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 Table of Contents  
META ANALYSIS
Year : 2015  |  Volume : 1  |  Issue : 6  |  Page : 201-208

Extracorporeal Photopheresis for Steroid-refractory Chronic Graft-versus-host Disease After Allogeneic Hematopoietic Stem Cell Transplantation: A Systematic Review and Meta-Analysis


1 Department of Hematology and Oncology, Zhongda Hospital, Medical School, Southeast University, Nanjing, Jiangsu, China
2 Department of Internal Medicine V (Hematology, Oncology, and Rheumatology), University Clinic of Heidelberg, Heidelberg, Baden-WÜrttemberg, Germany

Date of Submission27-Sep-2015
Date of Acceptance25-Nov-2015
Date of Web Publication30-Dec-2015

Correspondence Address:
Baoan Chen
Department of Hematology and Oncology, Zhongda Hospital, Medical School, Southeast University, Dingjiaqiao 87, Gulou District, Nanjing 210009, Jiangsu
China
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/2395-3977.172859

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  Abstract 

Aim: Recently, extracorporeal photopheresis (ECP) has become a promising therapeutic approach for steroid-refractory chronic graft-versus-host disease (cGVHD) because of its advantage over other therapies. The mechanism of action in ECP still remains to be elucidated. To investigate the evidence for clinical efficacy of ECP in the treatment of steroid-refractory cGVHD, we conducted a systematic search and meta-analysis comprising several databases and abstracts presented at recent annual meetings in the field.
Methods: A systematic review of publications indexed in the PubMed, Embase, the Cochrane-controlled trials registry, the Cochrane Library, and ISI Web of knowledge were performed on January 10, 2015. Eight studies including 176 patients were identified. Meta-analyses were carried out to calculate the overall response rate (ORR) and complete response rate (CRR) of cGVHD and the organ-specific responses.
Results: In patients with cGVHD, pooled ORR and CRR were 0.66 and 0.46, respectively, with organ-specific responses of 0.80 for skin, 0.79 for gut, 0.57 for oral mucosa, 0.57 for liver, 0.50 for eye, and 0.46 for joint involvement.
Conclusion: The present analysis revealed a promising clinical benefit of ECP for patients with steroid-refractory cGVHD. Further prospective trials with larger cohorts are mandatory.

Keywords: Extracorporeal photopheresis, meta-analysis, steroid-refractory chronic graft-versus-host disease


How to cite this article:
Chen R, Chen B, Dreger P, Schmitt M, Schmitt A. Extracorporeal Photopheresis for Steroid-refractory Chronic Graft-versus-host Disease After Allogeneic Hematopoietic Stem Cell Transplantation: A Systematic Review and Meta-Analysis. Cancer Transl Med 2015;1:201-8

How to cite this URL:
Chen R, Chen B, Dreger P, Schmitt M, Schmitt A. Extracorporeal Photopheresis for Steroid-refractory Chronic Graft-versus-host Disease After Allogeneic Hematopoietic Stem Cell Transplantation: A Systematic Review and Meta-Analysis. Cancer Transl Med [serial online] 2015 [cited 2019 Nov 17];1:201-8. Available from: http://www.cancertm.com/text.asp?2015/1/6/201/172859


  Introduction Top


Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is the only curative option for several hematological malignancies. However, graft-versus-host disease (GVHD) causes transplant-associated mortality in a significant percentage of patients thus reducing the overall survival.[1] GVHD occurs in 30–50% of patients transplanted with either an HLA-identical related or unrelated donor and is fatal to approximately 15% of transplant recipients.[2],[3] Patients with GVHD suffer from considerable organ damage, leading to significant morbidity, frequent hospitalizations, and high mortality rates.[4]

Unlike the acute GVHD (aGVHD) which is mediated by cytotoxic T-cell attack on host tissues, pathophysiology of chronic GVHD (cGVHD) is significantly more complex and the mechanisms of dysregulated adaptive and innate immune responses are poorly understood. cGVHD often affects different organs with varying severity like skin, gut, oral mucosa, liver, lungs, and eye.[5] Standard first-line treatment of cGVHD is based on corticosteroids and cyclosporine A,6-8 but only up to 40% patients respond completely to first-line treatment. Many patients require additional salvage therapy for corticosteroid-refractory GVHD and have a dismal prognosis.[3]

