2012 The UK Photopheresis Society Friday 28th September The Copthorne Tara Hotel Kensington, London.
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Transcript of 2012 The UK Photopheresis Society Friday 28th September The Copthorne Tara Hotel Kensington, London.
2012The UK
PhotopheresisSociety
Friday 28th September
The Copthorne Tara Hotel Kensington, London
Dr Peter Taylor
Introduction & Welcome
Dr Julia Scarisbrick
Secretary’s report
UKPS 2012
• Pharma Mix as secretariat• Website with online registrations for meetings• 2 meetings successfully run with excellent feedback from
delegates• Meeting attendance in January = 54• Meeting attendance in September = 52• Delegate communication before, during and after the event• Database established of haematologists, dermatologists,
pharmacists, nurses who may have an interest in photopheresis for meeting information
UKPS 2012
• Feedback from January was to have nurse led workshop which we have in September
• Selected slides will be available from the website
UKPS 2013
• 2 Meetings• Further development of website• Filming of photopheresis centres for inclusion
in the gallery• Promoting the group to more industry
partners to encourage funding
Society Updates
Debbie LancasterUK Registry
Society Updates
Dr Peter TaylorUK Quality Assurance / JACIE
The Rotherham NHS Foundation Trust
Photopheresis
Quality Assurance
To begin the debate
UKPS28 September 2012
Peter Taylor
The Rotherham NHS Foundation Trust
Quality assurance
The planned and systematic activities implemented in a quality system so that quality requirements for a product or service will be fulfilled
•Fit for Purpose
•Right First Time
The Rotherham NHS Foundation Trust
JACIE DRAFT STANDARDS
B7.2 There shall be a policy addressing safe administration of extracorporeal photopheresis (ECP).B7.2.1 There shall be a consultation with the facility that performs ECP prior to initiation of therapy.B7.2.2 Before ECP is undertaken, there shall be a written order from a physician specifying, at a minimum, the patient’s diagnosis, proposed regimen, timing of the procedure, and any other factors that may affect the safe administration of ECP.B7.2.3 A final report of the details of ECP administered, including an assessment of the response, shall be documented in the patient’s medical record.B7.2.4 The ECP procedure shall be performed according to written standard operating procedures of the facility performing the procedure appropriate for the clinical condition of the patient.B7.2.5 Outcomes, including adverse events, related to the administration of ECP to patients within the Clinical Program shall be analyzed annually.
The Rotherham NHS Foundation Trust
Standards
•Quality Management System
•Personnel
•Premises
•Equipment, Information systems & materials
•Treatment Process
•Evaluation
The Rotherham NHS Foundation Trust
Quality Management•Define organisation and management
•Service objective setting
•Management/Service review process
•User agreements / requirements (sharing arrangements)
•Documentation
The Rotherham NHS Foundation Trust
Personnel
•Head of service with JD
•Staffing
•Numbers, training, job descriptions, induction, staff records and review
•Regular meetings - ToR
The Rotherham NHS Foundation Trust
Premises
•Definition of working environment
•Facilities for staff & patients & storage
•Health & Safety
The Rotherham NHS Foundation Trust
Equipment, Information systems
•Management of equipment
•Management of data and information
•Management of materials
The Rotherham NHS Foundation Trust
Treatment Process
•Patient selection, information and review
•Treatment process – definitions & review
•Documentation
•Monitoring outcomes/evaluation
•Feedback on service
The Rotherham NHS Foundation Trust
Evaluation
•Staff feedback
•Patient feedback
•Clinical evaluation of service
•Complaints
•Incident reporting processes and feedback
The Rotherham NHS Foundation Trust
Way forward....
•1 Agree in principle
•2 Circulate draft document
•3 Develop assessors guidance
•4 Commence date??
Monica Minguzzi
Therakos – Current Developments
Dr Peter Taylor
ECP – Mechanism of Action
The Rotherham NHS Foundation Trust
Photopheresis
Mechanism of Action
Towards an understanding......
UKPS28 September 2012
Peter Taylor
The Rotherham NHS Foundation Trust
Objectives
What is known about the pathogenesis of chronic graft vs host disease ?
What is known about the effects of photopheresis ?
