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ECP versus ruxolitinib in steroid-refractory acute GVHD - a retrospective study by the EBMT transplant complications working party
Penack, O., Peczynski, C., Boreland, W., Lemaitre, J., Afanasyeva, K., Kornblit, B., Jurado, M., Martinez, C., Natale, A., Pérez-Simón, J. A., et al
Frontiers in immunology. 2023;14:1283034
Abstract
INTRODUCTION Extracorporal Photophoresis (ECP) is in clinical use for steroid-refractory and steroid-dependent acute GVHD (SR-aGVHD). Based on recent Phase-III study results, ruxolitinib has become the new standard of care for SR-aGVHD. Our aim was to collect comparative data between ruxolitinib and ECP in SR-aGVHD in order to improve the evidence base for clinical decision making. METHODS We asked EBMT centers if they were willing to participate in this study by completing a data form (Med-C) with detailed information on GVHD grading, -therapy, -dosing, -response and complications for each included patient. RESULTS 31 centers responded positively (14%) and we included all patients receiving alloSCT between 1/2017-7/2019 and treated with ECP or ruxolitinib for SR-aGVHD grades II-IV from these centers. We identified 53 and 40 patients with grades II-IV SR-aGVHD who were treated with ECP and ruxolitinib, respectively. We performed multivariate analyses adjusted on grading and type of SR-aGVHD (steroid dependent vs. refractory). At day+90 after initiation of treatment for SR-aGVHD we found no statistically significant differences in overall response. The odds ratio in the ruxolitinib group to achieve overall response vs. the ECP group was 1.13 (95% CI = [0.41; 3.22], p = 0.81). In line, we detected no statistically significant differences in overall survival, progression-free survival, non-relapse mortality and relapse incidence. DISCUSSION The clinical significance is limited by the retrospective study design and the current data can't replace prospective studies on ECP in SR-aGVHD. However, the present results contribute to the accumulating evidence on ECP as an effective treatment option in SR-aGVHD.
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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
Vogiatzis, R., Krüger, W., Jünger, M., Arnold, A.
Cureus. 2023;15(5):e38929
Abstract
INTRODUCTION 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). METHODS 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. RESULTS 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 outset or 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. CONCLUSION 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.
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Real-world clinical characterization, healthcare resource utilization and productivity loss in chronic graft versus host patients exposed to extracorporeal photopheresis in Sweden
Schain, F., Boissin, C., Laczik, T., Fedeli, S., Remberger, M., Blennow, O., Dykes, J., Eich, T., Jones, C., Mattsson, J., et al
Transfusion and apheresis science : official journal of the World Apheresis Association : official journal of the European Society for Haemapheresis. 2023;:103705
Abstract
BACKGROUND Extracorporeal photopheresis (ECP) is frequently used to treat moderate-severe chronic graft versus host disease (cGVHD), however limited data exists describing ECP treatment effects on healthcare and societal costs. We aimed to characterize clinical and health economic outcomes and productivity loss in cGVHD patients exposed to ECP. METHODS We identified 2708 patients aged ≥ 18 years with a record of allogeneic hematopoietic stem cell transplantation (HSCT) in the Swedish Patient Register between 2006 and 2020. Patients exposed to ECP from 3-months post HSCT (index) were included (n= 183). Data was linked to the Prescribed Drug Register, the Cause of Death Register, and the Longitudinal Integrated Database for Health Insurance and Labor Market Studies (LISA). RESULTS The median patient age at index was 51 years (IQR1-3; 38-61). In the 3-month period before ECP initiation compared to 9-12 months post-ECP, the cumulative three-month dose per patient decreased prednisolone/prednisone (1,381 mg vs. 658 mg, p < 0.001) and cyclosporin (12,242 mg vs. 3,501 mg, p < 0.001). Infection incidence also decreased over the same period (79.2% vs 59.1%, p < 0.001). Time spent in healthcare decreased from 68.9% to 22.1% from the first and fifth follow-up year respectively, and corresponding annual healthcare cost reduced from €27,719 to €1,981. Among patients < 66 years of age, sickness-related workplace absence decreased from 73.2% to 31.9% between the first and fifth follow-up year, with median annual productivity loss decreasing from €20,358 to €7,211 per patient. CONCLUSIONS ECP was associated with reduced use of corticosteroids, immunosuppressive agents, and fewer infections. Furthermore, cost and healthcare utilization decreased over time.
