Extracorporeal Photopheresis Therapy Research Articles

A Novel, Closed-Line Mini Extracorporeal Photopheresis (ECP) Technique Using the Therakos TM CellEx TM Photopheresis System, Developed for Patients with Contraindications Against Conventional ECP Therapy

Introduction: Conventional ECP has proven efficacy for treating several diseases, most significantly steroid-refractory chronic GVHD. Unfortunately, body weight and sufficient venous access limit the availability of this treatment modality. Children, in particular, usually have limited access to ECP. A simplified mini buffy coat ECP technique that allows treating small children and patients with apheresis contraindications has been tested in selected cases during the last 20 years. However, this method relies on an open-line system that requires a longer time and a cell processing laboratory, making this approach challenging. A new -closed-line- method, using the Therakos TM CellEx TM Photopheresis System, has been developed and evaluated in our Center. This method requires no processing laboratory or other special equipment and takes only 60-120 minutes, making the procedure potentially usable in routine practice. Design and methods: A 7-year-old girl had been treated at our Pediatric Bone Marrow Transplantation Unit with grade IV chronic steroid-refractory GVHD (skin, and less severe liver involvement). As all other options were exhausted, ECP became a desirable form of treatment. However, the patient's low body weight and serious venous access problems hindered conventional ECP treatment. We developed a solution that requires 200-250 ml whole blood collection from the patient, takes less than 2 hours, does not need special cell processing equipment, and allows the ECP treatment to commence in the form of a regular autotransfusion. Consent forms were obtained from the patient's caregivers as well as from the local Ethical Committe. The patient's age at the start of treatment was seven years, and her body weight was 28 kg. A total of 17 mini-ECPs were performed weekly up until the submission of this abstract, and the number of treatments per patient was 33. The duration of mini-ECP treatment has been five months. 5 to 8 mL/kg of whole blood was drawn from the patient. Separation of the white blood cell (WBC) rich buffy coat of the patient's blood - with donor blood product supplementation as needed - was performed through an individualized use of the CellEx TM photopheresis kit and blood prime program. The buffy coat was ultraviolet A (UVA)-irradiated after adding 8-methoxypsoralen (8-MOP) within the Therakos TM CellEx TM Photopheresis System and divided into two fractions under a laminar air flow cabinet. The autologous residual blood with the first fraction of the UVA irradiated buffy coat was transfused immediately. The second buffy coat fraction was stored at 4 °C and transfused the following morning through a peripheral vein. Results : The median volume of the collected whole blood was 250 mL (203-250 mL). The median volume was 72 ml (48-88 mL) for the first fraction of the irradiated buffy coat and 71 ml for the second fraction (48- 88 mL). Apoptosis and cell death were analyzed by annexin V staining; apoptosis and lymphocyte proliferation was measured by flow cytometry. UVA irradiation of the 8-MOP infused buffy coat resulted in significant induction of WBC apoptosis at 24 hours. No clinical side effects were observed during mini ECP treatment; all microbiological control tests were negative. Partial response was observed within three months (skin), and the tapering of systemic immunosuppression (methylprednisolone and ruxolitinib) began at five months. Conclusion: Mini whole blood ECP induces apoptosis and lymphocyte proliferation inhibition, both occurring after standard ECP. The closed-line method requires no special equipment and is not demanding for the patient, providing a viable solution to the technical difficulties children with the need for ECP treatment face.

A Retrospective Study of Extracorporeal Photopheresis (ECP) in Treatment of Cutaneous T-Cell Lymphoma (CTCL) Evaluating Global, Skin and Blood Responses