The Rotherham NHS Foundation Trust
Pathogenesis of chronic GvHD
The pathogenesis of chronic GvHD is not well understood
Much of our current knowledge is based upon animal studies, with no single animal model reflecting all aspects of cGvHD
The Rotherham NHS Foundation Trust
Variable clinical presentation involving:• Skin, mouth, eyes, liver, gut, upper respiratory tract,
oesophagus, genitalia and fascia
Variable pathology:• Inflammatory infiltrate leading dermal/epidermal junction
destruction and then fibrosis and sclerosis
• Tuboalveolar gland destruction
Chronic GvHD – Heterogeneous Disease
The Rotherham NHS Foundation Trust
Experimental Studies & cGvHD
Basic theories:
• Thymic damage and defective negative selection of T cells
• Fibrosis and aberrant production of TGFβ
• Altered B cell homeostasis
• Immune tolerance / T regulatory cells
The Rotherham NHS Foundation Trust
Failure of negative thymic selectionT cells with receptors for high affinity peptide-MHC self antigens are deleted by DC’s and thymic medullary epithelial cells
Depletion of DC’s allowed cCD4 with a cGvHD enhancing effect that was abrogated by KGF. Zhang J Immunol 2007 179, 3305
Anti KGF has not been found to be effective in human studies
Failure of T cell deletion can lead to acute GVHD in the presence of recipient epithelial antigens or cGvHD when they recognise antigens on marrow derived cells but not epithelial tissues (mouse)Jones J Clin Invest 2003 112, 1880
The Rotherham NHS Foundation Trust
Immune tolerance to Self Antigens and T regs• Acute GvHD impairs negative selection of T cells and the
development of T regsMorohashi Immunobiology 2000 202, 268
• cGvHD can develop in the absence of acute GvHD
• Conflicting data - T reg numbers in cGvHDReiger Blood 2006 107, 1717 vs Clark Blood 2004 103,2410
• T reg suppression of cGvHD mediated via cytokines TGFβ, IL-10, or by contact with DC’s via Indoleamine 2,3 dioxygenaseJ Clin Invest 2007 117, 2570
• Absence of T reg control of Th1 and Th17 cells is responsible for the autoimmune mediated pathology in cGvHDChen Blood 2007 110,3804
• Photodepletion of T cells but sparing T regs can raise T reg numbersBastien Blood 2010 116,4859
The Rotherham NHS Foundation Trust
Role of B cells
•Presence of autoantibodies
•Clinical presentation of cGvHD with autoimmune manifestations
• Improvement in cGvHD induced by anti-CD20 therapy
•Enhanced CD 86 expression after stimulation of B cells
•Raised BAFF levels
•High BAFF levels at 6 months in asymptomatic patients predicts onset of cGvHD
•Antibdies to mHA encoded on the Y chromosome in male recipients receiving female transplants have increased cGvHD incidence
The Rotherham NHS Foundation Trust
Photo-irradiates a methoxypsoralen primed buffy coat preparation which is returned to the donor.
UVA + Psoralen is used as a damaging agent to prompt apoptosis of the buffy coat cells
First described in the treatment of Cutaneous T cell Lymphoma, where the primed cells were assumed to be malignant
Photopheresis
The Rotherham NHS Foundation Trust
Photopheresis - Evidence
•Cellular Vaccination
•Apoptosis of ECP treated Lymphocytes
•Tumour peptides
•ECP modulation of Monocytes
•Distal Effects on untreated Lymphocytes
•T regulatory cells
•B cell Homeostasis
The Rotherham NHS Foundation Trust
‘Vaccination against autoimmunity’
Edelson Scientific American August 1988 referencing work of Cohen
Transferable anti-clonatypic response generated by infusion of pathogenic T cells
Processing of engulfed apoptotic cells yields T cell epitopes and preferential recognition of TCR hypervariable region by anti-idiotypic clonal T cells induced by T cell vaccination
The Rotherham NHS Foundation Trust
Apoptosis of ECP treated Lymphocytes
Both immediate and early apoptosis is induced
Majority of lymphocytes apoptose in 48 hours
Externalisation of phosphotidyl serine, with Annexin V as a hallmark of early apoptosis which is expressed almost immediately on 75% of lymphocytes