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Extracorporeal photopheresis as graft-versus-host disease prophylaxis: a randomized controlled trial: Prophylactic extracorporeal photopheresis to prevent graft-versus-host disease
Ali, M. M., Gedde-Dahl, T., Osnes, L. T., Perrier, F., Veierød, M. B., Tjønnfjord, G. E., Iversen, P. O.
Transplantation and cellular therapy. 2023
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Editor's Choice
Abstract
BACKGROUND Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is the only curative option for many patients diagnosed with hematological malignancies. A major obstacle is graft-versus-host disease (GvHD) causing significant morbidity and mortality. Extracorporeal photopheresis (ECP) is an increasingly applied GvHD treatment, partly due to its favourable safety profile. In contrast, the use of ECP in preventing GvHD is sparse, and randomized controlled trials (RCTs) are lacking. OBJECTIVE We therefore conducted a RCT to assess if ECP applied post-transplant, could prevent the development of GvHD within the first year of transplantation. STUDY DESIGN We enrolled 157 patients (18-74 years) with a hematological malignancy receiving first allo-HSCT: 76 randomized to the intervention group and 81 to the control group. ECP was initiated directly upon engraftment and was planned twice weekly for two weeks, then once weekly for four weeks. GvHD, relapse, and death were analyzed with Cox regression analysis. RESULTS During the first year, 45 patients in the intervention and 52 control patients developed GvHD (HR=0.82, 95% CI 0.55-1.22, P=0.32). There were no differences in acute or chronic GvHD or its organ distribution in this intention-to-treat RCT. A per-protocol analysis revealed a significant difference in GvHD between the intervention (per-protocol; n=39 of 76) and the control group (n=77), 46% vs 68%, respectively, (HR 0.47, 95% CI 0.27-0.80, P=0.006). Relapse occurred in 15 patients in the intervention group and in 11 patients among the controls (HR=1.38, 95% CI 0.64-3.01, P=0.42). GvHD-free relapse-free (GRFS) survival, event-free survival, overall survival and non-relapse mortality did not differ significantly between the two study groups. No significant difference in immune reconstitution between the two study groups was revealed. CONCLUSION This first intention-to-treat RCT, investigating ECP as GvHD prophylaxis in allo-HSCT for hematological malignancy does not support the use of ECP as adjunct to standard drug-based GvHD-prophylaxis. This trial was registered at www. CLINICALTRIALS gov as #NCT03204721.
PICO Summary
Population
Adults with a haematological malignancy receiving first allo-HSCT in a single centre in Norway (n=157)
Intervention
Extracorporeal photopheresis (ECP) therapy, 8 sessions over 6 weeks in addition to standard GvHD prophylaxis (n=76)
Comparison
Standard GvHD prophylaxis (n=81)
Outcome
During the first year, 45 patients in the intervention and 52 control patients developed GvHD (HR=0.82, 95% CI 0.55-1.22). There were no differences in acute or chronic GvHD or its organ distribution in this intention-to-treat RCT. A per-protocol analysis revealed a significant difference in GvHD between the intervention (per-protocol; n=39 of 76) and the control group (n=77), 46% vs 68%, respectively, (HR 0.47, 95% CI 0.27-0.80). Relapse occurred in 15 patients in the intervention group and in 11 patients among the controls (HR=1.38, 95% CI 0.64-3.01). GvHD-free relapse-free (GRFS) survival, event-free survival, overall survival and non-relapse mortality did not differ significantly between the two study groups. No significant difference in immune reconstitution between the two study groups was revealed.
