardless of other therapies
acute GVHD
5. grade IV with 1st and 2nd line therapies
Indications for ECP in the paediatric setting: guidelines
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Which system?
• „However the machine currently approved is designed for patients over 40 kg of body weight. Significant fluid shift and venous access are major concerns when ECP is performed in children. Various modifications of the ECP procedure have been tried to manage patients with los body weight. Expirience with ECP in children is limited but preliminary data also showed favorable response in children with resistant GVHD.“
Chan KW J Clin Apher.2006;21(1):60-4
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Extracorporeal volume of apheresis systems
0
100
200
300
400
500
600
700
Extracoporeal Volume
650
480
236 216
319
190 165 169 163
137
UVAR
UVAR XTS
CFS Single Needle
CFS Double Needle
Fenwal GRANULO/SVCCH
Fenwal SVSCH/SVCCH
COBEspectra
OPTIA
AMICUS
COM.TEC
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UVAR system
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ECP: on-line and off-line methods
On-line (Therakos) Off-line: I° step = MNC collection
Off-line: II° step = 8-MOP and UV-A irradiation
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ECP program from 2005 until today
• Patients non responsive to SIT and need for 2nd line treatment • aGVHD • cGVHD
• System • > 40 kg UVAR XTS, > 30 kg Cellex (no blood priming)
• < 40 kg AMICUS, Fenwal CS, AMICUS, OPTIA plus COMBI light plus and later on MACOGENIC
• (1x Apherese, 2x Reinfusion)
• in special cases „MINI“ ECP
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UVAR Cellex
• Double needle or single needle method applicable
• Validation and qualification is done at our department
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ECP program „offline method 1 apheresis 2 reinfusions“
day 1 day 2
divided in 2 stored over night +4oC
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10 ml/kg bw PB
densitygradient- Centrifugation or simple entrifugation
8-MOP MNC
2,5 J/m² 365 nm
This procedure can only be performed in a GMP laboratory
ECP Methods in Children: Mini-ECP
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……
……
Wednesday 9h-13h
Friday 9h-13h
Monday 12h-
13h
Wednesday 12h-
13h
Friday 12h-13h
Monday 9h-13h
Monday 9h-12h • Cryopreservation of mononuclear cells
• Sequential reinfusion of thawed and ECP treated cells
Reduction of the number of aphereses 46
Slides from Merlin E. ©
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Feuerstein 2000 Sarkar 2003
Cryopreservation induces lymphocyte apoptosis while retaining the
stimulatory function of dendritic cells 47
Cryopreservation for ECP Slides from Merlin E. ©
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Methods
• Healthy donors
• Isolation of PBMC by centrifugation on Ficoll-Hypaque gradients (density, 1.077)
• Cryopreservation – DMSO : 3,5 %
– Albumin : 10 %
– HES : 92,3 %
– -80°C without controlled-rate freezing
• Thawing in 40° water until completely melted, then RPMI is added, supplemented with 10% human AB serum. Washed twice to remove DMSO.
