Allogeneic hematopoietic cell transplantation (HCT) remains the only curative treatment option for many patients with various malignant and benign hematologic disorders [1
]. With the increasing utilization of allogeneic HCT in part due to the introduction of reduced intensity conditioning regimens, expansion of HCT to higher recipient age, increasing use of alternative donors and filgrastim-mobilized peripheral blood stem cells [2
] among others, the overall burden of patients surviving with graft-versus-host disease (GVHD) may also be growing worldwide [3
]. Despite improvements in pharmacologic prevention and treatment of GVHD, graft manipulation technologies, and advances in supportive care, GVHD continues to be the major source of disabling morbidity and mortality after allogeneic HCT limiting its broader application.
Pathophysiology of GVHD is complex and beyond the scope of this review; however, acute GVHD is mediated by tissue injury from preparative regimen, cytokines and alloreactive cytotoxic T cell responses, and chronic GVHD results from complex dysregulation of both adaptive and innate immune responses, resulting in a variety of autoimmune-like conditions. Corticosteroid remains the established standard first line therapy for GVHD, and multiple second-line therapies have been explored to regain responses in those patients with steroid-refractory or steroid-intolerant GVHD [4
]. Major obstacles of GVHD treatments are rather limited responses to treatments, long-term steroid toxicities, and global immunosuppression with increased risk of infections, morbidity and ultimate mortality. Extracorporeal photopheresis (ECP) is an attractive option for GVHD patients based on its immunomodulatory properties and promising responses. Here, we review and critically appraise the current literature on ECP as a treatment option for patients with acute and chronic GVHD.
2. Extracorporeal Photopheresis (ECP)
ECP exerts its immunomodulatory properties by extracorporeal exposure of peripheral blood mononuclear cells to 8-methoxypsolaren and ultraviolet (UV) A light in an apheresis procedure and subsequent reinfusion of the treated cells back into the patient’s circulation [5
]. ECP has been utilized for GVHD treatment since the 1980s [6
] but its only FDA-approved indication remains for the treatment of cutaneous T cell lymphoma. Proposed immunomodulatory properties of ECP may be derived from the following mechanisms: differentiation of monocytes into dendritic cells (DCs), apoptosis of cytotoxic cells, and/or impaired antigen presentation capacity. Additionally, studies have also shown increased natural killer (NK) cells, modulation of DCs, and skewing toward Th2 response [7
]. While clinical benefits of ECP treatment have been well documented, its exact mechanisms of action remain rather unclear.
ECP plays a pivotal role mostly as a second-line therapy for both acute and chronic steroid-refractory GVHD. Its steroid-sparing benefit and facilitation of steroid taper have been demonstrated in multiple studies, and it remains an attractive option especially for those who cannot tolerate corticosteroids [28
]. A large number of investigators have reported the efficacy of ECP in treating steroid-refractory GVHD with varying success rates and some studies have demonstrated survival benefits with ECP [28
]. A variety of ECP treatment schedules have been recommended but in general, intensive short courses of ECP may be considered in acute GVHD whereas longer treatment could be necessary in chronic GVHD. In terms of the organ specific responses, cutaneous GVHD seems to have the highest response rates and lung (chronic GVHD) on the other hand may have rather disappointing results.