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GVHD treatment with extracorporeal photopheresis in Brazil: a national survey
Fatobene, G., Cordeiro, A., Mariano, L., Silva, M., Bouzas, L., Hamerschlak, N., Macedo, M. C., Petta, A., Funke, V., Novis, Y., et al
Hematology, transfusion and cell therapy. 2022
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Extracorporeal photopheresis versus alternative treatment for chronic graft-versus-host disease after haematopoietic stem cell transplantation in children and adolescents
Buder, K., Zirngibl, M., Bapistella, S., Meerpohl, J. J., Strahm, B., Bassler, D., Weitz, M.
The Cochrane database of systematic reviews. 2022;6(6):Cd009898
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Editor's Choice
Abstract
BACKGROUND Chronic graft-versus-host disease (cGvHD) is a major cause of morbidity and mortality after haematopoietic stem cell transplantation, occurring in 6% to 65% of the paediatric recipients. Currently, the therapeutic mainstay for cGvHD is treatment with corticosteroids, frequently combined with other immunosuppressive agents in people with steroid-refractory manifestations. There is no established standard treatment for steroid-refractory cGvHD. The therapeutic options for these patients include extracorporeal photopheresis (ECP), an immunomodulatory treatment that involves ex vivo collection of mononuclear cells from peripheral blood, exposure to the photoactive agent 8-methoxypsoralen, ultraviolet radiation and re-infusion of the processed cell product. The mechanisms of action of ECP are not completely understood. This is the second update of a Cochrane Review first published in 2014 and first updated in 2015. OBJECTIVES To evaluate the effectiveness and safety of ECP for the management of cGvHD in children and adolescents after haematopoietic stem cell transplantation. SEARCH METHODS We searched the Cochrane Register of Controlled Trials (CENTRAL) (2021), MEDLINE (PubMed) and Embase databases from their inception to 25 January 2021. We searched the reference lists of potentially relevant studies without any language restrictions. We searched five conference proceedings and nine clinical trial registries on 9 November 2020 and 12 November 2020, respectively. SELECTION CRITERIA We aimed to include randomised controlled trials (RCTs) comparing ECP with or without alternative treatment versus alternative treatment alone in children and adolescents with cGvHD after haematopoietic stem cell transplantation. DATA COLLECTION AND ANALYSIS Two review authors independently performed the study selection. We resolved disagreements in the selection of trials by consultation with a third review author. MAIN RESULTS We found no studies meeting the criteria for inclusion in this 2021 review update. AUTHORS' CONCLUSIONS We could not evaluate the efficacy of ECP in the treatment of cGvHD in children and adolescents after haematopoietic stem cell transplantation since the second review update again found no RCTs. Current recommendations are based on retrospective or observational studies only. Thus, ideally, ECP should be applied in the context of controlled trials only. However, performing RCTs in this population will be challenging due to the limited number of eligible participants, variable disease presentation and the lack of well-defined response criteria. International collaboration, multicentre trials and appropriate funding for such trials will be needed. If treatment decisions based on clinical data are made in favour of ECP, recipients should be carefully monitored for beneficial and harmful effects. In addition, efforts should be made to share this information with other clinicians, for example by setting up registries for children and adolescents treated with ECP.
PICO Summary
Population
Children and adolescents with chronic graft-versus-host disease (GvHD) taking part in randomised controlled trials
Intervention
Extracorporeal photopheresis (ECP) with or without alternative treatment
Comparison
Alternative treatment alone
Outcome
The authors found no studies meeting the criteria for inclusion in this systematic review.
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Extracorporeal photopheresis versus standard treatment for acute graft-versus-host disease after haematopoietic stem cell transplantation in children and adolescents
Buder, K., Zirngibl, M., Bapistella, S., Meerpohl, J. J., Strahm, B., Bassler, D., Weitz, M.
