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

Abstract Introduction Although 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 Methods This 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. Results Six 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. Conclusion The 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.

Desafíos terapéuticos en la enfermedad injerto contra huésped / Therapeutic challenges in graft versus host disease

La enfermedad injerto contra huésped es una entidad en la cual las células inmunológicas competentes de un tejido injertado reconocen y dañan antígenos presentes en el receptor del trasplante, que es incapaz de defenderse de ellas. Es una complicación frecuente del trasplante alogénico de médula ósea, y con menor frecuencia se produce luego de trasplantes de órganos sólidos o transfusiones de hemoderivados no irradiados. Se comunica el caso de una paciente de sexo femenino de 23 años, con leucemia linfoblástica aguda.y trasplante alogénico de médula ósea, que presentó una enfermedad injerto contra huésped con compromiso cutáneo y gastrointestinal dependiente de corticoides, con mejoría de los signos y síntomas cutáneos luego del tratamiento con infliximab y fotoféresis extracorpórea. (AU)

Graft versus host disease is an entity in which competent grafted immune cells recognize and damage tissue antigens present in the transplant recipient, who is unable to defend from them. It is one of the most serious complications in patients undergoing allogeneic bone marrow transplantation, although less frequently it may be associated with solid organ transplants or transfusions of not irradiated blood products. We report the case of a 23 year-old patient with acute lymphoblastic leukemia and allogeneic bone marrow transplantation, that presented graft versus host disease with skin and gastrointestinal involvement, dependent on corticosteroids, that showed improvement in signs and skin symptoms after treatment with infliximab and extracorporeal photopheresis. (AU)

Cutaneous graft-versus-host disease after hematopoietic stem cell transplant - a review

Abstract Graft-versus-host disease (GVHD) is a major complication of allogeneic hematopoietic stem cell transplants (allo-HSCT) associated with significant morbidity and mortality. The earliest and most common manifestation is cutaneous graft-versus-host disease. This review focuses on the pathophysiology, clinical features, prevention and treatment of cutaneous graft-versus-host disease. We discuss various insights into the disease's mechanisms and the different treatments for acute and chronic skin graft-versus-host disease.

Fotoféresis en el tratamiento de Síndrome de Sézary: Caso clínico / Sézary syndrome treated with extracorporeal photopheresis: Report of one case

Sézary syndrome (SS) is an unusually aggressive T- cell lymphoma characterized by the triad of erythroderma, the presence of more than 1,000 Sézary cells in peripheral blood and lymphadenopathies. It is accompanied by generalized pruritus and poor quality of life. The management of SS depends on its stage, patient comorbidities, and treatment availability. Extracorporeal photopheresis (ECP) is the first line of treatment for patients with T-cell lymphomas in stage IVA1, IVA2 or SS. This treatment comprises three phases: leukapheresis, photoactivation and subsequent reinfusion of lymphocytes. As it is an immunomodulatory therapy it does not produce generalized immunosuppression. We report a 76 year-old male with SS stage IIIb initially treated with 12 sessions of ultraviolet phototherapy without response. After 10 well-tolerated sessions of ECP, itching and skin lesions eventually disappeared.

Advances on Extrocorporeal Photochemotherapy in the Treatment of Chronic Graft-Versus-Host Disease / 中国实验血液学杂志

