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2012 The UK Photopheresis Society

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1 2012 The UK Photopheresis Society
Friday 28th September The Copthorne Tara Hotel Kensington, London

2 Dr Peter Taylor Introduction & Welcome

3

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5 Dr Julia Scarisbrick Secretary’s report

6 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

7 UKPS 2012 Feedback from January was to have nurse led workshop which we have in September Selected slides will be available from the website

8 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

9 Society Updates Debbie Lancaster UK Registry

10 Society Updates Dr Peter Taylor UK Quality Assurance / JACIE

11 Photopheresis Quality Assurance To begin the debate UKPS
28 September 2012 Peter Taylor The Rotherham NHS Foundation Trust

12 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

13 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

14 Standards Quality Management System Personnel Premises
Equipment, Information systems & materials Treatment Process Evaluation The Rotherham NHS Foundation Trust

15 Quality Management Define organisation and management
Service objective setting Management/Service review process User agreements / requirements (sharing arrangements) Documentation The Rotherham NHS Foundation Trust

16 Personnel Head of service with JD Staffing
Numbers, training, job descriptions, induction, staff records and review Regular meetings - ToR The Rotherham NHS Foundation Trust

17 Premises Definition of working environment
Facilities for staff & patients & storage Health & Safety The Rotherham NHS Foundation Trust

18 Equipment, Information systems
Management of equipment Management of data and information Management of materials The Rotherham NHS Foundation Trust

19 Treatment Process Patient selection, information and review
Treatment process – definitions & review Documentation Monitoring outcomes/evaluation Feedback on service The Rotherham NHS Foundation Trust

20 Evaluation Staff feedback Patient feedback
Clinical evaluation of service Complaints Incident reporting processes and feedback The Rotherham NHS Foundation Trust

21 Way forward.... 1 Agree in principle 2 Circulate draft document
3 Develop assessors guidance 4 Commence date?? The Rotherham NHS Foundation Trust

22 Monica Minguzzi Therakos – Current Developments

23

24 Dr Peter Taylor ECP – Mechanism of Action

25 Towards an understanding......
Photopheresis Mechanism of Action Towards an understanding...... UKPS 28 September 2012 Peter Taylor

26 Objectives What is known about the pathogenesis of chronic graft vs host disease ? What is known about the effects of photopheresis ?

27 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

28 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

29 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

30 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 , 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 , 1880

31 Immune tolerance to Self Antigens and T regs
Acute GvHD impairs negative selection of T cells and the development of T regs Morohashi Immunobiology , 268 cGvHD can develop in the absence of acute GvHD Conflicting data - T reg numbers in cGvHD Reiger Blood , vs Clark Blood ,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 , 2570 Absence of T reg control of Th1 and Th17 cells is responsible for the autoimmune mediated pathology in cGvHD Chen Blood ,3804 Photodepletion of T cells but sparing T regs can raise T reg numbers Bastien Blood ,4859

32 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

33 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

34 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

35 ‘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

36 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

37 Apoptosis

38 Reduction in Bcl/Bax ratio in ECP treated cells
Text Reduction in Bcl/Bax ratio in ECP treated cells Bladon Dermatology , 104

39 Tumour peptides Edelson 1988 Tumour specific peptides are exposed which generate an idiotype-specific effector CD 8 response

40 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 , 443 Differential cell dose studies have demonstrated no correlation with monocyte dose

41 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 , 319

42 Monocytes and Dendritic cells post ECP
Modulation of circulating DCs in ECP treated patients with reduced CD80+, CD123+, mature DC phenotype Alcindor Blood , 1622 Immature DC are prevalent in ECP treated cell populations with retained: ability for activation phagocytosis increased anti-inflammatory cytokines Spisek Transfusion , 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 , 757

43 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 , 99

44 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 , 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 Gawdy Am J Respir Cell Mol Biol , 249

45 T regulatory cells and the emergence of ‘tolerance’
T reg numbers improve following ECP ? normalisation Bladon & Taylor Ther Apher Dial 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 ,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

46

47 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 , 120.