A second, later wave of apoptosis accounts for final cell death via caspase activation
Note - only 1% of the total lymphoid mass is treated, and cells localised to site of disease are not treated
The Rotherham NHS Foundation Trust
Apoptosis
The Rotherham NHS Foundation Trust
Text
Reduction in Bcl/Bax ratio in ECP treated cells
Bladon Dermatology 2002 204, 104
The Rotherham NHS Foundation Trust
Tumour peptides
Edelson 1988
Tumour specific peptides are exposed which generate an idiotype-specific effector CD 8 response
The Rotherham NHS Foundation Trust
ECP modulation Monocytes
Kinetics of monocyte apoptosis remain controversial
25% up to 6 days functional vs 80% apoptosed at 48 hours
Early apoptosis could lead to early removal and and ‘apoptotic cell load’
Later apoptosis may leave an opportunity for monocytes to contribute directly
Initial mouse studies showed rapid clearance of ECP treated cells to RES
Cell trafficking studies in ECP treated cells have demonstrated differential uptake between PMBC’s and neutrophils, with 80% uptake in liver & spleen at 24 hoursJust Exp Dermatol. 2012 21, 443
Differential cell dose studies have demonstrated no correlation with monocyte dose
The Rotherham NHS Foundation Trust
Monocytes and Dendritic cells post ECPIngestion by Antigen Presenting Cells (APCs) has a profound effect on immune regulationECP Inhibits pro-inflammatory cytokine productionBladon Transplantation Intl 2006 19, 319
The Rotherham NHS Foundation Trust
• Modulation of circulating DCs in ECP treated patients with reduced CD80+, CD123+, mature DC phenotypeAlcindor Blood 2001 98, 1622
• Immature DC are prevalent in ECP treated cell populations with retained: • ability for activation • phagocytosis • increased anti-inflammatory cytokines
Spisek Transfusion 2006 46, 55
• DC’s from post ECP samples and demonstrated reduced IL1, TNFα, IL-12, and signature chemokine receptor expression of CCR4 and CCR10Holtick Transplantation 2008 85, 757
Monocytes and Dendritic cells post ECP
The Rotherham NHS Foundation Trust
Distal Effects on untreated Lymphocytes - Th2 in CTCL
Normalisation of CD4/CD8 ratios - not universal
Th2 to TH1 in CTCL - (malignant clone Th2)Di Renzo Immunology 1997 92, 99
The Rotherham NHS Foundation Trust
Distal Effects on untreated Lymphocytes - Th1 in GvHD
In patients with symptomatic cGVHD there is an increase in CD8(+) central memory cells and a concomitant decrease in CD4(+) central memory cells
Statistically significant normalisation of the pattern of CD4(+) and a trend toward normalization of CD8(+) central memory T cells coincident with improvement of cGVHD.Yamashita Biol Blood Marrow Transplant. 2006 12, 22
Immune surveillance by T helper type 1 cells is not only critical for the host response to tumours and infection, but also contributes to autoimmunity and GVHD
BUT....
Hypothesis that pulmonary GVHD can occur independent of Th1 cells using T-bet-deficient donorsGawdy Am J Respir Cell Mol Biol. 2012 46, 249
The Rotherham NHS Foundation Trust
T reg numbers improve following ECP ? normalisationBladon & Taylor Ther Apher Dial. 2008 Aug;12(4):311-8
Syngeneic apoptotic cells (ECP) induced antigen specific T regs, loss of which was associated with loss of tolerance (mouse)Maeda 2005 J Immunol 174
Apoptotic cell infusions generate T regulatory cells (mouse) Mahnke Blood 2003
ECP treated splenocytes indirectly modulate T cell mediated alloreactivity via IL-10 producing DC’s not in the ECP innocularesulting in expansion of T reg (mouse)Capactini Biol Blood Marrow Transplant 2011 17,790
ECP reverses experimental GVHD, mediated via T regs (mouse)Gatza Blood 2008, 112, 1515
T reg function augmented by ECPScmitt 2009 Transplantation 87,1422
T regulatory cells and the emergence of ‘tolerance’
The Rotherham NHS Foundation Trust
The Rotherham NHS Foundation Trust
Future directions?
The PDL1-PD1 axis converts human Th1 cells into regulatory T cells Amarnath Sci Transl Med. 2011 3, 120.