Introduction: Cutaneous T-cell lymphoma (CTCL) is a rare form of T-cell lymphoma involving the skin in early stage, and blood, lymph nodes, and viscera in more advanced stages. Mycosis fungoides (MF) and Sezary syndrome (SS) are the most common subtypes of CTCL. Patients (pts) with advanced stage (AS)-MF and SS can have severe symptoms including erythroderma, pruritus, desquamation, and have a poor quality of life. Extracorporeal Photopheresis (ECP) was approved by FDA for CTCL in 1988. It is the recommended frontline therapy for SS and is also often used in AS-MF. ECP works by immunomodulatory mechanisms and has minimum side effects. However updated data is lacking on the efficacy of contemporary ECP. Most of the studies were published years ago and did not stage pts and evaluate responses using the current criteria. Blood response was not evaluated in most studies. Besides, ECP techniques including the administration of methoxsalen have changed. Seeking to understand the efficacy of ECP in current practice, we conducted a retrospective study including CTCL pts treated with ECP at Moffitt Cancer Center (MCC), FL, USA in the past 13 years. Methods: Pts with MF or SS who started ECP at MCC after Jan. 2010 were included. In our practice, pts are typically started on ECP alone. A systemic therapy is added in ~ 3 months when a pt does not respond. Response in blood and skin were evaluated every 3 months. Results: A total of 39 pts were included. 23 (59%) were male; 31 (82%) were Caucasian, 4 (11%) were African-American. When starting ECP, 33 (89%) had stage III/IV disease; 30 (77%) had erythroderma; 10.3%, 33.3% and 56.4% of pts had B0, B1 and B2 disease, respectively (Table 1). 18 (46.2%) pts achieved a best global response of complete response (CR), and 12 (30.8%) achieved partial response (PR). The median time to first global response was 6.5 months (range 3.2-19.8 months). At 3 months 28 pts were on ECP alone and 11 were on concurrent systemic therapy including: Interferon (4), retinoid acid (3), romidepsin (3), and pralatrexate (1). At 6 months 20 pts were on ECP alone and 19 were on concurrent systemic therapy including interferon (7), retinoid acid (4), Romidepsin (4), and 1 patient for each of mogamulizumab, vorinostat, methotrexate and interferon + retinoid acid. When evaluated at 3 months, the overall response rate (ORR) in skin was 8/39 (20.5%) in the entire cohort, and 5/28 (17.9%) in pts not on concurrent systemic treatment. When evaluate at 6 months the skin response rates were 16 (41.0%) and 9 (45.0%) in pts with and without concurrent systemic treatment, respectively. The ORR in blood at 3 months was 19/39 (48.7%) in the entire cohort and 13/28 (46.4%) in pts on ECP alone; at 6 months, the ORRs in blood were 25/39 (64.1%) and 13/20 (65%), respectively. With a median followup of 43 months, the median PFS was not reached (NR). The 5-year PFS rate was 58%. At the last followup, 7 pts who were on ECP alone were in CR, and 3 in PR. The response rates at 3 months, 6 months and the best response rates were not associated with baseline characteristics including blood stage (B0 vs B1 vs B2), global stage (I/II vs III/IV), and concurrent systemic therapy (p>0.1 for all, table 1, part of the data was not shown). Discussion: Our results showed the contemporary ECP therapy had excellent efficacy in SS and AS-MF (ORR 77%). Many pts achieved durable remission (5-year PFS 58%). However, it took a median of 6.5 months to achieve an objective response. Pts with AS-MF and SS have significant symptoms and poor quality of life. Research is needed to identify treatment combinations with ECP to induce a quicker response. One limitation of our study is, some pts received systemic therapy concurrently with ECP, thus making it difficult to isolate the treatment effect of ECP. As a sensitivity analysis, we evaluated responses of pts on ECP alone in the first 6 months, and in this way decreased the confounding effect. Our study is also limited by the retrospective nature and the limited sample size. Future prospective studies in larger scale are needed to confirm our results.

What Does the Future Hold for Biomarkers of Response to Extracorporeal Photopheresis for Mycosis Fungoides and Sézary Syndrome?

Extracorporeal photopheresis (ECP) is an FDA-approved immunotherapy for cutaneous T-cell lymphoma, which can provide a complete response in some patients. However, it is still being determined who will respond well, and predictive biomarkers are urgently needed to target patients for timely treatment and to monitor their response over time. The aim of this review is to analyze the current state of the diagnostic, prognostic, and disease state-monitoring biomarkers of ECP, and outline the future direction of the ECP biomarker discovery. Specifically, we focus on biomarkers of response to ECP in mycosis fungoides and Sézary syndrome. The review summarizes the current knowledge of ECP biomarkers, including their limitations and potential applications, and identifies key challenges in ECP biomarker discovery. In addition, we discuss emerging technologies that could revolutionize ECP biomarker discovery and accelerate the translation of biomarker research into clinical practice. This review will interest researchers and clinicians seeking to optimize ECP therapy for cutaneous T-cell lymphoma.

Extracorporeal photopheresis and the cellular mechanisms: Effects of 8-methoxypsoralen and UVA treatment on red blood cells, platelets and reactive oxygen species.

Extracorporeal photopheresis (ECP) is a widespread cellular therapy for graft-versus-host disease, autoimmune diseases and Sézary disease. One of the main effects of ECP is the apoptosis of leukocytes, but the therapeutic mechanisms are not completely known. The aim of this study was to investigate the effects on red blood cells, platelets and the induction of reactive oxygen species. We used human cells from healthy blood donors to simulate in vitro the composition in an apheresis bag. Cells were treated with 8-methoxypsoralen (8-MOP) and UVA. Red blood cell stability, platelet activity and induction of reactive oxygen species were analysed. After 8-MOP and UVA treatment, the red blood cells showed high cell integrity with low levels of eryptosis and no increase of free haemoglobin or red blood cell distribution width (RDW). Red blood cell immune-associated antigens CD59 and CD147 were hardly affected by the treatment. Platelet glycoproteins CD41, CD62P and CD63 indicated strong platelet activation after 8-MOP and UVA treatment. Reactive oxygen species were slightly but not significantly induced by the treatment. The effect of the ECP therapy is probably not exclusively mediated by leukocytes. Platelet activation is another striking effect caused by the treatment of the apheresis product with 8-MOP/UVA. However, since we could hardly identify any evidence for eryptosis or haemolysis, it is unlikely that red blood cell eryptosis is part of the therapeutic mechanism. Further research on this topic seems to be promising.

Effects of Extracorporeal Photopheresis on Quality of Life and the Course of Diseases in Patients With Mycosis Fungoides and Graft-Versus-Host Disease: A Single-Center Analysis.