Chronic graft-versus-host disease (cGVHD) is a common complication after allogeneic hematopoietic stem cell transplantation (allo-HSCT), which is also one of the major causes of patients' death following transplantation. Recently, extracorporeal photochemotherapy (ECP) has shown a considerable efficacy in cGVHD treatment, which is based on the infusion of autologous peripheral blood mononuclear cells collected by aphesis, incubated with the photoactivable drug 8-methoxypsoralen (8-MOP) and UV-A irradiation. The therapeutic effect of ECP is mainly achieved by the induction of cell apoptosis, influencing the function of dendritic cells and the induction of immune tolerance. ECP has many advantages in the treatment of cGVHD, such as no increasing the risk of infection in patients, unaffecting the graft-versus-leukemia effect, nearly no side effect and so on. Many medical centers have done a lot of research on the treatment of cGVHD in both children and adults by using ECP and achieved good results. CD19(+) CD21(-) B lymphocytes, serum BAFF and serum TNFα can be used to measure and early evaluate the efficacy of ECP treatment. The effect of ECP is associated with many factors, and certain complications may occur during the treatment. At present, the application of ECP treatment is limited by the unclear mechanisms, varying treatment cycles in different studies, and small number of patients in clinical research. In the near future, with deeper basic research, increasing the case number and standard clinical treatment, ECP will have a more extensive application prospects. This review focuses mainly on the clinical advances of ECP in the treatment of cGVHD.

Extracorporeal photopheresis for chronic graft-versus-host disease: a systematic review and meta-analysis

BACKGROUND: The safety of extracorporeal photopheresis (ECP) in steroid-refractory chronic graft-versus-host disease (SR-cGVHD) has been explored in multiple studies but reported response rates (RR) vary significantly across studies. METHODS: We conducted a meta-analysis to assess the efficacy of ECP for SR-cGVHD. A search of electronic databases for studies published between 1984 and 2012 was conducted. End points included RR: complete response (CR), overall response rates (ORR), and organ-specific RR. The initial search generated 312 studies, of which 18 met the selection criteria (N=595). A random effects model was used for pooled rates. RESULTS: Pooled CR rates and ORR were 29% (confidence interval [CI], 19-42%) and 64% (CI, 65-82%), respectively. One-year overall survival was available for 4 studies only and was 49% (CI, 29-70%). The pooled RR for skin, liver, ocular, oral, lung, gastrointestinal and musculoskeletal SR-cGVHD was 74%, 68%, 60%, 72%, 48%, 53%, and 64%, respectively. There was a significant heterogeneity among studies due to differences in ECP schedules and duration. No significant differences in responses to ECP for pediatric and adult populations were found. Sensitivity analysis could not be undertaken due to a limited number of prospective studies. CONCLUSION: ECP is an effective therapy for oral, skin, and liver SR-cGVHD, with modest activity in lung and gastrointestinal SR-cGVHD.

Advances of mechanism study on extracorporeal photochemotherapy to treat and prevent graft-versus-host disease in vitro--review / 中国实验血液学杂志

Extracorporeal photochemotherapy, also called extracorporeal photopheresis, or ECP for short, is now an effective method to treat and prevent patients from graft-versus-host disease (GVHD). It is generally accepted that the mechanism of ECP is to induce immune tolerance. Further researches show that ECP acts on several stages of GVHD by means of many complex mechanisms. Firstly, ECP induces apoptosis of T lymphocytes, inhibiting T cells from differentiating and proliferating, and promoting regulatory T cells. Besides, it also adjusts the number and proportion of helper T cells. Secondly, ECP affects antigen presenting cells. It induces apoptosis and inhibits maturation of antigen presenting cells. At the same time it affects the ability to process and present antigens of antigen presenting cells. Thirdly, ECP adjusts the cytokine secretion, in order to inhibit inflammatory response. This review discusses why ECP can treat and prevent patients from GVHD via the three aspects mentioned above.

Enfermedad de injerto contra huésped cutánea en el trasplante alogénico de médula ósea / Cutaneous graft versus host disease after allogenic hematopoyetic stem cell transplantation

Debido al incremento en la utilización del trasplante alogénico de médula ósea como terapéutica, es cada vez más frecuente observar la enfermedad injerto contra huésped como una de sus complicaciones de mayor relevancia. Ésta suele ser una causa importante de morbimortalidad en los pacientes trasplantados. Las manifestaciones cutáneas generalmente son las primeras en aparecer, y tanto su forma aguda como crónica presentan una gran variedad clínica. El objetivo de este trabajo es revisar la etiología, las características clínicas e histopatológicas, el diagnóstico y la terapéutica de la enfermedad de injerto contra huésped cutánea.