The Cochrane Database of Systematic Reviews. 2022;9(9):Cd009759
Abstract
BACKGROUND Acute graft-versus-host disease (aGvHD) is a major cause of morbidity and mortality after haematopoietic stem cell transplantation (HSCT), occurring in 8% to 85% of paediatric recipients. Currently, the therapeutic mainstay for aGvHD is treatment with corticosteroids. However, there is no established standard treatment for steroid-refractory aGvHD. Extracorporeal photopheresis (ECP) is a type of immunomodulatory method amongst different therapeutic options that involves ex vivo collection of peripheral mononuclear cells, exposure to the photoactive agent 8-methoxypsoralen and ultraviolet-A radiation, and reinfusion of these treated blood cells to the patient. The mechanisms of action of ECP are not completely understood. This is the second update of a Cochrane Review first published in 2014 and updated in 2015. OBJECTIVES To evaluate the effectiveness and safety of ECP for the management of aGvHD in children and adolescents after HSCT. SEARCH METHODS We searched the Cochrane Register of Controlled Trials (CENTRAL), MEDLINE (PubMed) and Embase (Ovid) databases from their inception to 25 January 2021. We searched the reference lists of potentially relevant studies without any language restrictions. We searched five conference proceedings and nine clinical trial registries on 9 November 2020 and 12 November 2020, respectively. SELECTION CRITERIA We sought to include randomised controlled trials (RCTs) comparing ECP with or without standard treatment versus standard treatment alone in children and adolescents with aGvHD after HSCT. DATA COLLECTION AND ANALYSIS Two review authors independently performed the study selection. We resolved disagreement in the selection of trials by consultation with a third review author. MAIN RESULTS We identified no additional studies in the 2021 review update, so there are still no studies that meet the criteria for inclusion in this review. AUTHORS' CONCLUSIONS The efficacy of ECP in the treatment of aGvHD in children and adolescents after HSCT is unknown, and its use should be restricted to within the context of RCTs. Such studies should address a comparison of ECP alone or in combination with standard treatment versus standard treatment alone. The 2021 review update brought about no additions to these conclusions.
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A Prospective, Multicenter Study of Closed System Extracorporeal Photopheresis for Children With Steroid-Refractory Acute Graft-Versus-Host Disease
Kitko, C. L., Abdel-Azim, H., Carpenter, P. A., Dalle, J. H., Diaz-de-Heredia, C., Gaspari, S., Gennery, A. R., Handgretinger, R., Lawitschka, A.
Transplantation and cellular therapy. 2022
Abstract
BACKGROUND Steroid-refractory (SR) acute graft-versus-host disease (aGvHD) therapy involves intensive immunosuppression, which is associated with significant infectious risk. Extracorporeal photopheresis (ECP) is used to treat SR-aGvHD and is considered to be more immunomodulatory than immunosuppressive. However, pediatric data are mostly retrospective and often involve multi-step ECP that includes apheresis followed by separate photosensitizing/reinfusion on another device. OBJECTIVE To prospectively evaluate the efficacy and safety of a single-device ECP system in children with SR-aGvHD. STUDY DESIGN Open-label, multicenter, phase 3 study of the THERAKOS® CELLEX® Photopheresis System in children/young adults aged 1 to 21 years with SR-aGvHD. Patients were treated 3 times per week for 4 weeks, then twice weekly through week 12 while maintaining standard aGvHD prophylaxis. The primary efficacy endpoint was the proportion of patients achieving overall response (OR) at day 28 without the addition of next-line systemic treatment. Secondary endpoints included the proportion of patients achieving OR at weeks 8 and 12; the mean weekly steroid dose at weeks 4, 8, and 12; and treatment-emergent adverse events (TEAEs). RESULTS Twenty-nine children (median age, 8 years) were enrolled. OR was 55% by day 28, 74% by week 8, and 79% by week 12. Progressive improvements were observed in the skin and the gastrointestinal tract. Mean steroid dose decreased from 1.54 mg/kg/day at baseline to 0.90 mg/kg/day at week 4; 35% of patients achieved >50% steroid dose reduction at week 4 and 75% achieved >50% steroid dose reduction at week 12. Of 168 TEAEs reported among 25 patients (86%), 28 (17%) events were infections and 14 (8%) events were considered to be probably treatment related (all nonserious). Of 627 ECP treatments administered in children/young adults, 68% required blood priming. Treatment-related AEs, including hypotension, hypocalcemia, central line infection, and catheter-site bruising, were rare (1 event each). Three deaths occurred and were deemed unrelated to ECP by the investigators. CONCLUSION Use of the THERAKOS® CELLEX® Photopheresis System was effective in children with SR-aGvHD, with more than half experiencing improvement by day 28 and further responses observed over 12 weeks. Very few TEAEs were attributable to ECP, and no new safety signals were observed.