The aim of the study was to systematically analyze the influence of extracorporeal photopheresis (ECP) on the quality of life (LQ) and the course of the disease in patients with Mycosis Fungoides (MF), as well as with Graft-versus-Host Disease (GvHD). LQ was monitored retrospectively by using the dermatology life quality index (DLQI) and Skindex-29 test before ECP onset and after the last ECP. Disease parameters were assessed by objective criteria i.e. number of associated medical drugs taken, intervals between therapeutic cycles, gradual change of the disease, and eventual side-effects and complications of ECP therapy. Fifty-one patients were treated with ECP during 2008-19; 19 out of 51 died, and follow-up was not completed in 13 patients. Finally, treatment protocols of 671 ECP procedures were evaluated in 19 patients (10 MF; 9 GvHD).MF and GvHD subpopulations did not differ in the individual scores of LQ questions, either before the outsetor after the last ECP. DLQI and Skindex-29 scores were ameliorated by the ECP therapy (p= 0.001 and p< 0.001, respectively) due to improvement of individual scores of feelings, daily/social activities (p< 0.05), and functionality (p≤ 0.05). The median interval between ECP cycles was extended from two to eight weeks (p= 0.001). Needs of GvHD patients for drugs being received for the underlying disease were reduced (p= 0.035). Two of the 10 MF patients worsened from stage IIA to IIIA. Severe or minor side effects leading to a therapy interruption were not recorded. Patients with GvHD experienced a notable decrease in the administration of drugs for their underlying condition, and there were no instances of severe side effects that resulted in the discontinuation of treatment. ECP is safe and effective for the treatment of MF and GvHD.

Extracorporeal Photopheresis Suppresses Transplant Fibrosis by Inducing Decorin Expression in Alveolar Macrophages.

Extracorporeal Photopheresis Suppresses Transplant Fibrosis by Inducing Decorin Expression in Alveolar Macrophages.

Extracorporeal photopheresis for the treatment of chronic graft versus host disease

ABSTRACT Objectives Chronic graft versus host disease (chronic GVHD) still remains the leading cause of late morbidity and mortality for allogeneic hematopoietic stem cell transplant (allo-HSCT) recipients. In this retrospective study, 53 consecutive allo-HSCT patients with chronic GVHD refractory to corticosteroids were treated with extracorporeal photopheresis (ECP). Methods This study was performed as a retrospective single-center study. Medical records of a total of 59 patients treated with ECP for chronic GVHD were reviewed. Results Best organ responses to ECP were observed in skin, mouth mucosa, eyes and liver. Overall response rate (ORR) to ECP was 81.2% (CR 17% and PR 64.2%). Overall survival (OS) was 84.9% and 36.7%, at 1 and 3 years, respectively. Female sex appears to have an advantage on ORR. Patients achieving ORR were able to maintain their responses with a prolonged continuation of treatments for +6 and +12 months indicating the benefits of longer ECP treatment. Discussion We found that patients with chronic GVHD who were treated with ECP for 12 months or longer had a higher response rate. Our findings in line with the data reported previously suggest that patients responding to ECP should continue longer therapy schedules to achieve a better and sustained response. In our cohort, long-term ECP therapy was safe and well-tolerated with no significant adverse effects. Best responses were observed in the patients with skin, eye, liver and oral involvement. The ECP procedure offers the advantage relative to the problems with typical immunosuppressive agents. The female sex appeared to have an advantage based on the cumulative probability of the OR after ECP for chronic GVHD.

Comparison of procedure times and collection efficiencies using integrated and multistep nonintegrated procedures for extracorporeal photopheresis.

BackgroundExtracorporeal photopheresis (ECP) is a blood‐based therapeutic procedure increasingly used for modulation of immune dysregulation in various underlying disease settings. The aim of this study was to compare the procedure times and blood collection efficiencies between the two approaches currently utilized in European centers: the integrated versus the multistep nonintegrated procedures.MethodsA retrospective data analysis was conducted, comparing treatment data from patients who received ECP therapy at the Central Institute for Blood Transfusion & Department of Immunology (ZIB) of the Tirol Kliniken GmbH, where the integrated and multistep nonintegrated procedures are routinely used in an approximated setup.ResultsDuring the observation period, a total of 15 patients who were treated with alternating systems on 2 consecutive days were identified. This allowed treatment pair comparisons with minimal interpatient variabilities, similar to a cross‐over design even though analyzed retrospectively. Total average procedure times with the integrated system were 99.3 vs 122.0 minutes with the multistep nonintegrated procedures, respectively. Significant differences were observed for all steps of the ECP procedure: (a) time for buffy coat collection, 66.5 vs 74.7; (b) handling/transfer, 2.8 vs 18.7; (c) irradiation, 20.3 vs 11.7; and (d) reinfusion/handling time, 9.6 vs 16.3 minutes. The calculated collection throughput was 7.79 mL/min for the integrated and 7.84 mL/min for the multistep nonintegrated procedures, and with a white blood cell (WBC) collection efficiency of 34.2% and 21.0%, respectively.ConclusionThe data presented in this study show a significant shorter overall procedure time and higher WBC collection efficiency for the integrated ECP system.

Extracorporeal photopheresis in chronic graft-versus-host disease: clinical description and economic study

IntroductionAlthough extracorporeal photopheresis (ECP) is a promising second-line therapy in the treatment of chronic graft-versus-host disease (cGVHD), its use is limited by its high cost. This study aims to describe the clinical evolution of patients who underwent ECP therapy for cGVHD and to perform an economic analysis of the therapy MethodsThis was a case series between 2016 and 2020 describing the clinical response to ECP and a micro-cost analysis of the therapy using time-driven activity-based costing. ResultsSix patients underwent ECP for corticosteroid-dependent cGVHD The cost per ECP session is 14,960.90 Brazilian reais (BRL), which primarily consists of the ECP kit with an activator (82.78%), followed by the hospital's physical structure (14.66%), human resources (2.48%) and exams/inputs (0.08%). The number of sessions performed ranged from 2 to 42. The total cost of the therapy per patient ranged from BRL 30,000 to 500,000. ConclusionThe response of the patient with cGVHD to treatment with ECP was variable. These micro-costing results can be used to develop remuneration and cost control strategies in hematopoietic stem cell transplantation programs, as well as in further economic studies.