• ECP: Vilber-Lourmat irradiator in UVA transparent bag (Macopharma)
48
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0
20
40
60
80
100
120
Before ECP h1 h24
Viab
le c
ells
(%)
ECP treated cells - Viability
Fresh cells
Cryopreserved cells
(Trypan Blue Exclusion)
49
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0
5
10
15
20
25
30
35
40
1 2
Fresh cells
Cryopreserved cells
ECP treated cells – Apoptosis (Annexin V – IP)
Annexin
+ c
ells
(%
)
H1 after ECP Before ECP 50
Cryopreservation for ECP – in vitro assessment Slides from Merlin E. ©
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0
500
1000
j0 h2 j1 j2 j3 j6
Fresh
Cryo
ECP
Cryo + ECP
Total apoptosisA
nnex
ine
+ ce
lls (%
)
Time
d0 h2 d1 d2 d3 d6
0
500
1000
j0 h2 j1 j2 j3 j6
Fresh cells
Cryopreserved cells
ECP-treated cells
Cryopreserved + ECP-treated cells
0
500
1000
j0 h2 j1 j2 j3 j6
Fresh cells
Cryopreserved cells
ECP-treated cells
Cryopreserved + ECP-treated cells
51
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A* B B A* B
CFSE
vs
Judgment criterion: proliferation in MLR
Measured with CFSE dye dilution
Stimulator cells: A* = mother - 30 Gys
Reactive cells : B = daughter – labelled with cfse
Tested cells: ECP treated B cells
7 days culture in RPMI-1640 supplemented with human AB serum, Hepes, antibiotics and glutamine
Test Control
Functional assessment - MLR
52
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A*+BCFSE 2:1
A*+ BCFSE + BECP 2:1:1
A*+ BCFSE + BECP CRYO 2:1:1
53
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0
10
20
30
40
50
60
Control ECP Cryo + ECP
Pro
lifer
atin
g ce
lls (
%)
54
Cryopreservation for ECP – in vitro assessment Slides from Merlin E. ©
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2 3 4 5 1
Cryopreserved-cell ECP for GVH in children – Clermont-Fd experience
Freezing
–DMSO : 3,5 %
–Albumin : 10 %
–HES : 92,3 %
–-80°C without controlled-rate freezing
Thawing Washing twice
Slides from Merlin E. ©
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Days of ECP therapy
Apheresis
Cell infusion (ECP)
0 10 20 30 40
ECP center Referring hospital
56
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57
Immunosuppression
Salt-free diet
Hypertension
Colitis
Troubles de l’humeur
Neutropenia
Fed up
Venous access
Transfusions
Logistical issues
Short term
ECP for GVH in children – Clermont-Fd experience
Slides from Merlin E. ©
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58
Immunosuppression
Salt-free diet
Hypertension
Colitis
Troubles de l’humeur
Neutropenia
Fed up
Venous access
Transfusions
Logistical issues
Shortterm
ECP for GVH in children – Clermont-Fd experience
Slides from Merlin E. ©
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MINI ECP → simple method
1. Drawing blood from peripheral vascular access
2. Fluid substitution with cristalloid solutions if needed
3. Centrifugation of the product
4. Squeezing of the buffy coat
5. Reinfusion of the residual erythrocyte fraction
6. Dilution of the buffy coat to hematocrit < 5%
7. Plus 8-Methoxypsoralen
8. Irradiation with UVA 2,0 - 2,5 J/cm²
9. Reinfusion of the treated buffy coat
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Time needed
60
2. 1.
3. + 4. + 6. +7. 8.
5. 9.
180 min
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Facility Ressources
61
2. 1.
3. + 4. + 6. +7. 8.
5. 9.
Day care center/ ward
GMP facility Laboratory
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MINI ECP in practise
• SCID (Omenn-Syndrom, RAG1 Mutation), 3y alt, multiple premorbidity pre SCT (viral infections, BCG infection, surgery Ileum resection ,...)