48 B cell Homeostasis Dysregulation of the B cell compartment is a hallmark of cGvHD Socie Blood , 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 ,6107

49 Reduced CD21+ cells is marker of response to GvHD
Immature CD21- immature transitional B cells and deficiency of CD 27+ memory cells is associated with cGvHD Greinix Biol Blood Marrow Transplant , 208 Reduced CD21+ cells is marker of response to GvHD Kuzmina Blood , 744

50 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

51 Mechanism of Action of ECP
Treg Anti-inflammatory cytokines (eg, IL-10, TGF- ß) 1 5 Proinflammatory cytokines (eg, IL-12, IFNγ) Leukocytes Tr Tr Stimulation T effector cells Reduction in BAFF Tr Tr Tr Tr 3 2 Phagocytosis + 4 Methoxalen UV radiation Tolerogenic DC/APC Apoptosis Receptor-mediated signaling Cross-linked DNA The Rotherham NHS Foundation Trust

52 Acknowledgements Dr A Alfred Scientific team R Whittle H Denney
J Bladon Data management F Hammerton

53 Professor Hildegard Greinix
Acute GvHD

54 Acute Graft-versus-Host Disease
Univ. Klinik für Innere Medizin I Acute Graft-versus-Host Disease Hildegard Greinix Medical University of Vienna Vienna, Austria

55 Pathophysiology of Acute GvHD and GvL Effects

56 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

57 Risk Factors for Acute and Chronic GvHD According to NIH
Flowers MED et al, Blood 17: , 2011

58 First-line Therapy of Acute GvHD

59 First-Line Therapy of Acute GvHD

60 Low dose Prednisone in Acute GvHD
Cum. steroid dose 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. Survival Mielcarek et al, Blood 2009

61 Transplant Outcome According to Response to First-line Steroid-Therapy
B Van Lint et al, Blood 2006 61

62 Salvage Therapy of Acute GvHD

63 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

64 Steroids as First-Line Therapy of Acute GvHD
Response to Steroids NRM and OS MacMillan et al, Blood 2010 Van Lint et al, Blood 2006

65 Efficacy of ECP in Steroid-Refractory Acute GvHD

66 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

67 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.

68 ECP in acute GvHD Inclusion criteria Exclusion 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

69 Intensified ECP in Acute Steroid - Refractory/Dependent GvHD Phase II Study
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

70 Comparison Pilot Study and Phase II Study
All N=59 Pilot N=21 Phase II 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 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 2.1 ( ) 2.6 ( ) 1.9 ( )* Greinix et al, Haematologica 2006

71 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 (1-8) Max. response after months 1.3 (0.5-6) 2 (0.5-6) 1.2 ( ) 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

72 ECP as Second-line Therapy in Acute Steroid-
Refractory and Steroid-Dependent GvHD SKIN LIVER GUT 100 CR PR NC NR 80 60 40 20 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

73 II III IV ECP as Second-line Therapy in Acute Steroid-
Refractory and Steroid-Dependent GvHD II III IV 100 CR PR NC NR 80 60 40 20 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

74 Months after start of ECP
TRM of Patients with Steroid-Refractory Acute GvHD According to Response to Second-Line ECP Hazard Ratios for TRM 100 Probability in % Months after start of ECP 80 60 40 20 16 32 46 66 84 CR P< PR NC NR Greinix et al, Haematologica 2006

75 Greinix et al, Haematologica 2006
Overall Survival of Patients with Steroid-Refractory Acute GvHD According to Best Response to Second-Line ECP Hazard Ratios for Overall Survival 100 Probability in % 16 32 46 66 84 80 60 40 20 p < CR to ECP PR to ECP NC NR Months after start of ECP Greinix et al, Haematologica 2006

76 ECP in Steroid-refractory Acute GvHD Long-Term Results (n=96)
Probability % OS TRM Relapse Months after HCT

77 Long-Term Survival according to Response (n=96)
ECP in Steroid-refractory Acute GvHD Long-Term Survival according to Response (n=96) CR to ECP p<0.0001 Probability % PR to ECP no response to ECP Months after HCT

78 Acute Steroid-Refractory/Dependent GvHD Outcome after ECP (n=96)
No (%) Alive 52 (54) No chronic GVHD 36/52 (69) Relapse 17 (18) Med. FU yrs 6 (0.5-15)

79 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

80 Salvage ECP in Acute Steroid-Refractory GvHD Rapid Steroid Reduction during ECP
Greinix 2000 and 2006, Salvaneschi 2001, Messina 2003, Garban 2005, Perfetti 2008 Perotti et al, Transfusion 2010 Perfetti et al, BMT 2008

81 Messina 2003 Perfetti 2008 Perotti 2010 Calore 2008
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 Probability in % 16 32 46 66 84 80 60 40 20 p < CR to ECP PR to ECP NC NR Greinix et al, Haematologica 2006

82 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

83 Second-Line ECP in Acute Steroid-Refractory GvHD
Intensified Second-Line ECP 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. STEROIDS CSA ECP a G V H D

84 ECP in Steroid-Refractory Acute GvHD
Publications (n=24) Published Patients (n=297)

85 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% ( %) ECP is effective and well-tolerated adjunct second-line therapy.