Th22 and Tfh Cell Elevation Is Associated with Clinical Response of Photopheresis Therapy in Patients with Steroid-Refractory/ Resistant Graft-Versus-Host Disease (GvHD)

In patients with steroid-refractory/resistant graft-versus-host disease (GvHD), extracorporeal photopheresis (ECP) has been identified as a promising therapeutic strategy due to its safety profile and convincing clinical response rates.While previous studies have reported on the role of Th1, Th2 and Treg cells in ECP therapy, further comprehensive analysis of T helper cells is necessary to provide better understanding of the underlying mechanisms. In this study, we thus investigated the influence of long-term ECP treatment on both Th cells as well as on immune checkpoint molecules and apoptosis. Overall, we investigated 27 patients with GvHD treated by ECP therapy, containing 13 patients with acute GvHD and 14 patients with chronic GvHD. 10/13 (76.9%) of aGvHD and 9/14 (64.3%) of cGvHD patients clinically responded to ECP therapy. Three (23.1%) patients reached CR and seven (53.8%) patients achieved PR under ECP treatment in patients with aGvHD, while in patients with cGvHD CR was achieved in one (7.1%) and PR in eight (57.1%) patients. Stabilization of disease was observed in five (35.7%) patients.On an immunological level, aGvHD, cGvHD and healthy donors (HD) patients showed different profiles of Th populations. In GvHD patients, significantly higher levels for Th2 (aGvHD vs. HD: 36.26% vs. 13.88%, p = 0.014; cGvHD vs. HD: 30.71% vs. 13.88%, p = 0.026), Th17 (aGvHD vs. HD: 19.21% vs. 7.49%, p = 0.038), Th22 (aGvHD vs. HD: 1.22% vs. 0.11%，p = 0.011; cGvHD vs. HD: 0.64% vs. 0.11%, p = 0.012) and GM-CSF + Th cells (aGvHD vs. HD: 1.15% vs. 0.14%, p = 0.022; cGvHD vs. HD: 0.84% vs. 0.14%，p = 0.012) and clearly lower levels for T follicular helper (Tfh) cells including Th1- (aGvHD vs. HD: 0.37% vs. 2.04%, p = 0.002; cGvHD vs. HD: 1.28% vs. 2.04%, p = 0.03) and Th2-like cells (aGvHD vs. HD: 1.17% vs. 4.19%, p = 0.033) were observed in comparison to HDs. This suggests Th cells account for a crucial role in GvHD pathogenesis. ECP therapy was able to accelerate recovery of Tfh cells, including Th1- (Time point 1 vs. Time point 2 in aGvHD: 0.37% vs. 0.97%, p = 0.028), Th2- (T1 vs. T2 in aGvHD: 1.17% vs. 1.35%, p = 0.049; T1 vs. T2 in cGvHD: 2.08% vs. 3.15%, p = 0.048) and Th17-like Tfh cells (T1 vs. T2 in aGvHD: 1.82% vs. 2.70%, p = 0.034), facilitating immune reconstitution after allo-HSCT and thereby alleviating GvHD. Clinical response in aGvHD patients was strongly associated with elevation of Th22 cells by ECP therapy showing 51% upregulation (T1 vs. T2: 0.86% vs. 1.3%，p=0.007). In addition, we also found that the expression of the Fas receptor on effector T cells could be further upregulated with ECP treatment (T1 vs. T2 in cGvHD: 49.65% vs. 56.46%, p = 0.011), which increases the susceptibility of these effectors T cells to Fas-mediated apoptosis. This could lead to the elimination of these overactivated effector T cells and the perseverance of immunological tolerance by triggering activation-induced cell death. In addition, a reduction of Tim-3-expressing effector T cells, which are associated with the severity of GvHD, with ECP therapy (T1 vs. T2 for aGvHD: 18.09% vs. 15.10%, p = 0.044) was discovered.In conclusion, ECP therapy exerts immunomodulatory effects by promoting balanced immune reconstitution and inducing immune tolerance, making it an attractive and promising treatment option for patients with GvHD. DisclosuresSchubert: Gilead: Consultancy. Hegenbart: Alnylam: Honoraria; Akcea: Honoraria; Janssen: Consultancy, Research Funding; Prothena: Research Funding; Pfizer: Consultancy, Honoraria. Schönland: Prothena: Honoraria, Other: Travel grants; Takeda: Honoraria, Other: Travel grants; Pfizer: Honoraria; Janssen: Honoraria, Other: Travel grants, Research Funding; Sanofi: Research Funding. Müller-Tidow: Pfizer: Research Funding; Bioline: Research Funding; Janssen: Consultancy, Research Funding. Dreger: Riemser: Consultancy, Research Funding, Speakers Bureau; Bluebird Bio: Consultancy; Roche: Consultancy, Speakers Bureau; AbbVie: Consultancy, Speakers Bureau; BMS: Consultancy; AstraZeneca: Consultancy, Speakers Bureau; Novartis: Consultancy, Speakers Bureau; Janssen: Consultancy; Gilead Sciences: Consultancy, Speakers Bureau. Schmitt: MSD: Membership on an entity's Board of Directors or advisory committees; Hexal: Other: Travel grants, Research Funding; Kite Gilead: Other: Travel grants; TolerogenixX: Current holder of individual stocks in a privately-held company; Bluebird Bio: Other: Travel grants; Novartis: Other: Travel grants, Research Funding; Apogenix: Research Funding. Schmitt: Therakos/Mallinckrodt: Research Funding; TolerogenixX Ltd: Current Employment; Jazz Pharmaceuticals: Other: Travel grant; Hexal: Other: Travel grant.

