Transcript ukps.org

2012
The UK
Photopheresis
Society
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 Lancaster
UK Registry
Society Updates
Dr Peter Taylor
UK Quality Assurance / JACIE
Photopheresis
Quality Assurance
To begin the debate
UKPS
28 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??
The Rotherham NHS Foundation Trust
Monica Minguzzi
Therakos – Current Developments
Dr Peter Taylor
ECP – Mechanism of Action
Photopheresis
Mechanism of Action
Towards an understanding......
UKPS
28 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
Chronic GvHD – Heterogeneous Disease
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
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 selection
T 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 regs
Morohashi Immunobiology 2000 202, 268
•
•
cGvHD can develop in the absence of acute GvHD
Conflicting data - T reg numbers in cGvHD
Reiger 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 dioxygenase
J Clin Invest 2007 117, 2570
•
Absence of T reg control of Th1 and Th17 cells is responsible for the
autoimmune mediated pathology in cGvHD
Chen Blood 2007 110,3804
•
Photodepletion of T cells but sparing T regs can raise T reg numbers
Bastien Blood 2010 116,4859
The Rotherham NHS Foundation Trust
Role of B cells
•
•
Presence of autoantibodies
•
Improvement in cGvHD induced by anti-CD20 therapy
•
Enhanced CD 86 expression after stimulation of B cells
•
Raised BAFF levels
•
•
Clinical presentation of cGvHD with autoimmune manifestations
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
Photopheresis
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
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 antiidiotypic 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 hours
Just 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 ECP
Ingestion by Antigen Presenting Cells (APCs) has a profound effect on
immune regulation
ECP Inhibits pro-inflammatory cytokine production
Bladon Transplantation Intl 2006 19, 319
The Rotherham NHS Foundation Trust
Monocytes and Dendritic cells post ECP
•
Modulation of circulating DCs in ECP treated patients with
reduced CD80+, CD123+, mature DC phenotype
Alcindor 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 CCR10
Holtick Transplantation 2008 85, 757
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 donors
The Rotherham NHS Foundation Trust
Gawdy Am J Respir Cell Mol Biol. 2012 46, 249
T regulatory cells and the emergence of ‘tolerance’
T reg numbers improve following ECP ? normalisation
Bladon & 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 innocula
resulting 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 ECP
Scmitt 2009 Transplantation 87,1422
The Rotherham NHS Foundation Trust
The Rotherham NHS Foundation Trust
Future directions?
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 PDL1-PD1 axis converts
human Th1 cells into regulatory T
cells
Amarnath Sci Transl Med. 2011 3,
120.
The Rotherham NHS Foundation Trust
B cell Homeostasis
•
Dysregulation of the B cell compartment is a hallmark of cGvHD
Socie Blood 2011 117, 2086
•
Clinical features of autoimmune disease
•
B cell Activating Factor (BAFF) is elevated in GVHD and is related to
production of autoimmunity
Sarantopoulos Clin Cancer Res 2007 13,6107
The Rotherham NHS Foundation Trust
Immature CD21- immature transitional B cells and deficiency of CD
27+ memory cells is associated with cGvHD
Greinix Biol Blood Marrow Transplant 2008 14, 208
Reduced CD21+ cells is marker of response to GvHD
Kuzmina 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 steroids
Whittle Bone Marrow Transplantation 2012 47
The Rotherham NHS Foundation Trust
Mechanism of
Action of ECP
Treg
Antiinflammatory
cytokines
(eg, IL-10, TGFß)
Proinflammator
1
Leukocytes
y cytokines
(eg, IL-12,
IFNγ) T
Stimulation
5
Tr
Tr
Tr
effector cells
2
+
3
Tr
Tr
Tr
Reduction in BAFF
Phagocytosis
4
Methoxalen
UV radiation
Tolerogenic
DC/APC
Apoptosis
Cross-linked DNA
Receptor-mediated
signaling
The Rotherham NHS Foundation Trust
Acknowledgements
Dr A Alfred
Scientific team
R Whittle
H Denney
J Bladon
Data management
F Hammerton
www.photopheresis.co.uk
The Rotherham NHS Foundation Trust
Professor Hildegard Greinix
Acute GvHD
The Rotherham NHS Foundation Trust
Univ. Klinik für
Innere Medizin I
Acute Graft-versus-Host
Disease
Hildegard Greinix
Medical University of Vienna
Vienna, Austria
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
Cum. steroid dose
Survival
• 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.