Immune surveillance by T helper type 1 cells is not only critical for the host response to tumours and infection, but also contributes to autoimmunity and GVHD
The Rotherham NHS Foundation Trust
•Dysregulation of the B cell compartment is a hallmark of cGvHDSocie Blood 2011 117, 2086
•Clinical features of autoimmune disease
• B cell Activating Factor (BAFF) is elevated in GVHD and is related to production of autoimmunitySarantopoulos Clin Cancer Res 2007 13,6107
B cell Homeostasis
The Rotherham NHS Foundation Trust
Immature CD21- immature transitional B cells and deficiency of CD 27+ memory cells is associated with cGvHDGreinix Biol Blood Marrow Transplant 2008 14, 208
Reduced CD21+ cells is marker of response to GvHDKuzmina Blood 2009 114, 744
The Rotherham NHS Foundation Trust
Persisting levels of BAFF at 4 weeks is predictive of response of cGvHD to ECP, independent of reduction in immunosuppression Whittle 2011 Blood 118, 6446
Persisting high BAFF levels are associated with an increased risk of GVHD failure or of need to re-escalate steroidsWhittle Bone Marrow Transplantation 2012 47
Mechanism of Action of ECP
MethoxalenUV radiation
Cross-linked DNA
Leukocytes
Apoptosis
Phagocytosis
Tolerogenic DC/APC
Tr
Tr Tr
Tr
Tr Tr
Anti-inflammatory cytokines (eg, IL-10, TGF-ß)
Treg
+
1
2 3
4
5Proinflammatory cytokines (eg, IL-12, IFNγ)Stimulation T
effector cells
Reduction in BAFF
Receptor-mediated signaling
The Rotherham NHS Foundation Trust
The Rotherham NHS Foundation Trust
Acknowledgements
Dr A Alfred
Scientific teamR WhittleH DenneyJ Bladon
Data managementF Hammerton
www.photopheresis.co.uk
The Rotherham NHS Foundation Trust
Professor Hildegard Greinix
Acute GvHD
Acute Graft-versus-Host Disease
Hildegard Greinix
Medical University of Vienna
Vienna, Austria
Univ. Klinik für Innere Medizin I
Pathophysiology of Acute GvHD and GvL Effects
Acute GvHD is Serious Complication of Allo HCT
• Challenge: GvL effect vs. morbidity and mortality due to severe GvHD
• GvHD has significant negative impact on survival
• Challenge: Efficacy vs toxicity of IS
Risk Factors for Acute and Chronic GvHD According to NIH
Flowers MED et al, Blood 17:3214-3219, 2011
First-line Therapy of Acute GvHD
First-Line Therapy of Acute GvHD
Low dose Prednisone in Acute GvHD
• 733 pts with mainly acute GvHD I-II
• Retrospective analysis• 2 mg/kg vs 1 mg/kg of steroids• No difference in NRM, relapse
and OS• Reduced fungal infections in
low-dose steroid group• Reduced duration of
hospitalization in low-dose steroid group.
Cum. steroid dose
Survival
Mielcarek et al, Blood 2009
Transplant Outcome According to Response to First-line Steroid-Therapy
Van Lint et al, Blood 2006
A B
Salvage Therapy of Acute GvHD
Salvage Therapies for Steroid-Refractory
Acute GvHD: Challenges • Limited consensus on definition of steroid refractoriness
– Dose and duration of first-line steroids– Time alloted to assess treatment response
• Limitations in study design– Only 1 randomized trial– Mostly retrospective series or early phase trials with small sample
sizes• Therapeutic impact of salvage agent difficult to discern
– Multiple agents used in short periods of time– Limited consensus on time alloted to assess treatment response
• Limited understanding of biology of steroid-refractoriness
Steroids as First-Line Therapy of Acute GvHD
Response to Steroids
MacMillan et al, Blood 2010
NRM and OS
Van Lint et al, Blood 2006
Efficacy of ECP in Steroid-Refractory Acute GvHD
Development of ECP for Clinical Use
1981First ECP
1987ECP Approval for CTCL
1994ECP in Chronic GVHD
1998ECP in acute GVHD
2008 ECP Rand. Study. cGVHD
Increasing use of ECP
Pilot Study of ECP in Acute Steroid-Refractory GvHD
• To evaluate the safety and efficacy of ECP.• In addition to CSA and steroids at 2 mg/kg ECP performed on 2
consecutive days at 1 to 2 week intervals until improvement, then every 2 to 4 weeks until maximal response.
ECP in acute GvHD
• Inclusion criteria– Grades II to IV– Steroid-refractory (steroids at 2mg/kg b.w. for