• SCT MUD (BM) 17.12.2013
• Fulminatn engraftment (d+13)
• Severe acut GvHD skin/liver/gut:
exanthema
Bilirubin increase
bloody diarrhea (transfusion dependend)
• Nonresponse to IST with steroid, high dose CSA/FK506
and MMF (MMF ex d +28)
start MINI ECP d +20 (05.01.2014): 2x/week
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Mini ECP in very low bodyweight patients(< 10kg BW)
Hickman ZVK single lumen
Cave circulatory ! Monitoring: HF, RR
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Hickman CVCsingle lumen
Bag with ACD-A
pRBC (isovolemic Hemodilution))
HA 5%
Syringe to take blood
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steps: 1. Drawing 10ml blood from CVC
2. Direct to sample bag 3. Reinfuse pRBC 1:1 with HA 5%
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outcome
0
5
10
15
20
25
0
10
20
30
40
50
60
70
80
90
100
GPT
Bili
ECP
Reduction of the liver size Decrease of skin rush
skin: remission liver: remission gut: partial response
Reduction of steroids
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Celldose [cellsx10e06/kg bw]
Lymphocyte Monocyte Granulocyte
MINI (n=65)
5,37 2,44 3,99
OFFLINE (n=136) 46,7 20,3 14,9
INLINE*) (n=134) 25,4 6,2 21,8
*)INLINE = UVAR XTS
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ECP FOR ACUTE GVHD WITH DIFFERENT METHODS (MINI;
OFFLINE; INLINE) IN PEDIATRIC PATIENTS
Volker Witt, Herbert Pichler, Christina Peters, Susanne Matthes, Anita Lawitschka, Wolfgang Holter
St. Anna Kinderspital,UKKJ Medical University Vienna, Austria, Kinderspitalgasse 6, 1090 Vienna, Austria, [email protected]
Poster EBMT 2014, Milano
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aGHVD ECP method
6
13
4
0
2
4
6
8
10
12
14
MINI offline inline
n=
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n ECP / patient
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aGVHD method of ECP
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Chi-Quadrat Degree of freedom P
0,047293083 2 0,976630847
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aGVHD response at 3 months to ECP
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Conclusion aGVHD
• ECP is in our hands an effective second line therapy in acute GVHD. Neither the method used nor the individualized schedule applied seems to influence the outcome. Due to the small patient number, this report could be only a step forward to prospective randomized trials, bringing hopefully an answer to these questions. Interestingly we could show in our collective, that the response to ECP treatment for aGVHD is a predictor of overall survival.
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Conclusion MINI ECP
• Interesting method
• No international aggreement or acceptance whether blood, tissue or ATMP regulations should be applied
• Low technical efforts, low economic expenses => ? Low budget ECP?
• Data registry needed
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Outcome
Acute GVHD
• 14/14 improved after in median after 11 treatments • Organ involvement
• 14 skin (14 improved) • 6 liver (5 improved) • 4 GI (4 improved)
• 4 died due to infection and MOF not due to the apheresis procedure (Mini ECP) and improvement could not be evaluated.
Chronic GVHD
• 17 improved • 17 skin • 3 gut • 3 liver • 6 mucosa
• 7 did not improved • 4 skin (but in 2 skin improved) • 3 mucosa • 1 liver • 1 gut
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0
500
1000
1500
2000
2500
3000
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24
Tag
e n
ach
1.
EC
P
Patient
duration of immunosuppressiv treatment in cGVHD
KS CSA Tacrolimus MMF Rituximab Imatinib
verstorben
c
verstorben
verstorben
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Outcome from all patients with acute, overlap and chronic GVHD from 1999 until today
00.10.20.30.40.50.60.70.80.9
1
0 2 4 6 8 10 12
pro
ba
bili
ty o
ve
rall
su
rviv
al
Interval from date of Tx [years]
improved
not improved
0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1
0 0.5 1 1.5 2 2.5 3 3.5
pro
ba
bil
itiy
patients with acute graft versus host disease Intervall first ECP => outcome
acute GVHD
0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1
0 2 4 6 8 10 12
pro
ba
bil
ity
patients with chronic graft versus host disease interval first ECP => outcome
chronic GVHD
improved
not improved
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Survival and Improvement in patients with cGVHD
0
0,2
0,4
0,6
0,8
1
1,2
0 1000 2000 3000 4000 5000
d_survival_1.ECP
Wah
rsch
ein
lich
keit
Ausfälle
n
y
0
0,2
0,4
0,6
0,8
1
1,2
0 1000 2000 3000 4000 5000
d_survival_1.ECP
Wah
rsch
ein
lich
keit
Ausfälle
n
y
p = 0,818744365
p = 0,001948581
timepoint:
1.ECP + 1 month
End point +3 months
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Conclusions ECP in children: • ECP is an approach to GvHD therapy that appears to offer control of GvHD without
generalized immunosuppression and its associated complication
• Outcome is associated with response to ECP
• Despite different harvest and photochemotherapy methods, response to treatment seems to be independent
• High response rates in cutaneous and extracutaneous GVHD manifestations
• Steroid-sparing effect
• Improved quality of life and OS
• No negative effect on GvL
• Well tolerated, minimal side-efects during therapy and no reported long term side effects
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Thank you for your attention