Extracorporeal photopheresis (ECP, also known as extracorporeal photochemotherapy, extracorporeal photoimmunotherapy, or just photopheresis) is an established, effective, and widely accepted second-line therapy to treat a variety of disorders associated with immune dysregulation. This includes aGVHD and cGVHD, rejection in solid organ transplantation, systemic sclerosis, Crohn's disease, and other diseases.[9],[10] ECP is particularly valuable where alternative therapies are typically highly toxic, immunosuppressive, and increase the likelihood of a second malignancy. The procedure of ECP is based on the immunomodulating action of ultraviolet-A (UV-A) irradiation on autologous blood mononuclear cells collected by apheresis, photosensitized by 8-methoxypsoralen, and thereafter re-infused into the patient.[11],[12],[13],[14],[15] The complete mechanisms of action behind these effects are only partly understood.[16] The most important effects of ECP seem to be altered T-cell functions and modulation of dendritic cell (DC) maturation.[17] In recent years, ECP as a therapeutic option has been widely studied in patients with GVHD. In particular, ECP has demonstrated positive effects in patients with steroid-refractory or steroid-intolerant cGVHD.[15],[18] However, most studies are unicentric and not randomized, thereafter it is difficult to truly know whether the treatment is more effective than the alternatives. Here, we performed a systematic review of the literature and a meta-analysis of all known prospective trials to assess the value of ECP for the treatment of patients with steroid-refractory cGVHD. Furthermore, we reviewed the international guidelines for the use of ECP in patients with steroid-refractory, steroid-dependent, or steroid-intolerant cGVHD and summarized ECP treatment schedules accordingly.[9],[10],[15],[19]


  Methods Top


Search strategy

A systematic review of publications indexed in the PubMed, Embase, the Cochrane-controlled trails registry, the Cochrane Library, and ISI Web of knowledge were performed on January 10, 2015, according to the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines.[20] The search strategy included the following phrases of “extracorporeal photopheresis”, “extracorporeal photochemotherapy”, “extracorporeal photoimmunotherapy”, “photopheresis” or “PUVA therapy” pairing independently with “chronic graft-versus-host disease”, “chronic GVHD”, or “cGVHD”. The reference lists were screened all of the identified studies and of the comprehensive reviews in the field.

Inclusion and exclusion criteria

For inclusion, the trials had to be prospective (randomized controlled trials [RCTs] or observational trials) examining ECP as a treatment for steroid-refractory or steroid-intolerant cGVHD after allo-HSCT. We included full texts and did not apply any restriction on age, gender, or ethnicity. Retrospective studies, case reports, and review articles were excluded along with studies with < 5 patients. When multiple publications reported on the same population, only the most recent study was included.

Data extraction and quality assessment

Two reviewers (Runzhe Chen and Baoan Chen) independently selected studies by examining titles and abstracts to determine those potentially relevant to our study question. Reported results of these identified studies were further analyzed for inclusion. Disagreement was settled by discussion and review of the articles. The following information was extracted for each study: (1) the first author's last name, (2) year of publication, (3) country of study, (4) name of study (if available), (5) study design, (6) number of subjects, (7) mean age of subjects, (8) definition of steroid-refractory GVHD, (9) the procedure and duration of ECP, (10) effect size (95% confidence interval [CI]), and (11) confounders used for adjustment. Quality of included RCTs was assessed using the Cochrane tool for assessment of bias [21] and for noncomparative cohort studies using the Newcastle-Ottawa scale modified for single-arm cohort.[22]

Statistical analysis

As there were so few published studies examining the area of interest, meta-analyses were not stratified neither by adult, pediatric or mixed age cases nor by complete response or partial response. However, the use of a random-effects model should account for some of the interstudy variation. All statistical analyses were conducted by using the STATA (version 12.0, Stata Corporation, College Station, TX, USA) software. All test results were considered to be statistically significant at P < 0.05. We estimated relative risk with their 95% CI using the standardized mean difference. Heterogeneity was evaluated by using I2 values. We considered significant heterogeneity to be present when the I2 statistic was > 50%, and moderate heterogeneity when the I2 statistic was > 30%. Funnel plots were used to assess the potential publication bias of the studies.