Response to extracorporeal photopheresis therapy of patients with steroid-refractory/-resistant GvHD is associated with up-regulation of Th22 cells and Tfh cells

Extracorporeal photopheresis (ECP), a personalized cellular immunotherapy, constitutes a promising treatment for steroid-refractory/-resistant graft-versus-host disease (SR-GvHD), with encouraging clinical response rates. To further investigate its mechanism of action, ECP's effects on T helper (Th) cells as well as on expression of immune checkpoint (PD-1 and Tim-3) and apoptotic (Fas receptor [FasR]) molecules were investigated in 27 patients with SR-GvHD. Our data show that GvHD patients had significantly higher levels of Th2, Th17, Th22 and granulocyte-macrophage colony-stimulating factor (GM-CSF)-positive Th (ThG) cells and clearly lower levels of T follicular helper (Tfh) cells, including Th1- and Th2-like cells, compared with healthy donors. ECP therapy for GvHD was effective through the modulation of different Th subsets: increases of Th22 (1.52-fold) and Tfh cells (1.48-fold) in acute GvHD (aGvHD) and increases of Th2-like Tfh cells (1.74-fold) in chronic GvHD (cGvHD) patients were associated with clinical response. Expression of FasR was further upregulated in CD4+CD8+ T cells. Additionally, Tim-3–expressing effector T cells associated with the severity of GvHD were reduced. Taken together, these data show that ECP therapy exerts immunomodulatory effects by promoting a balanced immune reconstitution and inducing immune tolerance. Therefore it represents an attractive option for the treatment of GvHD.

Prec-P-01 - Preclinical investigation of new targeted combination therapies in cutaneous T-cell lymphoma

Prec-P-01 - Preclinical investigation of new targeted combination therapies in cutaneous T-cell lymphoma

A Randomized Controlled Study of Extracorporeal Photopheresis (ECP) Therapy with UVADEX® (Methoxsalen) for National Institutes of Health (NIH)-Graded Moderate to Severe Chronic Graft-Vs-Host Disease (cGVHD)

A Randomized Controlled Study of Extracorporeal Photopheresis (ECP) Therapy with UVADEX® (Methoxsalen) for National Institutes of Health (NIH)-Graded Moderate to Severe Chronic Graft-Vs-Host Disease (cGVHD)

Extra-Corporeal Photopheresis Plus Low-Dose Interleukin-2 for Steroid-Refractory Chronic Graft-Vs.-Host Disease: Efficacy, Safety and Immune Correlates