at least 4 days)– Steroid-dependent (flare-up during taper)– Karnofsky > 50%– Signed written informed consent
• Exclusion criteria– Uncontrolled infection– ANC < 1.0 X 109/l– Plts < 20 X 109/l– Hemodynamic instability– Hypersens. to 8-MOP– Poor compliance
Intensified ECP in Acute Steroid - Refractory/Dependent GvHD
Phase II Study
• ECP started earlier (steroids at 2mg/kg b.w. for at least 4 days or flare-up during steroid taper)
• Grades II to IV• ECP on 2 consecutive days per week• No maintenance ECP
STEROIDS
CSA
ECP
aGVHD
Greinix et al, Haematologica 2006
Comparison Pilot Study and Phase II Study
AllN=59
Pilot N=21
Phase IIN=38
II/III/IV at ECP 36/13/10 10/6/5 26/7/5
Skin aloneSkin+liverSkin+liver+gutOthers
311387
8931
23*456
HCT-ECP d 37 (17-70) 41 (20-70) 36 (17-69)*
D steroids prior ECP 17 (4-49) 21 (9-49) 16 (4-43)*
Cum.steroid dose first-line mg/kg 2.8 (2-10.4) 3.9 (2-10.4) 2.1 (2-6.5)*
Med.steroids at start of ECP mg/kg
2.1 (0.7-10.4) 2.6 (1.1-10.4) 1.9 (0.7-2.3)*
Greinix et al, Haematologica 2006
Acute Steroid-Refractory and Steroid-Dependent GvHD
Results of ECPAll Pilot Phase II
No ECP cycles 7 (1-45) 11 (1-45) 5 (1-16)
Length ECP mo 3 (0.5-31) 5 (1-31) 1.5 (0.5-7)
Max. response after ECP cycle
4 (1-13) 4 (1-13) 4 (1-8)
Max. response after months
1.3 (0.5-6) 2 (0.5-6) 1.2 (0.5-4.5)
DC steroids d 55 (17-284) 53 (18-122) 56 (17-284)
Steroid dose 4 weeks after start
0.9 (0-5) mg/kg 1.1 (0-5) mg/kg 0.7 (0-2) mg/kg
Steroid dose 8 weeks after start
0.3 (0-1.5)mg/kg 0.3 (0-1.3)mg/kg 0.2 (0-1.5)mg/kg
Greinix et al, Haematologica 2006
100
80
60
40
20
0PILOTN=21
Ph IIN=36
CR
PR
NC
NR
PILOTN=12
Ph IIN=11
PILOTN=4
Ph IIN=11
SKIN LIVER GUT
Greinix et al, Haematologica 2006
ECP as Second-line Therapy in Acute Steroid-Refractory and Steroid-Dependent GvHD
100
80
60
40
20
0PILOT N=10
Ph IIN=26
CR
PR
NC
NR
PILOTN=6
Ph IIN=7
PILOTN=5
Ph IIN=5
II III IV
Greinix et al, Haematologica 2006
ECP as Second-line Therapy in Acute Steroid-Refractory and Steroid-Dependent GvHD
TRM of Patients with Steroid-Refractory Acute GvHD According
to Response to Second-Line ECP
100
Pro
ba
bil
ity
in
%
Months after start of ECP
80
60
40
20
00 16 32 46 66 84 100
CR
P< 0.0001
PR
NCNR
1 1 0
lo w e r T R M h ig h e r T R M
0 .1
Fem ale gender
H igher grade of G VHD during first-line
H igher grade of G VHD at start of ECP
M ore organs involved during first-line
M ore organs involved at start of ECP
Shorter interval from D0 to start o f E CP
Tim e to start o f stero ids
Days of stero ids prior EC P
Higher cum . steroid dose first-line
H igher stero id dose at start o f ECP
Low er num ber of ECP given
Shorter duration of ECP
Stero ids < 1 m g/kg b .w. 4 w eeks after start o f E CP
No CR 3 m onths after start of ECP
Stero ids < 0.5 m g/kg b.w. 8 w eeks after start of EC P
Variable
Hazard Ratios for TRM
Greinix et al, Haematologica 2006
Overall Survival of Patients with Steroid-Refractory Acute GvHD According to Best Response to
Second-Line ECP 1 1 0
Fem ale gender
Higher grade of G VHD during first-line
Higher grade of G VHD at start of ECP
M ore organs involved during first-line
M ore organs involved at start of ECP
Shorter interval from D0 to start o f E CP
Tim e to start o f stero ids
Days of stero ids prior EC P
Higher cum . steroid dose first-line
Higher stero id dose at start o f ECP
Low er num ber of ECP given
Shorter duration of ECP
Stero ids < 1 m g/kg b .w. 4 w eeks after start o f ECP
No CR 3 m onths after start of ECP
Stero ids < 0.5 m g/kg b.w. 8 w eeks after start of EC P
b e tte r O S w o rs e O S
0 .1
Variable
100
Pro
ba
bil
ity
in
%
0 16 32 46 66 84
80
60
40
20
0
p < 0.0001
CR to ECP
PR to ECP
NC
NR
Hazard Ratios for Overall Survival
Greinix et al, Haematologica 2006
Months after start of ECP
ECP in Steroid-refractory Acute GvHDLong-Term Results (n=96)
Months after HCT
Pro
bab
ility
%
6012 24 36 48 72 84 96 108 120 132 144 156 168 180 192 2040
100
80
60
40
20
0
Relapse
OS
TRM
ECP in Steroid-refractory Acute GvHDLong-Term Survival according to Response (n=96)
Months after HCT
Pro
bab
ility
%
100
80
60
40
20
0
