Therese Callaghan October 2014 Post allogeneic transplant Donor derived immune cells, primarily T lymphocytes, react against recipient tissues Acute Classic: first 100 days Late onset : after 100 days Chronic Classic : post 100 days Overlap Skin GIT Liver Oral Eye Lung Genitalia Diarrhoea N&V Anorexia Weight loss Abdominal pain Cholestatic jaundice 5 year survival 10% OB/BOS = bronchiolitis obliterans syndrome Similar to lung transplantation Road pollution a risk factor May occur many years post transplant Female dryness, dyspareunia Male dysuria, painful glans, erythematous papules, lichenoid lesions EBMT-ELN working group Recommendations for standard practice Myeloablative standard prophylaxis = cyclosporin +short course methotrexate +/- ATG Reduced intensity conditioning (RIC) cyclosporin + MMF +/- ATG Cord cyclosporin + MMF EBMT-ELN working group/BCSH Recommendations for standard practice First line methylprednisolone 2mg/kg/day Topical steroids for skin No standard second line Mycophenolate (MMF) ECP etc EBMT-ELN working group/BCSH Recommendations for standard practice Treatment Steroids Calcineurin inhibitors (cyclosporin) -steroid sparing No standard second line ECP (skin, mouth, liver) Imatinib MMF Treatment topical steroids, topical tacrolimus, antifungals for concurrent candidal infection, saliva substitutes, cancer surveillance Treatment Lubricants Steroids Autologous serum eye drops Cyclosporin Punctal occlusion Amniotic membrane Systemic immunosuppression Azithromycin etc Lung transplant EXTRACORPOREAL PHOTOPHERESIS

It s all Greek to me...... ECP procedure

Blood drawn into cell separator instrument centrifuged leucocytes/mononuclear cells collected () red cells & plasma returned to the patient Buffy coat treated with photosensitising agent 8-MOP (UVADEX) Photoactivation by UVA light Treated leucocytes returned to patient

From www.therakos.com

Photoactivating agent

UVADEX = 8 methoxypsoralen 10ml vial / 200 µg of 8-MOP Injected directly into collection bag Current & Potential Applications of ECP

Malignancy CTCL , Sezary syndrome GVHD Chronic Acute Solid organ transplant rejection Autoimmune Progressive systemic sclerosis, SLE, RA, psoriatic arthritis, pemphigus vulgaris Other CTCL : apoptotic leucocytes phagocytosed by antigen presenting cells (APCs) with production of specific tumour suppressor cells GVHD : no answer yet, ?multifactorial Hypotheses include: Cellular vaccination of ECP-treated lymphocytes Direct effect of ECP on effector cells ECP modulation of peripheral blood monocytes and dendritic cells Distal effects on untreated lymphocytes in GVHD Emergence of regulatory populations during ECP treatment Improvement in dysregulation of B cell homeostasis MIG (monokine induced by interferon gamma) BAFF CD13 Elafin skin CLX16 - liver ECP induces neutrophilic myeloid suppressor cells (nMDSCs) in cGVHD

ECP downregulates T cell response Mechanism not known Hypothesis ECP induces myeloid cell population that dampens T cell response Study found distinct subpopulation of nMDSCs following ECP ECP technical aspects

CELLEXTM machine (Therakos) (has replaced XTS) Extracorporeal volume (double needle) 180 ml - can treat low weight patients including paediatrics Treatment 1.5 2 hours (dual needle) Heparin 10,000 15,000 units used as AC, returned to patient Minimum count = 20 Minimum haematocrit = 0.27 Exclusion criteria: Aphakic patients Low haematocrit (<27) /neutrophils/platelets Uncontrolled infection Diarrhoea > 1000 mL daily History of heparin induced thrombocytopenia (HIT) Known sensitivity to compounds

Weight < 25 kgs (Therakos CellexTM), below this need albumin/blood prime

Photosensitivity need for eye & skin protection for 24 hours

Lipaemia (e.g. parenteral feeding) - blocks activation

Bleeding risk (heparin) Minimum haematocrit Liquid bolus in small children Hickman line? SEs: mainly minor fall in bp BCSH guidelines 2012 recommendation second line treatment in both chronic and acute GVHD ASFA Guidelines 2012 skin : ECP accepted as second line non-skin: role of ECP not established UK Photopheresis Expert Group consensus statement 2008 recommendation Chronic extensive GVHD (Seattle criteria), refractory, dependent or intolerant of corticosteroids, affecting skin, mucous membranes (mouth/eye), liver Not first line Not acute Comparison of studies difficult Limited consensus on patient selection, treatment scheduling, assessment of response & subsequent tapering of ECP Few laboratory parameters for objective assessment Published experience of use in acute GVHD much more limited than in chronic Response to ECP in GVHD

Complete : resolution of active GVHD without systemic immunosuppression Partial: > 50 % improvement of organ involvement scores (skin, liver, oral mucosa) from baseline and/or > 50% reduction of immunosuppression Minimal : < 50% improvement and/or 25-50% reduction in immunosuppression Progressive : worsening or new manifestation or increased immunosuppression Maximal : partial response stable for 3 months with reduced or stable immunosuppression ECP in cGVHD : treatment schedule (UK Expert Group consensus statement)

Initially one cycle of 2 consecutive days ECP every fortnight Assess at 3 months/after 7-8 cycles Complete or partial (>50%) response reduce to monthly to 6 months Minimal (< 50%) response or no change despite reduction of steroids by 50% - continue fortnightly to 6 months If neither (i.e.progressive or stable) stop If continuing continue 3 monthly assessments ECP in cGVHD : treatment schedule UK consensus statement

Immunosuppression should be withdrawn in order of: corticosteroids reduced, other immunosuppressants kept at stable dose once steroids reduced to minimal dose or stopped other immunosuppression tapered/stopped

No objective response after 3 months - cease ECP Not currently recommended by UK consensus group but recommended as second line by BCSH Optimal treatment schedule not established One regimen - weekly cycles for minimum 8 weeks, continue till maximum response Acute GvHD early responses within first 2 - 3 treatments maximal responses after 6 8 weeks Chronic GVHD Manifestations take longer to respond If no improvement observed in 3 4 months then response unlikely ECP as second line allows reduction of immunosuppression Response to ECP in GVHD

Chronic GVHD : best responses skin (up to 80% complete response), mucous membranes (moth, eye) liver variable responses reported GI tract/lung no consistent evidence

Acute GVHD: skin 80%, high proportion complete gastrointestinal & liver 35-60%, usually partial Funding agreed by NHS England for patients in England with cGVHD meeting criteria of UK consensus statement Funding agreed for North West patients with CTCL For other cases e.g. outside England, acute GVHD individual funding agreement (IFR) required Extracorporeal photopheresis

150 centres worldwide UK includes : Belfast Birmingham Bristol (NHSBT) Glasgow London Rotherham Newcastle upon Tyne North West (Liverpool & Manchester) (NHSBT) Oxford (NHSBT) UK consensus statement on the use of extracorporeal photopheresis for treatment of cutaneous T-call lymphoma and chronic graft-versus-host disease. JJ Scarsbrick et al on behalf of the Photopheresis Expert Group, Br J Dermatology 2008 1-20

BCSH guidelines 2012: 1. Organ specific management of supportive care in chronic graft- versus-host disease 2. Chronic graft-versus-host disease diagnosis and management 3. Acute graft-versus-host disease diagnosis and management