CD4+CD25+FOXP3+ regulatory T cells (Treg) are dominant suppressors of innate and adaptive immune effector cells that enhance tolerance. Treg augmentation can control immune activation underlying chronic graft-versus-host disease (cGVHD). In prior studies, daily subcutaneous (SC) low-dose interleukin-2 (IL-2) therapy for 8-12 weeks induced preferential Treg expansion in-vivo, with objective clinical responses in over half of evaluable participants (NEJM 2011, Blood 2016). Alternative immunomodulatory approaches like extra-corporeal photopheresis (ECP) also have efficacy in cGVHD and may function via Treg augmentation. Combining ECP plus IL-2 could offer therapeutic synergy.We report on a prospective single arm phase 2 trial of twice-weekly ECP (weeks 1-16) plus sequential low-dose IL-2 (1x106 IU/m2/d SC, weeks 9-16) for treatment of steroid-refractory cGVHD. The study enrolled 25 participants (48% male, 88% HLA-matched, 100% PBSC grafts, 52% prior aGVHD). Median participant age was 62 years (range, 34-76). Median time from HSCT and from cGVHD onset to start of treatment was 919 days (range, 177-2842) and 524 days (range, 58-2697) respectively. Participants had a median of 3 cGVHD organ sites (range, 2-5). The median follow-up time in survivors is 16 months (range, 2.1-26).ECP plus IL-2 was well tolerated: 1 participant withdrew due to IL-2 adverse effects (AE) (myalgia, fatigue), and 3 were additionally unevaluable (1 cardiac arrest; 1 parainfluenza infection, 1 still undergoing treatment). None required IL-2 dose reduction. There were four grade 3 AEs during the 16-week study (1 participant had dehydration/hypotension/syncope, possibly IL-2-related;1 had ECP-related anemia). None experienced relapse. At week 16, cGVHD objective partial responses (PR) were documented in 14 of 21 evaluable participants (67%). None had cGVHD progression. Response sites included skin (n=9/18), joint/fascia/muscle (n=7/16), liver (n=1/1), lung (n=2/9), and GI tract (n=3/5). 18 participants with clinical benefit (PR, and stable disease with minor response) proceeded to extended ECP plus IL-2 therapy.Immunologically, 8 weeks of ECP alone did not induce significant changes in buffy coat WBC or absolute lymphocyte count (ALC). Peripheral blood CD3 T cell counts/µL fell, with a median CD8 and CD4 conventional T cell (Tcon) decrement of -109 (Q1, Q3: -220, -13; p<0.001) and -68 (Q1, Q3: -244, -19; p=0.023), respectively, at week 8 (Figure 1A). There was an early fall in Treg cell counts/µL, with a median decrement of -4 (Q1, Q3: -9, 0; p=0.033) at week 4, without change in NK or B cell counts or Treg:Tcon ratio. The addition of low-dose IL-2 thereafter induced a >5-fold increase in median Treg count/µL (p<0.001), from a baseline of 9 (Q1, Q3: 5, 17) at week 8 to a peak of 72 (Q1, Q3: 22, 186) at week 10, plateauing at 50 (Q1, Q3: 33, 71) at week 16 (Figure 1A). No significant change in CD4 Tcon or B cell count was noted. NK cell count increased 1.7-fold (p=0.009). The median Treg:Tcon ratio increased 4-fold (p<0.001): from a baseline of 0.06 (Q1, Q3: 0.03, 0.08) at week 8 to a peak of 0.26 (Q1, Q3: 0.12, 0.42) at week 12, and remained elevated at 0.17 (Q1, Q3: 0.14, 0.34) at week 16 (Figure 1B). Treg count and Treg:Tcon ratio remained elevated in responders during extended ECP plus IL-2 therapy.Immunologically, clinical responders had a higher median Treg count/µL vs. non-responders after 1 and 6 weeks of IL-2 therapy (21 vs. 11, p<0.001; 73 vs. 29, p=0.016 respectively). Treg:Tcon ratio at week 2 and 6 after IL-2 therapy was also higher in responders (0.29 vs. 0.15, p=0.038; 0.28 vs. 0.13, p=0.016 respectively). Applying our previous cutoffs (Blood 2016), Treg:Tcon ratio ≥0.2 after 1 week of IL-2 was also predictive of clinical response (p=0.05).In summary, in steroid-refractory cGVHD, ECP was associated with a fall in peripheral CD8, CD4 Tcon, and Treg counts. The addition of low-dose IL-2 thereafter induced profound Treg and NK cell augmentation. Clinical responses (PR) to combination ECP plus IL-2 therapy were documented in 67% of the evaluable participants. Those with early rise in Treg count and Treg:Tcon ratio after the addition of IL-2 were likelier to benefit. However, the overall clinical efficacy of ECP plus IL-2 did not appear markedly higher than low-dose IL-2 alone. [Display omitted] DisclosuresKoreth:Prometheus Labs: Research Funding; Kadmon Corp: Membership on an entity's Board of Directors or advisory committees; Millennium Pharmaceuticals: Research Funding; Takeda Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Amgen Inc.: Consultancy. Armand:Bristol-Myers Squibb: Consultancy, Research Funding; Merck & Co., Inc.: Consultancy, Research Funding; Sequenta/Adaptive: Research Funding; Sigma Tau: Research Funding; Tensha: Research Funding; Affimed: Research Funding; Roche: Research Funding; Pfizer: Consultancy, Research Funding; Genmab: Consultancy; Infinity: Consultancy; Otsuka: Research Funding. Antin:Gentium SpA/Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees.

The Efficacy of Extra-Corporal Photopheresis for Bronchiolitis Obliterans Syndrome after Hematopoietic Cell Transplantation: A Retrospective, Matched, Case-Control Study