Fotoferese extracorpórea / Extracorporeal photopheresis

Fotoferese extracorpórea é uma modalidade de terapia celular que tem demonstrado eficácia e segurança em pacientes portadores de doenças auto-imunes e mediadas por células T, incluindo esclerodermia, linfoma de células T cutâneo/ Síndrome de Sézary e doença enxerto-contra-hospedeiro após transplante de células-tronco hematopoiéticas. Tem sido empregada, ainda, com o intuito de induzir tolerância em transplantes de órgãos sólidos. O tratamento se baseia no efeito biológico de uma substância fotossensibilizante, o 8-metoxipsoraleno, e da radiação ultravioleta A, nas células mononucleares coletadas por aférese e reinfundidas ao paciente. O mecanismo de ação parece ser devido à indução de imunidade anticlonotípica direcionada a clones patogênicos de células T. O tratamento induz a apoptose de células T patogênicas, e a ativação de células apresentadoras de antígenos desempenha papel importante no processo imunomodulador.

Extracorporeal photopheresis is a method of cell therapy that has demonstrated efficacy in autoimmune diseases, cutaneous T-cell lymphoma/Sézary syndrome and graft-versus-host disease after hematopoietic stem-cell transplantation. This technique has also been employed as a treatment strategy to induce tolerance after solid organ transplants. Treatment is based on the biological effect of ultraviolet A radiation and a photosensitizing drug, 8-methoxypsoralen, on mononuclear cells collected by apheresis and reinfused into the patient. The suggested mechanism of action is related to the induction of anticlonotypic immunity directed against pathogenic clones of T lymphocytes. Treatment induces apoptosis of pathogenic T-cells, and it appears that activation of antigen-presenting cells has an important role in this process.

Effect of Extracorporeal Photopheresis on Steroid Resistant Acute GVHD Refractory to High Dose Steroid Treatment

BACKGROUND: The mortality of patients with steroid resistant acute graft-versus-host disease (GVHD) after allogeneic hematopoietic stem cell transplantation (HSCT) is high due to multiple organ failure and infection. Recently, the use of extracorporeal photopheresis (ECP), which is believed to have a low risk of infection, has been applied for the treatment of GVHD. METHODS: Of 23 patients who were steroid resistant acute GVHD that was resistant even to high dose steroid treatment as second-line treatment, 10 patients received ECP (ECP group) and 13 patients received a third-line treatment other than ECP (non-ECP group). The outcome including the response rate and survival for the ECP group and non-ECP group was analyzed. RESULTS: The response rate of the ECP group including complete remission and partial remission, was 30%. The survival rate was 30% for the ECP group and 0% for the non-ECP group. The estimated mean survival time was 229.3+/-89.3 days for the ECP group and 41.8+/-14.6 days for the non-ECP group (P=0.028). CONCLUSION: ECP can be considered as a treatment option for the steroid resistant acute GVHD that is refractory to high dose steroid treatment.

Papulose linfomatóide - relato de dois casos / Lymphomatoid papulosis - Report of two cases

A papulose linfomatóide (PL) constitui uma variante rara dos linfomas cutâneos de células T com a presença de amplo infiltrado intracutâneo de células T positivas para CD30. O exame histológico sugestivo de doença altamente maligna e agressiva opõe-se ao curso crônico-recidivante, muitas vezes auto-limitado, presente na maioria dos casos. São apresentados os relatos de dois pacientes. Uma mulher com 64 anos de idade e história de 10 anos de PL recebeu terapia Puva em creme, sendo a doença controlada. No segundo caso, uma mulher de 42 anos apresentava história de 18 anos de PL tratada com Puva e, posteriormente, com fotoquimioterapia extracorpórea (FEC). Durante a FEC, observou-se rápida disseminação metastática que não pôde ser controlada por poliquimioterapia. A paciente foi a óbito após um ano, em razão de metástase no sistema nervoso central

