Extracorporeal Photopheresis Application Update

Dr. Hind AlHumaidan, MD,FRCPA Consultant Hematopathologiest Director, Bank, Donor, Transfusion Services, & 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:

• (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 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 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 • 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) – 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 Photopheresis

Contraindications: • Pts known sensitivity to psoralen compounds are contraindicated for such therapies • Pts having aphakia (risk of retinal damage) • Pregnancy • Uncontrolled infection Extracorporeal Photopheresis

Side Effects:

There are very few adverse reactions reported with each ECP • Reaction related to volume shift. • Citrate toxicity. • Bleeding cannula. Extracorporeal Photopheresis

Cont. Side Effects:

• Psoralen related side effects: ➢ Increase urinary output ➢ Metallic taste ➢ Mild fever ➢ Tiredness ➢ Hematuria ➢ Sparkly bits in the eyes Need of ECP

• ECP facilitates steroid tapering

• No established biomarkers predict therapeutic efficacy

• Cost effectiveness ECP needs to be analyzed

• ECP cost –effectiveness data are needed in Saudi Arabia Rational

Pros

• Fewer side effects compared to immunosuppressive agents.

• Dose tapering or discontinuation of pharmacotherapy

• May be effective in medication refractory patients

Rational

Cons

• Specialized equipment and apheresis staff requirements

• Vascular access complications

• Adverse events related to procedure Future Plan

• Continue to update protocol with more evidence

• Careful selection of patients

Thank You