Background:Bronchiolitis obliterans syndrome (BOS) is associated with major morbidity and mortality in hematopoietic cell transplant (HCT) recipients. Due to the suboptimal response to conventional therapies, extracorporeal photopheresis (ECP) has been explored as a possible therapeutic option. However, to date, only a few case series, without control groups, examining the effectiveness of ECP for BOS after HCT (Del Fante et al, 2016; Lucid et al, 2011 ), have been published. We carried out this first matched case-control study to assess the impact of ECP therapy for BOS after HCT.Methods:After IRB approval, our institutional database of 304 consecutive AML patients that underwent allogeneic HCT between 2005 and 2015 was reviewed. A retrospective diagnosis of BOS was made in patients who developed a new obstructive pulmonary function test (PFT) with progressive FEV1 decline of ≥ 10% over 3 months without complete resolution on subsequent testing. Patients with BOS diagnosis were classified into case or control groups according to treatment with or without ECP, respectively. ECP was started on a weekly basis with two apheresis sessions a week followed by gradual taper at the discretion of treating physicians. Methoxsalen was administered at a dose of 0.35 mcg per ml of pheresed buffy coat. Propensity score analysis was performed to match cases with controls on a 1:1 ratio. The rate of change in FEV1 (% change from baseline per month) was calculated using linear regression models. Wilcoxon signed-rank test was used to compare paired data at different time intervals.Results:ECP-treated cases consisted of 10 patients (median age 52 years, male 50%), who developed BOS a median of 9 (3-44) months after HCT. ECP was started a median of 9 (range 1-15) months after BOS diagnosis and continued for a median of 50 (range 26-80) sessions. Controls consisted of 24 patients (median age 51 years, male 50%), who developed BOS a median of 10 (range 3-25) months after HCT. There was no significant difference in baseline transplant characteristics between the two groups. Pre-HCT FEV1 was similar between cases and controls (median 92% vs. 99% predicated, p = 0.21). ECP-treated cases, however, had a significantly lower FEV1 at the time of BOS diagnosis (median 48% vs. 68% predicted, p = 0.006) and at six months after non-ECP therapy (median 48% vs. 72% predicted, p = 0.008), consisting of fluticasone/azithromycin/ montelukast (FAM) and/or increased immunosuppression. Propensity score-matched analysis was performed using the covariates of FEV1 nadir and time to FEV1 nadir before ECP initiation or during a matched period for the cases and controls, respectively. Matched controls (n = 10) had similar FEV1 nadir (median 45% vs. 48% predicted, p = 0.76) and time to FEV1 nadir (median 7.5 vs. 9 months, p = 0.81). Within the ECP group, the rate of FEV1 change was significantly more negative before ECP than after ECP (-2.1% / month vs. -0.1% /months; p = 0.004) (Figure 1). Similarly, within the matched control group, the rate of change in FEV1 significantly decreased when periods matched with pre- and post-ECP intervals were compared (median -1.9% / month vs. -0.5% / month; p = 0.03). Across group comparison between ECP and matched controls did not reveal a significant difference in the rate of FEV1 change (p = 0.31). In spite of comparable rates of FEV1 changes between the two groups, and a higher prevalence of non-pulmonary GVHD observed at the time of BOS diagnosis in the ECP group (90% vs. 40%, p = 0.05), patients treated with ECP had a better overall survival in comparison to matched non-ECP controls (estimated median: NR vs. 41 months, p = 0.03) (Figure 2). Two (50%) of 4 deaths in the ECP group and 4 (57%) of 7 deaths in the non-ECP group were attributed to respiratory failure ± superimposed infection.Conclusion:In our retrospective, propensity score-matched analysis, we find that while ECP therapy for HCT patients with BOS did not significantly change FEV1 values in comparison to non-ECP therapies, there was a survival benefit accorded to those treated with ECP. It is plausible that ECP may confer additional benefits that are not reflected in PFTs. This would be best assessed by prospective randomized studies. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Photopheresis Abates the Anti-HLA Antibody Titer and Renal Failure Progression in Chronic Antibody-Mediated Rejection.

Chronic renal antibody-mediated rejection (ABMR) is a common cause of allograft failure, but an effective therapy is not available. Extracorporeal photopheresis (ECP) has been proven successful in chronic lung and heart rejection, and graft versus host disease. The aim of this study was to evaluate the effectiveness of ECP in chronic ABMR patients. We investigated ECP treatment in 14 patients with biopsy-proven chronic ABMR and stage 2-3 chronic renal failure. The primary aim was to e valuate the eGFR lowering after 1 year of ECP therapy. The ECP responders (R) showed eGFR reduction greater than 20% vs the basal levels. We also evaluated the effectiveness of ECP on proteinuria, anti-HLA antibodies (HLAab), interleukin 6 (IL-6) serum levels, and CD3, CD4, CD8, CD19, NK, Treg and T helper 17 (Th17) circulating cells. Three patients dropped out of the study. The R patients were eight (72.7%) out of the 11 remaining patients. Because ECP was not associated with any adverse reaction, the R patients continued such treatment for up to 3 years, showing a persisting eGFR stabilization. Twenty four hour proteinuria did not increase in the R patients over the follow-up when compared to the non-responder patients (NR). In the R patients, the HLAab levels were reduced and completely cleared in six out of eight patients when compared with the NR patients. The NR HLAab levels also increased after the discontinuation of the ECP. The ECP in the R patients showed a decrease in CD3, CD4, CD8, CD19, and NK circulating cells. The ECP treatment in the R patients also induced Tregs and Th17 cell increases, and a decrease of the IL-6 serum levels. ECP abates the HLAab titer and renal failure progression in patients with chronic renal ABMR, modulating the immune cellular and humoral responses.

Case Report: Extracorporeal Photophoresis for Treatment of Severe Cytomegalovirus Infection after Heart Transplantation in a Patient with Giant Cell Myocarditis

Introduction We present the case of a patient (38 years, male) who underwent heart transplantation (HTx) 06/2017 due to giant cell myocarditis (GCM). Post-HTX, the patient suffered from acute cellular rejection (ACR) and antibody mediated reaction (AMR) and developed a severe symptomatic CMV infection with symptomatic organ manifestation. Most likely, the underlying diagnosis of GCM and the resulting alteration of the immune system provoked enhancing donor specific antibodies and thus rejection.The aim of this case report is to demonstrate an example of successful extracorporeal photopheresis (ECP) after HTx as a treatment option for therapy resistant CMV infection and rejection. Case Report Endomyocardial biopsies (EMBs) were taken after 3 weeks and 3, 6, 12, 24, 48 and 70 months after HTx. Severe CMV infection was initially treated with i.v. ganciclovir and human CMV-immunoglobulins, and, thereafter with valganciclovir in the outpatient setting. ECP was started in 11/2019 with initially 8 cycles per month, followed by 2 × 4 cycles per months and 2 cycles monthly thereafter. Clinical follow-ups were performed every 3 months and included blood work, CMV-PCR and echocardiography. After 3 weeks post HTx, AMRII (ISHLT 2013) without hemodynamic compromise was diagnosed, and EMBs showed recurring rejections throughout the course. After 22 months, the patient developed severe CMV infection with organ manifestation (esophagitis, gastritis, parotitis, carditis), which was treated with i.v. ganciclovir and CMV-immunoglobulines. However symptomatic CMV-infection returned in outpatient care despite ongoing oral antiviral therapy. Thus, we started ECP therapy. No severe adverse effects were seen during ECP. After start of ECP, EMBs showed persisting low-grade ACR without hemodynamic compromise and no more signs of AMR. The patient fully recovered from CMV infection and presented asymptomatically at the latest follow up. Summary ECP had shown to be a safe and feasible treatment option for this patient with convincing results regarding both the course of severe CMV infection as well as ACR and AMR.