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Extracorporeal photopheresis vs standard therapies for steroid-refractory chronic graft-vs-host disease: Pharmacoeconomic assessment of hospital resource use in Spain
Boluda, B., Solana-Altabella, A., Cano, I., Acuña-Cruz, E., Rodríguez-Veiga, R., Ballesta-López, O., Megías-Vericat, J. E., Martínez-Cuadrón, D., Gómez, I., Solves, P., et al
Journal of clinical apheresis. 2021
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Abstract
BACKGROUND This study assessed pharmacoeconomic costs associated with extracorporeal photopheresis (ECP) compared with other available second-line therapies for chronic graft-vs-host disease (cGvHD) in a tertiary Spanish institution. METHODS Patients (=18?years) diagnosed with steroid-refractory cGvHD were eligible. Data were collected retrospectively from index date until 1 year or relapse. Patients were distributed in two cohorts (ECP vs non-ECP), matched by age (= or?>?40), hematopoietic stem cell transplant (HLA-identical sibling donor or other) and number of previous immunosuppressive lines (1, 2, or?=?3). Costs were assigned using the 2016 diagnosis-related group (DRG) system: DRG 579 (€22?383) overnight stay due to major complication (ie, sepsis, pneumonia, parenteral nutrition, or respiratory failure), and DRG 875 (€5154) if no major complication. The primary endpoint was healthcare resource utilization per patient. RESULTS Forty patients (n = 20 per cohort) were included. Median age was 49, and 37.5% were female. Mean total cost per patient was €25?319 (95% CI: €17 049-€33 590) across the two cohorts, with a slightly lower mean cost per ECP-treated patient (€23?120) compared with the non-ECP cohort (€27?519; P = .597). Twenty-seven inpatient hospitalizations occurred among ECP-treated patients, vs 33 in the non-ECP cohort. Day hospital and external consultations were more frequent in the ECP cohort. However, fewer inpatient admissions included DRG 579 compared with the non-ECP cohort (44% vs 58%). Inpatient length of stay was slightly shorter in the ECP cohort (30 vs 49?days; P = .298). CONCLUSIONS ECP treatment may yield economic savings in Spain through resource savings and moving costs toward outpatient care.
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Infectious risks in patients treated with extracorporeal photopheresis for graft-versus-host disease: A retrospective cohort study
Thevenet, U., Daguenet, E., Beszera, S. M., Cornillon, J., Tavernier, E., Schein, F., Honeyman, F., Guyotat, D.
Journal of clinical apheresis. 2021
Abstract
BACKGROUND Infections are common with significant mortality and morbidity in patients with graft-versus-host disease (GvHD). Extracorporeal photopheresis (ECP) is an advantageous treatment option for patients with GvHD because it is not immunosuppressive. The objective of this study was to assess the rate of infections and to determine risk factors in patients with GvHD. MATERIALS AND METHODS In a single-center cohort, we retrospectively collected data on infectious episodes by evaluating the clinical records of patients with GvHD treated by ECP since 2011. RESULTS A total of 47 patients were included in this study. At ECP initiation, there were 10 patients with acute GvHD and 37 with chronic GvHD. At the final follow-up, 200 infectious episodes were diagnosed in 91.5% of patients with an average follow-up of 25.9 months (ie, 1.97 infections per patient per year). Most episodes had positive outcomes as there was no death related to infections, and only six infections required long-term treatment. Higher dose of corticosteroids at the initiation of ECP was significantly associated with a shorter onset of the first infection (hazard ratio [HR] = 2.05; 95% confidence interval [CI] [1.17, 3.57]; P = .013). Unrelated donor transplants were significantly associated with a lower rate of infection (HR = 0.61; 95% CI [0.39, 0.95]; P = .028). CONCLUSION The results of our study suggest that ECP is associated with a low infection rate and an optimal clinical efficacy. Thus, ECP is still a suitable treatment for GvHD. Yet, a future study with a larger cohort will be necessary to deepen the identification of risk factors for infection.