Indução de resistência à infecção por Leishmania amazonensis (Kinetoplastida: Trypanosomatidae) no modelo murino por formas atenuadas do parasito / Induction of resistance against Leishmania amazonensis (Kinetoplastida: Trypanosomatidae) infection in murine model by attenuated forms of the parasite

As leishmanioses tegumentares compreendem importantes doenças em termos de morbidade, principalmene em áreas tropicais do mundo. No Brasil, a Leishmaniose Tegumentar Americana encontra-se em expansão em todas as regiões, sendo assinalada em praticamente todos os Estados. O controle da leishmaniose torna-se difícil pela grande variedade de espécies distintas de Leishmania e seus respectivos perfis epidemiológicos. Uma solução seria o desenvolvimento de vacinas contra a doença, o que se torna extremamente difícil devido ao polimorfismo genético e à diversidade biológica dos parasitos. No presente trabalho, os processos de fotoferese (associação do 8-metoxipsoraleno com a radiação UVA) e exposição à radiação-g foram utilizados como mecanismos de atenuação das formas promastigotas de L. amazonensis, visando à indução de resistência contra a infecção com as formas virulentas do parasito no modelo murino. Foi observado que, apesar das formas promastigotas tratadas pela dose de 50 Krad de radiação-g não provocarem lesões cutâneas características de L. amazonensis, as mesmas não foram capazes de induzir imunidade protetora em camundongos suíços, fato verificado através do desafio com formas virulentas do parasitos, onde foi observada uma alta carga parasitária no local da inoculação. A imunomodulação da vacinação com promastigotas g-irradiadas pelo BCG conferiu proteção aos camundongos desafiados, evidenciada pelo estudo histopatológico, que demonstrou ausência de parasitos e presença de reação inflamatória local. A vacinação com promastigotas tratadas pelo 8-MOP associado à radiação UVA induziu resistência dos camundongos ao desafio com formas virulentas, não sendo observados parasitos através de estudo histopatológico até 90 dias após o desafio. A vacinação com formas tratadas somente pela radiação UVA ou pelo 8-MOP, no entanto, não foi capaz de induzir tal imunidade, verificando-se lesões semelhantes às da infecção pelas formas virulentas do parasito. A reinfecção com formas promastigotas de L. amazonensis realizada seis dias após a primeira inoculação também foi indutora de resistência, uma vez que não foram encontrados parasitos nos camundongos reinfectados até 90 dias após a dose reinfectiva através de estudo histopatológico.

Inmunointervencion: Fotoferesis, radioferesis y vacunacion con celulas dentriticas / Inmunointervention: photoferesis, radioferesis and vaccination with dentritic cells

El reconocimiento de la participación de mecanismos inmunológicos en la fisiopatología de muchas enfermedades ha estimulado el desarrollo de nuevas estrategias terapéuticas de inmunointervención como la fotoféresis, la radioféresis y la vacunación con células dendríticas. Las observaciones clínicas han mostrado efectos positivos y resultados alentadores en la utilización de estas terapias

Terapéutica de pénfigo-no esteroidea / Non-steroid therapy in pemphigus

Se hace una revisión de los recursos terapéuticos no esteroideos, empleados en el tratamiento de las diferentes formas clínicas de pénfigo. Se enumeran los factores que condicionan la elección de dicha terapéutica; forma clínica, edad, embarazo, concomitancia con otras enfermedades, interacción con otros fármacos y efectos adversos. El esteroide continúa siendo la droga de primera elección, debiendo estar asociado con otras medicaciones adyuvantes, habitualmente desde su inicio, a fin de promover un descenso más rápido del mismo, con menor incidencia de complicaciones. En los pénfigos graves se preferirá su asociacián con inmunosupresores, en primer lugar con la azatioprina o bien con ciclofosfamida. La dapsona, como las tetraciclinas, será alternativa para algunas formas más leves de pénfigo, mientras que los pulsos de ciclofosfamida, así como la plasmaféresis, deberán reservarse para aquellos casos graves que no hayan respondido a las terapéuticas convencionales