6012 24 36 48 72 84 96 108 120 132 144 156 168 180 192 2040
no response to ECP
CR to ECP
PR to ECP
p<0.0001
Acute Steroid-Refractory/Dependent GvHD
Outcome after ECP (n=96)Outcome No (%)
Alive 52 (54)
No chronic GVHD 36/52 (69)
Relapse 17 (18)
Med. FU yrs 6 (0.5-15)
Earlier Start of ECP Improved Response Rates
• 23 pts with steroid-refractory aGvHD
• ECP started a median of 56 (14-148) days after onset of aGvHD
• ↑ responses (83% vs 47%) in pts treated within 35 days from onset of aGvHD
Perfetti et al, BMT 2008
Salvage ECP in Acute Steroid-Refractory GvHD
Rapid Steroid Reduction during ECP
Greinix 2000 and 2006, Salvaneschi 2001, Messina 2003, Garban 2005, Perfetti 2008
Perfetti et al, BMT 2008 Perotti et al, Transfusion 2010
Salvage ECP in Acute Steroid-Refractory GvHD
Improved Survival in ECP-Responders
• Messina 2003– 69% vs 12% at 5 years
• Perfetti 2008– 38% vs 14% in
controls with grades III-IV aGvHD
• Perotti 2010– 62% vs 6%
• Calore 2008
100
Pro
ba
bil
ity
in
%
0 16 32 46 66 84
80
60
40
20
0
p < 0.0001
CR to ECP
PR to ECP
NC
NR
Greinix et al, Haematologica 2006
ECP for Treatment of Acute GvHD in Children
• 16 steroid-responder• 15 given ECP for steroid-
resistance, dependence or viral reactivations (n=4)
• 6 months of ECP• 73% CR, 27% PR• 10/15 (67%) d.c. IS• Mild hypotension and
abdominal pain (n=8)
Calore et al, BMT 2008
• ECP is effective and well-tolerated adjunct second-line therapy.
• Start ECP early for ↑ CR and ↓ TRM.
• Apply ECP weekly on 2-3 days.
• Short ECP treatment times, no flare-ups.
• Rapid steroid taper: ↓ TRM and ↑ OS.
• GvL not affected.
Second-Line ECP in Acute Steroid-Refractory GvHD
STEROIDS
CSA
ECP
aGVHD
Intensified Second-Line ECP
ECP in Steroid-Refractory Acute GvHD
0
10
20
30
40
50
60
1995 1996 1997 1998 1999 2000 2001 2002 2003 2005 2006 2007 2008 2010
pts pts pts 0
10
20
30
40
50
60
70
1995 1996 1997 1998 1999 2000 2001 2002 2003 2005 2006 2007 2008 2010
pts
Publications (n=24)
Published Patients (n=297)
ECP in Steroid-Refractory Acute GvHD
297 pts reported in 24 publications.
CR/PR Skin 75% (50-100%)
CR/PR Liver 47% (0-100%)
CR/PR Gut 58% (0-100%)
OS 60% (37.5-85%)
ECP is effective and well-tolerated adjunct second-line therapy.
ECP in Steroid-Refractory Acute GvHD
Author Pts CR/PR Skin %
CR/PRLiver %
CR/PR Gut %
OS %
Salvaneschi 01 9 89 20 60 67
Dall‘Amico 02 14 79 57 70 57
Messina 03 33 82 60 75 69
Kanold 07 12 100 67 83 75
Greinix 06 59 93 65 74 47
Calore 08 15 92 100 71 85
Perfetti 08 23 66 27 40 48
Perotti 10 50 83 67 73 64
ECP vs Anticytokine Therapy• Retrospective comparison of patients with aGvHD given
second-line treatment– Steroid-Refractory: progression after 3 d or no response after 7 d– Steroid-Dependent: recurrence during taper
• Patient selection criteria– HCT after January 2005– > grade 2– Steroids > 1 mg/kg/day alone as first-line therapy
• Continuation of CNIs during second-line therapy• Comparison of extracorporeal photopheresis with
anticytokines– Inolimomab (anti-IL2R): 0.3 mg/kg/d x 8 d, 0.4 mg/kg x 3/w for
3 w– Etanercept (anti-TNR): 25 mg x 2/w for 4 w, 25 mg/w for 4 w– ECP: 2-3 d/week
Greinix et al, EBMT 2012
Patient and Transplant Characteristics
Patient Characteristics N (%) ( n=127)
Center ECP (n=86) Non-ECP (n=41)
Vanderbilt 29 -
Nottingham 22 -
Vienna 35 -
Paris - 41
Gender
Male 48 (56%) 25 (61%)
Female 38 (44%) 16 (39%)
Age (y) (median) 47 (range, 17-67) 44 (5-64)
Diagnosis
Acute Leukemia 50 (58%) 21 (51%)
Lymphoma 18 (21%) 5 (12%)
Myeloid Disorders 16 (19%) 10 (24%)
Myeloma 2 (2%) 5 (12%)
0
5
10
15
20
25
30
35
40
45
50
Skin 3-4 GI 3-4 Liver 3-4 Grade 3-4 >- 2 organs
priorend
0
10
20
30
40
50
60
70
Skin 3-4 GI 3-4 Liver 3-4 Grade 3-4 >- 2organs
priorend
Response to Anticytokine Therapy (n=41)Response to ECP (n=86)
Variable ECP N (%) Non-ECP N (%)
Overall Response* p<0.0001 62 (73%) 13 (32%)
PR 9 (11%) 5 (12%)
CR** p<0.001 53 (62%) 8 (20%)
Survival and NRM: ECP vs. Non-ECP
Greinix et al, EBMT 2012
ECP
ECP
ECP Safety Profile
Safety
• Excellent safety profile• Reported adverse events
