ReviewExtracorporeal photopheresis for paediatric patients experiencing graft-versus-host disease (GVHD)
Introduction
Graft-versus-host disease (GVHD) limits the success of allogeneic haematopoietic stem cell transplantation (HSCT) and remains a clinical challenge, being fatal in approximately 15% of transplant recipients [1]. The pathogenesis of GVHD is largely immune-mediated involving recognition of recipient, either major or minor, histocompatibility antigens by donor T cells and has been extensively reviewed elsewhere [1], [2]. Clinical GVHD is classically divided into an acute form and a chronic form. The former is characterized by skin, liver and gastrointestinal tract damage, whereas chronic GVHD has diverse clinical manifestations, resembling those typical of autoimmune syndromes [2]. Standard front-line treatment of GVHD builds on a backbone of corticosteroids and cyclosporine A (CSA), whereas refractory disease is currently treated with a plethora of other therapeutics, including, for the acute form, monoclonal antibodies targeting cytokines or their receptors, mycophenolate mofetil, mechanistic target of rapamycin (MTOR) inhibitors, pentostatin, tacrolimus, anti-thymocyte globulin, mesenchymal stromal cells [3], [4], [5], [6], [7] and, for the chronic form, imatinib mesylate, thalidomide, azathioprine, low-dose methotrexate, mycophenolate mofetil, pentostatin, anti-CD20 monoclonal antibody, psoralen and ultraviolet light (PUVA) [8], [9], [10], [11]. These approaches mainly target T cells and are therefore likely to negatively impact on graft-versus-tumour (GVT) responses and on post-transplant recovery of adaptive immunity, this underpinning the urgent need for more selective strategies. In this respect, our current understanding of the immune pathogenesis of GVHD, mostly based on findings in mouse models of GVHD, is expected to pave the way to the development of cellular immunotherapy trials centred around natural and induced regulatory T cells (Treg), myeloid-derived suppressor cells, tolerogenic dendritic cells (DC) or individual cytokines, such as IL-2 [1], [12], [13], [14].
Despite aggressive treatments, GVHD remains uncontrolled in a significant percentage of affected patients. In view of incomplete response rates and toxicity of conventional treatments, favouring the development of life-threatening infections and secondary malignancies, as well as the occurrence of severe tissue damage, alternative approaches are being investigated as second-line therapy in patients with treatment-refractory GVHD. In children, who may be particularly vulnerable to the consequences of GVHD itself and of prolonged treatments with steroids or other immunosuppressive agents, the use of extracorporeal photochemotherapy (ECP) is particularly attractive.
ECP, initially developed to treat psoriasis and cutaneous T-cell lymphoma (CTCL) [15], is based on the immune-modulating action of ultraviolet-A (UV-A) irradiation on autologous blood mononuclear cells collected by apheresis, photosensitized by 8-methoxypsoralen (8-MOP) and then re-infused into the patient. The exact mechanism(s) of action of ECP have not been fully elucidated yet [16], but they involve apparently diametrically opposed immune effects, namely, up-regulation of anti-tumour immune responses to treat CTCL and down-regulation of T-cell dependent, immune-mediated diseases, such as GVHD. Only 5–15% of circulating lymphocytes (i.e., <1% of the total lymphoid mass) are exposed to psoralen and UV-A (PUVA) during an ECP procedure. Importantly, pathogenic T cells may be located at inflamed or lymphoid tissues, being excluded from irradiation. This implies that the beneficial effects of ECP are not solely due to direct cell death of pathogenic T cells reactive against recipient’s tissues, but also to distal effects on T-cell populations. In this respect, central memory CD8+ T cells have been reported to increase in patients treated with ECP for chronic GVHD [17]. ECP can also induce the differentiation of monocytes into immature DC, simply as a result of transient adherence of monocytes to the plastic flow chamber [18]. In this respect, DC from patients treated with ECP for refractory chronic GVHD may acquire phenotypic and functional features of immature DC, such as the ability to release interleukin (IL)-10 [12], [18]. The emergence of Treg populations during treatment with ECP has been correlated with clinical response [19]. Of interest, ECP treatment affects arginine metabolism, leading to down-regulation of pro-inflammatory interferon (IFN)-γ and tumour necrosis factor (TNF)-α and to up-regulation of anti-inflammatory IL-10 [20]. Finally, proportions of immature CD19+CD21− B lymphocytes may be correlated with ECP response in patients with chronic GVHD, pointing to dysregulation of B-cell homeostasis as a contributing pathogenetic factor [21].
From a clinical standpoint, the acute side effects of ECP are minimal, mainly consisting of occasional hypotensive episodes, mild pyrexia during reinfusion of the irradiated cells, tiredness and lethargy lasting 24–48 h following each treatment cycle [22]. To date, no long-term side effects have been reported. Although most published reports on paediatric ECP consist of case studies or single-centre, historic series, overall, a recent survey indicates that 64% of paediatric teams favour the inclusion of this therapeutic modality in the second-line therapy for GVHD [23]. Herein, we will focus on efficacy and safety of ECP in paediatric patients, reviewing the currently available evidence supporting a broader application of ECP to children with treatment-refractory GVHD.
Section snippets
Acute and chronic GVHD in children
Acute GVHD occurs in a significant proportion of children; large paediatric transplant studies report cumulative incidences of grade II–IV acute GVHD ranging from 28% to 56% [24], [25], [26]. Although BM remains the predominant haematopoietic stem cell (HSC) source used in paediatric HSCT [27], the expanded use of peripheral blood HSC and unrelated donors has translated into an increase of chronic GVHD incidence. It is generally appreciated that the rates of chronic GVHD, a debilitating illness
Features peculiar to ECP in children and practical issues
The use of ECP, a steroid-sparing approach not associated with infectious morbidity and mortality, is particularly attractive for children with GVHD [31]. However, apheresis in children is associated with unique challenges. The main reasons for the restriction in the use of ECP in paediatric settings may be related to the technical difficulties of leukapheresis procedures (venous access, hemodynamic, metabolic, and haematological tolerance) and the necessity of an adapted approach to paediatric
Clinical experience with ECP in paediatric GVHD
Although studies evaluating ECP for GVHD have been run primarily in adults, some trials have included or exclusively enrolled children. These paediatric experiences consist of relatively small series of patients with steroid-refractory acute and chronic GVHD. The optimal schedule and duration of ECP have yet to be established. A certain degree of consensus exists about treatment schedules, especially for acute GVHD, with a single-day treatment two/three times a week or 2 consecutive days once a
Conclusions
Also based on the recently published guidelines on the use of therapeutic apheresis in clinical practice from the American Society for Apheresis (ASFA) [49], ECP can be viewed as an established second-line therapy for steroid-refractory chronic GVHD, particularly when involving the skin, and as an adjunctive first-line therapy for selected paediatric patients with acute GVHD. Published data show that ECP is a safe, effective and well tolerated treatment for GVHD resistant to conventional
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