  Results Top


Literature search

In total, we initially identified 1199 potentially eligible studies, among which, 428 studies were identified and considered as potentially relevant studies. After screening the title or abstract, 363 studies were excluded for several reasons indicated in [Figure 1], and 65 reports were retrieved and evaluated in detail. Totally, 57 of these studies met the exclusion criteria, and eventually eight complete peer-reviewed papers met the selection criteria and were included in this meta-analysis.
Figure 1. Flow chart of the outcome of the comprehensive search strategy to identify studies meeting entry criteria for the meta-analysis. ECP: Extracorporeal photopheresis; cGVHD: Chronic graft-versus-host disease

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Study characteristics and qualities

The design features and participant characteristics of the studies are presented in [Table 1], which included seven single-arm pilot studies [23],[24],[25],[26],[27],[28],[29] and one RCT.[30] Seven prospective studies enrolled a total of 128 patients. The overall quality of these seven studies was moderate according to Newcastle-Ottawa scale [Table 2].[22] In the only RCT including 95 patients, 48 patients with cGVHD were treated by ECP.[30] This study demonstrated that ECP had a better effect when compared to the standard therapy because with ECP therapy a higher proportion of patients suffering from cGVHD achieved 50% reduction of corticosteroids (after 12 weeks of ECP treatment). Superiority of ECP was also observed in various organs affected by cGVHD. The quality of this study was adequate according to Cochrane tool for assessment of bias [Table 2].[21]
Table 1: Characteristics of the studies included in this survey

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Table 2: Quality of eight included studies

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Responses of chronic graft-versus-host disease

Overall response rate (ORR) data were extracted from six studies (100 patients).[23],[24],[26],[27],[28],[29] Within these studies, there was a high heterogeneity (I2 =66.0%), the pooled proportion of ORR was 0.66 (95% CI, 0.51–0.81), P < 0.05 [Figure 2]a and the funnel plot was generally symmetrical indicating that publication bias was relatively minor [Figure 2]b. Data on complete response rate were extracted from three studies (44 patients).[24],[27],[28] Heterogeneity between these studies was high (I2 = 85.4%), the pooled proportion of CR was 0.46 (95% CI, 0.12–0.79), P < 0.05 [Figure 3]a, the funnel plot was not generally symmetrical revealing potential publication bias of the studies [Figure 3]b.
Figure 2. Overall response rate to extracorporeal photopheresis treatment in patients with chronic graft-versus-host disease. (a) Overall response rate and (b) funnel plot of selected studies. ES: Effect size; s.e. of r: Standard error of regression

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Figure 3. Complete response rate to extracorporeal photopheresis treatment in patients with chronic graft-versus-host disease. (a) Complete response rate and (b) funnel plot of selected studies. ES: Effect size; s. e. of r: Standard error of the regression

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Responses based on cGVHD organ specificity were as follows: pooled ORR for skin involvement in three studies (39 patients)[24],[26],[28] was 0.80 (95% CI, 0.69–0.91) [Figure 4]a, for GI involvement in two studies (9 patients)[26],[28] 0.79 (95% CI, 0.53–1.05) [Figure 4]b, for oral mucosa involvement in two studies (25 patients)[24],[26] 0.57 (95% CI, 0.36–0.77) [Figure 4]c, for liver involvement in three studies (33 patients)[23],[24],[28] 0.57 (95% CI, 0.19–0.95) [Figure 4]d, for eyes involvement in two studies (4 patients)[24],[28] 0.50 (95% CI, −0.19–1.19) [Figure 4]e, and for joints involvement in three studies (13 patients)[24],[26],[28] 0.46 (95% CI, 0.19–0.73) [Figure 4]f.
Figure 4. Organ-specific response to extracorporeal photopheresis treatment in patients with chronic graft-versus-host disease: (a) Skin, (b) gastrointestinal tract, (c) oral mucosa, (d) liver, (e) eyes, and (f) joints. ES: Effect size; s. e. of r: Standard error of the regression

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Potential side effects of extracorporeal photopheresis treatment