– Hypotension in 2-4%– Dizziness in up to 4%– Chills in up to 5%– Anemia
• Catheter-related side effects– CVC-related infections– Venous thrombosis
Efficacy of ECP is not a Result of Generalized Immunosuppression
• No increase of opportunistic infections or relapse during ECP
• No suppression of T-or B-cell responses to novel or recall antigens after ECP
Improvement in immune reconstitution after ECP in experimental allo BMT
Gatza et al, Blood 2008
Suchin et al, J Am Acad Dermatol 1999
ECP in Steroid-refractory Acute GvHD
Long-Term Results on Relapse (n=96)
Months after HCT
Pro
bab
ility
%
100
80
60
40
20
0
6012 24 36 48 72 84 96 108 120 132 144 156 168 180 192 2040
no response to ECP
CR to ECP
PR to ECP
p=0.42
Präclinical Model of ECP
Mouse Model (Multiple Minor HA-Disparate, CD8+ T Cell Driven) of Experimental Allo BMT for
Treatment of GvHD with ECP
Gatza et al, Blood 2008
0 7 14 21 28 35 42 490
1
2
3
4
5
6
GV
HD
Sco
re
Days post BMT
ECP Reduces GvHD and Mortality in Minor-MM Mouse Model
ALLO + Spl + ECP (n=34)
ALLO + Diluent (n=26)
SYN +/- ECP (n=15)
ALLO + Spl w/o ECP (n=19)
*
*p<0.004 vs L-15
*p=0.0007 vs L-15
*
0
20
40
60
80
100
0 10 20 30 40 50 60P
erce
nt
Su
rviv
al
Days post BMT
Gatza et al, Blood 2008
Infusion of ECP-treated Splenocytes Increases Donor Treg after Allo BMT
Gatza et al, Blood 2008
Acute GvHD Treatment Guidelines
ASBMT Recommendations: Second-line Therapy
• Second-line therapy indicated when:– After 3 days with progression– After 1 week with persistent unimproving grade
III GvHD– After 2 weeks with persistent unimproving
grade II GvHD
Martin PJ et al, BBMT 2012 in press
Basis of ASBMT Recommendations
• Comprehensive and critical review of published reports 1990-2011
• Retrospective and prospective studies• Excluded: <10 pts, case reports, not
commercially available agents• 13 reports on initial systemic therapy• 67 reports on secondary therapy
Martin PJ et al, BBMT 2012 in press
Rating System for Assessing Published Reports
• Adequately defined eligibility criteria• Documented minimization of bias in patient
selection• Consistent treatment regimen• Objective criteria for response assessment
in organs affected by GvHD• Unambiguous criteria for assessment of
overall response
Martin PJ et al, BBMT 2012 in press
Rating System for Assessing Published Reports
• Assessment of response at specified time• Accounting for effects of concomitant treatment• Identification of well-established control
benchmark• Formal statistical hypothesis and consideration of
statistical power• Display of overall survival, ideally with at least 6
months of follow-up
Martin PJ et al, BBMT 2012 in press
Initial Agreement between EvaluatorsCriterion % AgreementEligibility criteria 60Minimization of selection bias 81Consistent treatment regimen 61Organ response criteria 82Overall response criteria 75Prespecified time of assessment 84Concomitant treatment 60Historical benchmark 93Statistical hypothesis 97Survival curve 76
Basis of ASBMT Recommendations• 2 individuals independently evaluated
reports• Joint review to arrive at consensus• 38 reports met 0 to 4 indicators• 29 studies met >5 indicators• Extracted information and analysis:
– CR, CR/PR, 6-mo OS– Aggregated results from all studies– Binomial distribution to determine 95% CI
Martin PJ et al, BBMT 2012 in press
Frequency of Treatments Evaluated in Literature Review of ASBMT
Paul J Martin et al, BBMT in press
ASBMT Recommendations: Second-line Therapy
• 5 studies with outlier 6-mo OS– High OS of 0.86: Rao 2009, Daclizumab+Infliximab,
med. age 5.6 yrs.– High OS of 0.76: Messina 2003, ECP, med. age 9.6
yrs.– Low OS of 0.17: Khoury 2001, horse ATG. 54% grade
IV, 52% liver (5% and 11% in MacMillan study)– Low OS of 0.28: Perales 2007, Daclizumab, 26%
grade IV, 32% liver– Low OS of 0: Martinez 2009, Alemtuzumab, all grade
III or IV, 50% liver
Martin PJ et al, BBMT 2012 in press
ASBMT Recommendations: Second-line Therapy
• Evaluation of 6-month survival does not support the choice of any specific agent for secondary therapy of acute GvHD.