Mielcarek et al, Blood 2009
Transplant Outcome According to Response
to First-line Steroid-Therapy
A
B
Van Lint et al, Blood 2006
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 steroidrefractoriness
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 SteroidRefractory Acute GvHD
Development of ECP for Clinical Use
Increasing use of ECP
2008 ECP Rand.
Study. cGVHD
1987
ECP Approval for CTCL
1981
First ECP
1994
ECP in Chronic GVHD
1998
ECP in acute GVHD
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
a
Phase
II
Study
G
V
H
D
CSA
ECP
STEROIDS
• 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
Greinix et al, Haematologica 2006
Comparison Pilot Study and Phase II Study
All
Pilot
Phase II
N=59
N=21
N=38
II/III/IV at ECP
36/13/10
10/6/5
26/7/5
Skin alone
Skin+liver
Skin+liver+gut
Others
31
13
8
7
8
9
3
1
23*
4
5
6
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
2.6 (1.1-10.4)
1.9 (0.7-2.3)*
2.1 (0.7-10.4)
Greinix et al, Haematologica 2006
Acute Steroid-Refractory and Steroid-Dependent GvHD
Results of ECP
All
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
ECP as Second-line Therapy in Acute SteroidRefractory and Steroid-Dependent GvHD
100
SKIN
LIVER
GUT
CR
PR
NC
80
NR
60
40
20
0
PILOT
N=21
Ph II
N=36
PILOT
N=12
Ph II
N=11
PILOT
N=4
Ph II
N=11
Greinix et al, Haematologica 2006
ECP as Second-line Therapy in Acute SteroidRefractory and Steroid-Dependent GvHD
II
III
IV
100
CR
PR
NC
80
NR
60
40
20
0
PILOT
N=10
Ph II
N=26
PILOT
N=6
Ph II
N=7
PILOT
N=5
Ph II
N=5
Greinix et al, Haematologica 2006
TRM of Patients with SteroidRefractory Acute GvHD According
to Response to Second-Line ECP
Hazard Ratios for TRM
0.1
Variable
Female gender
100
Higher grade of GVHD during first-line
NR
P< 0.0001
NC
Higher grade of GVHD at start of ECP
More organs involved during first-line
80
Probability in %
More organs involved at start of ECP
Shorter interval from D0 to start of ECP
60
Time to start of steroids
PR
Days of steroids prior ECP
40
Higher cum. steroid dose first-line
Higher steroid dose at start of ECP
20
Lower number of ECP given
CR
Shorter duration of ECP
Steroids < 1 mg/kg b.w. 4 weeks after start of ECP
0
0
16
32
46
66
84
Months after start of ECP
100
Steroids < 0.5 mg/kg b.w. 8 weeks after start of
ECP
No CR 3 months after start of ECP
Greinix et al, Haematologica 2006
1
lower TRM
10
higher TRM
Overall Survival of Patients with
Steroid-Refractory Acute GvHD
According to Best Response to
Second-Line ECP
Hazard Ratios for
Overall Survival
0.1
Variable
Female gender
100
Higher grade of GVHD during first-line
p < 0.0001
Higher grade of GVHD at start of ECP
Probability in %
80
More organs involved during first-line
More organs involved at start of ECP
CR to ECP
60
Shorter interval from D0 to start of ECP
Time to start of steroids
40
Days of steroids prior ECP
PR to ECP
Higher cum. steroid dose first-line
Higher steroid dose at start of ECP
20
NC
Lower number of ECP given
Shorter duration of ECP
NR
0
Steroids < 1 mg/kg b.w. 4 weeks after start of ECP
0
16
32
46
66
Months after start of ECP
84
Greinix et al, Haematologica 2006
Steroids < 0.5 mg/kg b.w. 8 weeks after start of
ECP
No CR 3 months after start of ECP
1
better OS
10
worse OS
ECP in Steroid-refractory Acute GvHD
Long-Term Results (n=96)
100
Probability %
80
60
OS
40
TRM
20
Relapse
0
0
12 24 36 48 60 72 84 96 108 120 132 144 156 168 180 192 204
Months after HCT
ECP in Steroid-refractory Acute GvHD
Long-Term Survival according to Response (n=96)
100
CR to ECP
Probability %
80
60
p<0.0001
40
PR to ECP
20
no response to ECP
0
0
12 24 36 48 60 72 84 96 108 120 132 144 156 168 180 192 204
Months after HCT
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 steroidrefractory 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
Perfetti et al, BMT 2008
Perotti et al, Transfusion 2010
Greinix 2000 and 2006, Salvaneschi 2001, Messina 2003,
Garban 2005, Perfetti 2008
Salvage ECP in Acute Steroid-Refractory GvHD
Improved Survival in ECP-Responders
• Messina 2003
100
p < 0.0001
– 69% vs 12% at 5 years
Probability in %
80
• Perfetti 2008
CR to ECP
60
40
– 38% vs 14% in
controls with grades
III-IV aGvHD
PR to ECP
20
• Perotti 2010
NC
– 62% vs 6%
NR
0
0
16
32
46
66
84
Greinix et al, Haematologica 2006
• Calore 2008
ECP for Treatment of Acute
GvHD in Children
• 16 steroid-responder
• 15 given ECP for steroidresistance, 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
Second-Line ECP in Acute SteroidRefractory GvHD
Intensified Second-Line ECP
a
G
V
H
D
CSA
ECP
STEROIDS
• ECP is effective and welltolerated adjunct secondline 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.
