Extracorporeal Photopheresis Application Update Dr. Hind AlHumaidan, MD,FRCPA Consultant Hematopathologiest Director, Blood Bank, Donor, Transfusion Services, APHERESIS & Stem Cell Cord Blood Bank Saudi Arabia chairperson of AATM Extracorporeal Photopheresis • Immune modulating therapy majorly targeting the T cells of the Immune system. • ECP induces an anti-inflammatory condition with tolerogenic responses without inducing a global immunosuppression state. • Clinical indication of ECP has grown over time Extracorporeal Photopheresis • Edelson et al first scientists to develop ECP as a treatment for patients with CTCL. Edelson R, Berger C, Gasparro F, Jegasothy B, Heald P, Wintroub B, Vonderheid E, Knobler R, Wolff K, Plewig G N Engl J Med. 1987 Feb 5; 316(6):297-303. • 1988, the FDA, approved the use of ECP standard therapy Extracorporeal Photopheresis ECP has been applied as a treatment modality for several autoimmune T-cell mediated conditions: • Pemphigus vulgaris • systemic sclerosis • rheumatoid arthritis • Crohn's disease • multiple sclerosis ECP • Solid organ allograft rejections. • Acute and chronic graft-versus-host disease. Extracorporeal Photopheresis HISTORY: • Origin of ECP dates back to ancient Egypt (Pharaoh). • People with vitiligo ingested a plant (Ammi majus) found on the banks of the Nile river. • Bathed in the sun, and noticed recovery in melanin production. Extracorporeal Photopheresis Cont. HISTORY: • Psoralen (8-methoxypsoralen [8-MOP]) is inert photo-reactive substance isolated from these plants. • Ultraviolet –A (UVA ) • PUVA treatment. Extracorporeal Photopheresis Technical Aspects: Extracorporeal Photopheresis Asian J Transfus Sci. 2017 Jul-Dec: 11(2): 81-68 Machines for ECP ➢ Two machines for ECP were developed by Therakos and approved by FDA: • Uvar XTS - “second generation discontinuous flow instrument” • Cellex - “third generation continuous flow instrument” Instrument Comparison UVAR XTS • Discontinuous flow • Minimum weight: 40kg • Off-label fluid boluses / blood prime for low TBV • Longer average run time • Lower collection efficiency Instrument Comparison CELLEX • Continuous or discontinuous flow • weight limit 20 kg and above • manufacturer approved volume prime for low TBV • Shorter average run time • Improved collection efficiency compared to UVAR. Extracorporeal Photopheresis Mechanism of Action: Mechanism resulting in the therapeutic activity of ECP is under investigation. • Theories: • ECP affect primarily the T-cell component of the immunological activity. • upregulation of the immune system in cases of CTCL. • downregulation in cases of graft-versus-host disease (GVHD) post transplant and in cases of solid organ allograft rejection. Extracorporeal Photopheresis Mechanism of Action: Extracorporeal Photopheresis • The photoactivated 8-MOP binds to pyrimidine bases of DNA resulting in cross-linking of the two DNA strands induces apoptosis along activating (APC) • 5%–15% of treated mononuclear cells undergo apoptosis on reinfusion • mainly localize in spleen or liver Extracorporeal Photopheresis Scope in Saudi Arabia: • Allogenic bone marrow transplants (BMTs) are increasingly offered by tertiary care centers like our centers. • Availability of unrelated donor marrow registries & haploidentical transplants. • Field is growing. Extracorporeal Photopheresis Extracorporeal Photopheresis • As we grow our center has to offer treatment post transplant complications GvHD. • ECP novel treatment option. • Our center first to install in the region. Extracorporeal Photopheresis • Steroids are the only treatment option available to treat these complications. • ECP offers reduction in alloreactivity in acute and chronic GvHD without global immunosuppression on the contrary of steroids GRAFT-VERSUS-HOST DISEASE (GVHD) Incidence: Post allogeneic HSCT: • aGVHD Grade II-IV 10-60% • cGVHD Moderate-severe 6-80% GRAFT-VERSUS-HOST DISEASE (GVHD) • GVHD remains a major cause of morbidity and mortality following HSCT. • aGVHD occurs before day 100. • Inflammatory tissue injury & necrosis with skin and gastrointestinal (GI) tract inflammation, cholangiohepatic liver injury & cholestatic jaundice. GRAFT-VERSUS-HOST DISEASE (GVHD) • cGVHD after 100 days typically affects skin, GI, liver, lungs, oropharynx, eyes, genital tract and/or musculoskeletal systems without aGVHD features. GRAFT-VERSUS-HOST DISEASE (GVHD) • aGVHD results activation donor T cells by host APCs, leading T cell and cytokine-mediated tissue injury. • cGVHD is due dysregulated allo- or autoreactive T cells, B cells, APCs and NK cells leading fibrosis, inflammation, sclerosis & atrophy tissues. GRAFT-VERSUS-HOST DISEASE (GVHD) Management • aGVHD grade II-IV tx corticosteroids & calcineurin inhibitors. • 5% pt not completely respond. GRAFT-VERSUS-HOST DISEASE (GVHD) Management • cGVHD managed corticosteroids ± other systemic immunosuppressive therapies. • SR or SD extensive cGVHD include other immunosuppressive therapies and ECP. GRAFT-VERSUS-HOST DISEASE (GVHD) Mechanism • ECP works ↥ dendritic cell differentiation, ↧ regulation of autoreactive B cells, alterations in Th & lymphocyte homing antigen display. • Switch from proinflammatory to anti-inflammatory cytokine production, & generation of Treg. GRAFT-VERSUS-HOST DISEASE (GVHD) Overall response rates for SR aGVHD: • reportedly range 52-100%. 