• No evidence that any specific agent should be avoided for secondary therapy of acute GvHD.
Martin PJ et al, BBMT 2012 in press
ASBMT Recommendations: Second-line Therapy
• CR for aggregated 28 studies: 32%• 12 studies had higher CR, 11 lower CR
– Age differences, less stringent response definition, differences in grades III-IV, small cohort size, lack of consistent treatment regimen, differences in time points of assessment.
Martin PJ et al, BBMT 2012 in press
ASBMT Recommendations: Second-line Therapy
• Evaluation of CR rates does not support the choice of any specific agent for secondary therapy of acute GvHD.
• No evidence that any specific agent should be avoided for secondary therapy of acute GvHD.
Martin PJ et al, BBMT 2012 in press
ASBMT Recommendations ECP for Second-line Therapy
• Toxicity concerns Limited, blood loss from the extracorporeal circuit,
hypocalcemia due to anticoagulant, mild cytopenia, catheter-associated bacteremia but on increased risk of overall infections
• Significant interactions: None• Viral reactivation concerns: Not increased• Schedule
3 in week 1, 2 per week weeks 2-12 and 2 per 4 weeks thereafter.
ASBMT Recommendations Second-line Therapy of aGvHD
Toxicity Sig. interactions Viral reactivation
ECP Limited None Not increased
Steroids High None High
MMF Cytopenia, GI Myelosuppress. Moderately high
Denileukin Diftitox ↑ hepatic transam. None High
Sirolimus Cytopenia, HUS/TAM CYP3A or P-glyc. Moderate
Infliximab None None Very high
Etanercept None None High
Pentostatin Myelosuppress., liver, renal None Very high
Horse ATG Anaphylaxis, cytopenia None Very high
Rabbit ATG Cytopenia, infections None Very high
Alemtuzumab Pancytopenia, infusion-AE None Very high
ASBMT Recommendations Second-line Therapy of Acute GvHD
• Choice of second-line regimen should be guided by considerations of:– Effects of any previous treatment– Potential toxicity (infections)– Interactions with other agents– Familarity of physician with agent– Prior experience of physician with agent– Convenience– Expense
• Steroids should be continued after starting second-line agent for therapy of steroid-refractory acute GvHD.
Martin PJ et al, BBMT 2012 in press
BCSH and BSBMT Recommendations on Second-Line Therapy of Acute GvHD
• The following agents are suggested:– ECP– Anti-TNFα antibodies– mTOR inhibitors– MMF– IL-2R antibodies
• Level of evidence: 2C (suggest, current evidence from observational studies, case series)
Dignan FI et al, BJH 2012
Future Strategies• Biomarkers to identify patients with high risk for
morbidity and mortality– IS treatment plans tailored to patients in several risk
strata– Intensification of prophylaxis– Preemptive therapy
• ECP for primary treatment or prophylaxis– Excellent safety profile– ?? Optimal schedulle– ?? Combination with novel IS drugs
Randomized Phase II Study for Initial Treatment of Acute GvHD with ECP+Steroids or Steroids Alone
Aim: – Demonstrate efficacy of ECP as adjunct upfront therapy of newly
diagnosed acute GvHD grades II-IV in comparison to control group given steroids alone.
– Comparison of CR rates, steroid-sparing, infections, TRM, relapse and OS
CSA
R
+ P + ECP
CSA + PGrades> II< 72 hrs of steroids
GvHD Study Group Vienna BMT Unit
- M. Mitterbauer- P. Kalhs- W.Rabitsch- Z. Kuzmina- S. Wöhrer- C. Zielinski
Dept. Immunology- W.F. Pickl- U. Körmöczy
Dept. Dermatology- R. Knobler- U. Just- A. Tanew- G. Bauer
Dept. Transfusion Medicine- N.Worel- G. Leitner
Dept. Gastroenterology - J. Hammer - E. PennerDept. Pulmonology - V. Petkov
Clinical Case Presentations
Dr A Alfred RotherhamDr F Dignan LondonDr P Taylor RotherhamDr J Scarisbrick BirminghamDr R Malladi Birmingham
Dr Peter Taylor
Summary