ECP in Steroid-Refractory Acute GvHD
Publications (n=24)
60
Published Patients (n=297)
50
70
40
60
30
50
20
40
10
30
0
20
1995 1996 1997 1998 1999 2000 2001 2002 2003 2005 2006 2007 2008 2010
pts pts pts
10
0
1995 1996 1997 1998 1999 2000 2001 2002 2003 2005 2006 2007 2008 2010
pts
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/PR
Liver %
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
3w
– 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
Male
48 (56%)
25 (61%)
Female
38 (44%)
16 (39%)
Age (y) (median)
47 (range, 17-67)
44 (5-64)
Acute Leukemia
50 (58%)
21 (51%)
Lymphoma
18 (21%)
5 (12%)
Myeloid Disorders
16 (19%)
10 (24%)
Myeloma
2 (2%)
5 (12%)
Gender
Diagnosis
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%)
Response to ECP (n=86)
Response to Anticytokine Therapy (n=41)
70
50
45
60
40
35
50
30
40
prior
end
25
20
15
prior
end
30
20
10
10
5
0
0
Skin 3-4
GI 3-4
Liver 3-4 Grade 3-4 >- 2 organs
Skin 3-4
GI 3-4
Liver 3-4 Grade 3-4 >- 2organs
ECP
Survival and NRM:
ECP vs. Non-ECP
ECP
Greinix et al, EBMT 2012
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
Improvement in immune reconstitution
after ECP in experimental allo BMT
• No suppression of T-or Bcell responses to novel or
recall antigens after ECP
Suchin et al, J Am Acad
Dermatol 1999
Gatza et al, Blood 2008
ECP in Steroid-refractory Acute GvHD
Long-Term Results on Relapse (n=96)
100
Probability %
80
60
p=0.42
40
CR to ECP
20
no response to ECP
PR to ECP
0
0
12 24 36 48 60 72 84 96 108 120 132 144 156 168 180 192 204
Months after HCT
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
ECP Reduces GvHD and Mortality in Minor-MM
Mouse Model
Gatza et al, Blood 2008
6
*p<0.004 vs L-15
100
4
3
*
2
1
Percent Survival
GVHD Score
5
80
*
60
40
20
*p=0.0007 vs L-15
0
0
0
7
14 21 28 35 42 49
Days post BMT
0
10
20
30
40
Days post BMT
SYN +/- ECP (n=15)
ALLO + Spl + ECP (n=34)
ALLO + Diluent (n=26)
ALLO + Spl w/o ECP (n=19)
50
60
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 Evaluators
Criterion
Eligibility criteria
Minimization of selection bias
Consistent treatment regimen
Organ response criteria
Overall response criteria
Prespecified time of assessment
Concomitant treatment
Historical benchmark
Statistical hypothesis
Survival curve
% Agreement
60
81
61
82
75
84
60
93
97
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
Aim:
Randomized Phase II Study for Initial Treatment of
Acute GvHD with ECP+Steroids or Steroids Alone
– 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
+ P +
CSA
+ P
R
Grades> II
< 72 hrs of steroids
ECP
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. Penner
Dept. Pulmonology
- V. Petkov
Clinical Case Presentations
Dr A Alfred
Dr F Dignan
Dr P Taylor
Dr J Scarisbrick
Dr R Malladi
Rotherham
London
Rotherham
Birmingham
Birmingham
Dr Peter Taylor
Summary