A simplified extracorporeal photopheresis procedure based on single high-dose ultraviolet A light irradiation shows similar in vitro efficacy.

Extracorporeal photopheresis (ECP) is one of the most widely used and effective cell-based therapies for the treatment of T-cell-mediated diseases. The patients' white blood cells (WBCs) are collected by apheresis and exposed to the photosensitizer 8-methoxypsoralen (8-MOP) and ultraviolet A (UVA) light before retransfusion. The UVA/8-MOP combination has been in use in ECP for more than 4 decades; however, whether ECP can be simplified by UVA light irradiation only has never been analyzed. Peripheral blood mononuclear cells were treated with classical ECP or different UVA light doses only (UVAonly ). Treatment efficacy was investigated by apoptosis induction in WBC subsets, inhibition of T-cell proliferation, and the ability of monocytes to induce allogeneic T-cell expansion and to respond to lipopolysaccharide and interferon-γ stimulation in vitro. High-dose UVAonly treatment (5 J/cm2 ) was as efficient as ECP to induce apoptosis within 48 hours. UVAonly treatment modulated the composition of the surviving cells by improving monocyte survival and promoting CD8+ T-cell apoptosis. Both ECP and UVAonly treatment inhibited anti-CD3/anti-CD28 triggered T-cell proliferation. Interestingly, whereas ECP-treated monocytes exhibited a markedly reduced capacity to respond to stimulation and to induce allogeneic T-cell proliferation, UVAonly treatment preserved monocyte functionality to some degree. High-dose UVAonly and standard ECP showed comparable efficacy in inducing apoptosis and inhibiting direct T-cell proliferation. Hence, UVAonly treatment can be a simplified alternative to ECP therapy. Furthermore, increased monocyte survival with partially preserved functionality after UVAonly treatment may provide a novel method for immunoregulation.

Outcomes Following Extracorporeal Photopheresis for Chronic Lung Allograft Dysfunction Following Lung Transplantation: A Single-Center Experience

IntroductionSurvival following lung transplantation (LTx) is limited by the development of chronic lung allograft dysfunction (CLAD), for which there are few effective therapies and no standardized management. Several small studies have demonstrated the effectiveness of extracorporeal photopheresis (ECP) as a therapeutic option for CLAD. MethodsA retrospective descriptive audit of 12 LTx recipients who received rescue ECP for CLAD over 5 years (2013-2018) at the Alfred Hospital, Melbourne, Australia, was completed. Nonresponders to ECP were defined as patients who experienced a 20% decrease in forced expiratory volume (FEV1) within 6 weeks of commencing therapy. ResultsMean time since LTx was 849 days and mean time since diagnosis of CLAD was 131 days. Fifty-eight percent of patients were male (n = 7) and 67% responded to ECP therapy (n = 8). Among responders, the mean (95% confidence interval) decline in FEV1 pre-ECP was 9.0 mL/day (5-12 mL/day), compared to 1.4 mL/day (0-4 mL/day) post-ECP (P = .01). Among nonresponders, mean (95% confidence interval) decline in FEV1 was 7.2 mL/day (4-10 mL/day) pre-ECP and 5.0 mL/day (3-7 mL/day) post ECP (P = .2). Nonresponders were more likely to be female (P = .01) and neutropenic (P = .005). Patients with prior exposure to anti-thymocyte globulin had a lowered response to ECP. ConclusionRescue ECP arrested the decline of lung function in 67% of patients with CLAD. Sex, pre-ECP neutrophil count, and exposure to anti-thymocyte globulin may help determine response to ECP. Future clinical trials are needed to confirm this effect, help predict response to therapy, and ultimately guide the placement of ECP in the treatment algorithm for CLAD.

Therapeutic implications of extracorporeal photopheresis for rheumatic diseases

Extracorporeal photopheresis (ECP) procedure is based on mononuclear cells (MNC) apheresis and their extracorporeal UVA exposure. It has been applied mainly in hematology and transplantation. Over thirty years of experience confirmed its effectiveness, outstanding safety profile and good tolerance. These observations encourage the implementation of ECP in the treatment of autoimmune connective tissue diseases. The procedure might be considered in refractory cases, when the first line treatment strategies do not control disease activity or immunosuppressants are contraindicated and in the group of patients with high risk of infections. Current literature about using ECP in rheumatology is scarce and most data come from case reports and small observational studies. Systemic sclerosis is the most studied rheumatic disease in the field of ECP use. The disease appeared on the list of clinical applications of ECP therapy according to American Society for Apheresis. However, no European or American guidelines, or recommendations for the treatment in rheumatology suggest ECP as the treatment option. There are no standards in performing ECP in rheumatic diseases concerning indications, length of therapy, concomitant immunosuppressive treatment, follow up or patients characteristic. In this review, we have searched literature concerning ECP use in rheumatic diseases.