Although numerous studies on ECP, including those with open label randomized designs, are available, the quality of evidence on the ECP as a treatment option for GVHD is somewhat limited in part due to the absence of blind studies of ECP. Many of the studies quoted in the recommendations are also retrospective in nature. Acknowledging the limitations of clinical evidence which supports the use of ECP, the procedure has benefits to GVHD patients not only based on its therapeutic efficacy but also based on its well-established safety profile. Of more than 500,000 ECP treatments performed worldwide since 1987, the incidence of reported adverse events is less than 0.003% [19
]. The most commonly reported side effects are mild and include nausea, fever and headache. On the other hand, significant reactions such as vasovagal syncope or infections secondary to indwelling catheters are infrequent [19
Though ECP is generally safe, a few considerations are worth noting. First, the ECP circuit has a relatively small fluid volume (typically < 500 mL). ECP would be best performed in a closely monitored outpatient unit or in the hospital, and one has to be mindful of the volume status of potentially ill GVHD patients. Secondly, intravenous 8-methoxypsolaren is only licensed in the Therakos closed system, and those patients who are photosensitive or have a sensitivity to psolaren compounds are excluded from ECP option. Additionally, weight under 40 kg is contraindicated in the ECP Therakos UVAR-XTSTM
machine as low body mass patients would unlikely be able to tolerate the volume shifts during ECP treatment. However, the closed system CELLEXTM
(Therakos) has recently replaced the UVAR-XTSTM
(Therakos) system. The CELLEXTM
(Therakos) system allows shorter treatment time (down to one and a half hour from typical three-hour treatment) and treatment of lower body weight patients expanding the ECP indications to pediatric population [19
]. Both heparin or citrate can be fused to prevent thrombosis during the ECP but citrate may be the preferred method of anticoagulation in patients with risk of bleeding from especially GVHD (such as GI or liver). A low platelet count (such as <20 × 109
/L) is considered a contraindication to ECP. Additionally, patients would need to have appropriate venous access such as photopheresis-compatible port-a-cath or central venous catheter. Physicians should discuss risks and potential complications associated with central venous access such as bleeding, thrombosis and infections. Patient access to ECP sites may be somewhat limited, though it is estimated that over 200 locations (mostly at transplant or academic medical centers) may be available worldwide [19
]. Further expansion of ECP availability would help GVHD patients who are refractory to corticosteroids and in need of additional therapy.
The exact mechanism by which ECP induces tolerance in patients with GVHD remains an open question. There are several observations that may help to grasp current understanding of immunologic mechanisms of ECP. Data suggest that ECP-induced T-cell tolerance seems to depend on T-cell apoptosis, the presence of CD11c+ monocytes and regulatory T-cell (T-reg) induction [44
]. Hannani et al. also suggested that alloreactive T-cells derived from GVHD patients are particularly susceptible to the pro-apoptotic effects of ECP [48
]. However, only a small fraction (likely 5 to 10%) of circulating monocytes are exposed to UVA irradiation during ECP procedure, and it is less likely that this mechanism alone would explain the tolerance induction by ECP [49
]. Additional considerations may need to be given to ECP effects on DCs as well as interactions of T-cells and DCs implicating the complex interplay of immunologic cells in exerting tolerance induced by ECP. The role of B-cells in the development of GVHD has also been investigated further in the recent past. Emerging data suggest profoundly impaired B cell immunity in chronic GVHD patients and some studies found that markers of B-cell activation may correlate with ECP responses [50
]. Further research is needed to elucidate the mechanisms of GVHD response following ECP, to address questions regarding the differential effects on specific organs, and to develop new methods to improve ECP treatment responses in non-cutaneous GVHD.
Steroid-refractory GVHD remains a major cause of disabling morbidity and mortality after allogeneic HCT. ECP is an attractive second- and third-line option for those patients with GVHD, but its use may be influenced by clinical experience, center preference and patient access due in part to the lack of high-quality randomized clinical trials comparing ECP with other modalities, and paucity of algorithms incorporating ECP over other therapeutic options. The current decisions to prescribe ECP are largely made on an individual patient basis. The procedure has an excellent safety profile and it would be an ideal option for those who are unable to tolerate higher doses of corticosteroids. Extensive literature, albeit mostly retrospective in nature, exists on the efficacy of ECP in GVHD, and clinicians should consider ECP early on as a promising therapeutic modality for those patients who require corticosteroids for the treatment of GVHD. The standardization of ECP treatment may be important in delivering consistent therapy and produce reliable outcomes. With emerging GVHD therapies modulating JAK-STAT and BTK pathways, the treatment options for GVHD patients are growing, but ECP would be a useful therapeutic armamentarium for those GVHD patients undergoing life-threatening medical conditions.