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


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


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.


Standards

•Quality Management System

•Personnel

•Premises

•Equipment, Information systems & materials

•Treatment Process

•Evaluation


Quality Management•Define organisation and management

•Service objective setting

•Management/Service review process

•User agreements / requirements (sharing arrangements)

•Documentation


Personnel

•Head of service with JD

•Staffing

•Numbers, training, job descriptions, induction, staff records and review

•Regular meetings - ToR


Premises

•Definition of working environment

•Facilities for staff & patients & storage

•Health & Safety


Equipment, Information systems

•Management of equipment

•Management of data and information

•Management of materials


Treatment Process

•Patient selection, information and review

•Treatment process – definitions & review

•Documentation

•Monitoring outcomes/evaluation

•Feedback on service


Evaluation

•Staff feedback

•Patient feedback

•Clinical evaluation of service

•Complaints

•Incident reporting processes and feedback


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


Photopheresis

Mechanism of Action

Towards an understanding......

UKPS28 September 2012

Peter Taylor


Objectives

What is known about the pathogenesis of chronic graft vs host disease ?

What is known about the effects of photopheresis ?


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


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


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


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


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


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


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


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


‘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


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


Apoptosis


Text

Reduction in Bcl/Bax ratio in ECP treated cells

Bladon Dermatology 2002 204, 104


Tumour peptides

Edelson 1988

Tumour specific peptides are exposed which generate an idiotype-specific effector CD 8 response


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


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


• 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


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


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


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’


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


•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


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


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



Acknowledgements

Dr A Alfred

Scientific teamR WhittleH DenneyJ Bladon

Data managementF Hammerton

www.photopheresis.co.uk

http://www.photopheresis.co.uk/


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)*


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


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


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


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


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


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


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)


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.


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


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


Infusion of ECP-treated Splenocytes Increases Donor Treg after Allo BMT


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


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


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


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


Frequency of Treatments Evaluated in Literature Review of ASBMT

Paul J Martin et al, BBMT in press


• 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



• 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.



• 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.



• 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.


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.


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

2012 the uk photopheresis society friday 28th september the copthorne tara hotel kensington, london

Documents

ecp procedure

quality requirements

safe administration

details of ecp

quality system

uk photopheresis society

photopheresis centres

patients diagnosis