86 ECP in Steroid-Refractory Acute GvHD
Author Pts CR/PR Skin % CR/PR Liver % Gut % OS % Salvaneschi 01 9 89 20 60 67 Dall‘Amico 02 14 79 57 70 Messina 03 33 82 75 69 Kanold 07 12 100 83 Greinix 06 59 93 65 74 47 Calore 08 15 92 71 85 Perfetti 08 23 66 27 40 48 Perotti 10 50 73 64

87 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 Are they informations on patient selection criteria correct? Sterroid dose was variable but at least 1 mg/kg/day at onset of aGVHD Greinix et al, EBMT 2012 87

88 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%) What are myeloid disorders? Includes MDS, CML. CMML 88 88

89 Overall Response* p<0.0001
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)

90 Survival and NRM: ECP vs. Non-ECP
The median follow-up of surviving pts after SLT is 29.7 (range ) months (m) (ECP-33.7 m vs. non-ECP-17.9 m, P=0.005). Median and 2-yr survival for all patients is 20 (95% CI 0-43) m and 47%, respectively. Survival and ECP vs. non-ECP : Use of ECP (not reached (NR) vs. 4.9 m P<0.001). 6 month Cumulative incidence of NRM with death from relapse as a competing risk: 23% for ECP and 60% for non-ECP (P <0.001) ECP Greinix et al, EBMT 2012 90 90

91 ECP Safety Profile

92 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

93 Efficacy of ECP is not a Result of Generalized Immunosuppression
Improvement in immune reconstitution after ECP in experimental allo BMT No increase of opportunistic infections or relapse during ECP No suppression of T-or B-cell responses to novel or recall antigens after ECP Suchin et al, J Am Acad Dermatol 1999 Gatza et al, Blood 2008

94 Long-Term Results on Relapse (n=96)
ECP in Steroid-refractory Acute GvHD Long-Term Results on Relapse (n=96) p=0.42 Probability % CR to ECP no response to ECP PR to ECP Months after HCT

95 Präclinical Model of ECP

96 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

97 ECP Reduces GvHD and Mortality in Minor-MM Mouse Model
Gatza et al, Blood 2008 * *p<0.004 vs L-15 7 14 21 28 35 42 49 1 2 3 4 5 6 GVHD Score Days post BMT 20 40 60 80 100 10 30 50 Percent Survival Days post BMT *p= vs L-15 * SYN +/- ECP (n=15) ALLO + Spl + ECP (n=34) ALLO + Diluent (n=26) ALLO + Spl w/o ECP (n=19)

98 Infusion of ECP-treated Splenocytes Increases Donor Treg after Allo BMT
Gatza et al, Blood 2008

99 Acute GvHD Treatment Guidelines

100 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

101 Basis of ASBMT Recommendations
Comprehensive and critical review of published reports 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

102 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

103 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

104 Initial Agreement between Evaluators
Criterion % Agreement Eligibility criteria 60 Minimization of selection bias 81 Consistent treatment regimen 61 Organ response criteria 82 Overall response criteria 75 Prespecified time of assessment 84 Concomitant treatment Historical benchmark 93 Statistical hypothesis 97 Survival curve 76

105 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

106 Frequency of Treatments Evaluated in Literature Review of ASBMT
Paul J Martin et al, BBMT in press

107 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

108 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

109 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

110 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

111 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.

112 ASBMT Recommendations Second-line Therapy of aGvHD
Toxicity Sig. interactions Viral reactivation ECP Limited None Not increased Steroids High MMF Cytopenia, GI Myelosuppress. Moderately high Denileukin Diftitox ↑ hepatic transam. Sirolimus Cytopenia, HUS/TAM CYP3A or P-glyc. Moderate Infliximab Very high Etanercept Pentostatin Myelosuppress., liver, renal Horse ATG Anaphylaxis, cytopenia Rabbit ATG Cytopenia, infections Alemtuzumab Pancytopenia, infusion-AE

113 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

114 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

115 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

116 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 + P + ECP R Grades> II < 72 hrs of steroids CSA + P

117 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

118

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120 Clinical Case Presentations
Dr A Alfred Rotherham Dr F Dignan London Dr P Taylor Rotherham Dr J Scarisbrick Birmingham Dr R Malladi Birmingham

121 Dr Peter Taylor Summary


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