66-100% skin. 40-83% GI tract. 27-71% in liver. • Multicenter comparative analysis ECP Verses anticytokine therapy in SR aGVHD reported Higher response in ECP 66% versus 32% (Jagasia ,2013) • Authors suggested earlier use ECP acute phase of inflammation improve complete response rate. GRAFT-VERSUS-HOST DISEASE (GVHD) Overall response rates for SR cGVHD: Variable • Skin 74%. • Liver 68%. • Ocular 60%. • Oral 72%. • Lunge 48% • GI 53% (Malik ,2014) GRAFT-VERSUS-HOST DISEASE (GVHD) • Non-Blinded Assessment Difference recorded 40% complete & partial response in ECP compered 10% non-ECP ,steroids quickly tapered in ECP group. (Flowers,2008) • Randomized study after 24-weeks course ECP showed skin response 33%,extracutaneous tissue 70% suggesting prolonged ECP necessary optimal therapeutic effect. (Greinix, 2011) GRAFT-VERSUS-HOST DISEASE (GVHD) • Maximal responses for cGVHD require 2-6 months of treatment. • Steroid sparing effect occurs even in absence of organ improvement, improves quality of life. • ECP improve/slow lung function decline in cGVHD patients with bronchiolitis obliterans syndrome (BOS) after standard treatment failure. • Recommend consideration of ECP as adjunctive first-line modality for GVHD associated BOS. Journal of Clinical Apheresis (2019) ECP Indications Category I: • Cutaneous T Cell lymphoma (CTCL) Category II: • Graft vs host disease (GVHD) • Acute • Chronic • Solid organ transplant rejection or prophylaxis • Heart • Lung ECP Indications Category III • Atopic dermatitis • Crohn’s disease • Nephrogenic systemic fibrosis • Pemphigus vulgaris • Psoriasis • Scleroderma • Liver solid organ desensitization / rejection Categorized NOT • Kidney • Ulcerative colitis Establishment of ECP Program in KFSH&RC Establishment of ECP Program in KFSH&RC • ECP Program in KFSH&RC started in 2008 to February 2014 • Uvar XTS Machine x 1 • Total of 30 patients o 22 GvHD o 7 CTCL o 1 Lung Transplant Establishment of ECP Program in KFSH&RC • Protocol total of 18 sessions 1st 3 months: 2 sessions back/back bi-weekly 2nd 3 months: 2 sessions back/back monthly ECP Program at KFSH&RC Program stopped due to logistic reasons. ECP Program • Program re-started on August 2016 & renewed October 2019. • Machine Cellex x 3 Advantages of Cellex • Smaller Extracorporeal Volume (ECV) • Shorter procedure times • Procedure both machines not specify lower limit patients WT, HCT, other laboratory parameters. Advantages of Cellex • Users must determine patient safe ECV based on protocol blood volume and HCT using tables procedure manual • No recommended quality control ECP Patients Currently, we now have a total of 75 patients • Adult patients o GvHD – 49 patients o Dermatology – 11 patients o Organ Transplant – 3 patients • Low weight patients – 12 patients ECP Patients • GVHD -55 • Dermatology-11 SEZARY-5 Mycosis-1 Scleroderma-1 Morphea -2 pemphigus Vulgaris-1 • ORGAN TX- Lung Rejection -3 Extracorporeal Photopheresis Heterogeneity of protocols and length of ECP in literature “lack (RCTs)” Protocol for Adult Patients • We started with a total of 18 sessions with the previous protocol and modified to 24 sessions. Adults: Q1 week 2 sessions back/ back 1 month: 8 Q2 week – 2 sessions back / back 2 month: 8 sessions Q month –2sessions 4 month: 8 sessions Protocol for Pediatric Patients • Protocol for pediatric patients 22 sessions Low weight patients: Q1 week – 2 sessions back/back 1 month: 8 sessions Q2 week –2 sessions back/back 2 month: 8 sessions Q month –2 sessions back/back 3 month: 6 sessions Pediatric ECP • Apheresis in children is technically challenging • Low weight patients ECP distinct adult ECP o Significant fluid shift o Vascular Access o Hematologic and metabolic disturbances require close monitoring o Sedation of infants and toddlers Extracorporeal Photopheresis Patient Preparation for ECP and Follow-Ups: • Each session of ECP is an invasive procedure • Patient variables to be assessed for the initiation of therapy: – hemoglobin level (>10 g/dl) – platelets count (>20 × 109/L) – weight (>20 kg) Extracorporeal Photopheresis Post Session: • Patient should be prescribed high SPF sun cream (15 or above) • UVA sunglasses (for 48 h post each session) Extracorporeal