The safety of ECP is excellent. No long-term complications were reported when compared to other immunosuppressive therapies.[9] In the eight studies selected for this analysis, adverse events (AEs) were reported: Renal failure, acute respiratory distress syndrome, ischemic heart disease, colitis, and urosepsis. All these AEs were observed in not more than one patient, respectively. Here one needs to be taken into consideration that all patients received a stem cell graft as therapy for an underlying malignant disease and were under heavy immunosuppression for treatment of aGVHD or cGVHD. No evidence demonstrated that these complications were caused by ECP treatment. Mortality of patients occurred in almost every study although no deaths were attributed to ECP. Nevertheless, careful assessment of the patients for eligibility to ECP and close monitoring of the patients while on ECP therapy are required.


  Discussion Top


Main findings

ECP is currently approved by the Food and Drug Administration only for cutaneous T-cell lymphoma refractory/resistant to conventional therapies, but it is also used as an off-label therapy for GVHD and other diseases.[11] cGVHD may involve the skin, oral mucosa, eyes, genital tract, gastrointestinal tract, liver, lungs, joints, and fasciae.[19] Treatment of steroid-refractory cGVHD has constituted a challenge over the past 20 years due to a high mortality risk.[2] In this comprehensive meta-analysis, we evaluated the efficacy of ECP treatment in steroid-refractory cGVHD comprising the latest prospective research.[29] We identified eight studies including one RCT and seven single-arm studies with 176 patients. Our analysis indicates that ECP is a suitable option for patients with steroid-refractory cGVHD, being effective in a proportion of patients according to our results. Skin involvement predicts a higher probability of response in cGVHD, followed by gut, oral mucosa, liver, eyes, and joints. The efficacy of ECP in patients with lung involvement (i.e., bronchiolitis obliterans) remains to be proven.

Comparison with other meta-analyses of extracorporeal photopheresis therapy for graft-versus-host disease

Compared with other meta-analyses, our meta-analysis included the most comprehensive literature in the field of ECP treatment in steroid-refractory cGVHD, collected the most recent papers,[29] thus assessing the largest cohort ever of ECP patients (n = 176), and employed modern statistical methods like funnel plots to evaluate heterogeneity of studies on the effect of ECP in patients with cGVHD thoroughly in our analysis, which could better help guide clinicians in the ECP application.

Part of research for cGVHD conducted by Abu-Dalle et al.[31] had similar methods and results; however, we added a new study in our meta-analysis,[29] and we furthermore used a different statistical method: The STATA (version 12.0, Stata Corporation, College Station, TX, USA) software will automatically exclude the results whose pooled proportion equals 0 or 1 for not trusted by the default of this software; however, the Stats-Direct version 2.7.8 (StatsDirect Ltd, Altrincham, UK) used by Abu-Dalle et al.[31] could not exclude those studies whose pooled proportion equals 0 or 1. As a result, we interpreted the original papers in a different way.

In a recent study by Weitz et al.,[32] the authors searched RCTs comparing ECP with standard treatment for aGVHD and cGVHD in pediatric patients, respectively; however, no studies met their inclusion criteria because no RCTs have currently evaluated the efficacy of ECP in the treatment of aGVHD or cGVHD in pediatric patients after HSCT. In another meta-analysis also about ECP in the treatment of cGVHD,[33] the authors included both prospective and retrospective studies, which may result in a bigger bias of the final conclusion.

Because in China except our group no previous ECP work have been investigated, we believe together with our previous study of ECP for aGVHD,[34] this study of ECP for cGVHD will stimulate the particular interests of many Chinese clinicians and scientists and promote the study of ECP in China, so that patients with GVHD in China will receive ECP treatment and might benefit from it in this most populous country. As a result, ECP can get more focus the worldwide.

Limitations

Although a number of ECP therapeutic modalities have demonstrated responses in steroid-refractory cGVHD, several limitations associated with this meta-analysis and our selected studies were recognized. First, no general recommendation could be made on treatment schedule due to missing evidence. To overcome this limitation, we screened the international guidelines for ECP treatment schedules and summarized these in [Table 3]. Most of the studies we included had different starting criteria, treating regimens, and protocols. In addition, the ECP system was not uniform, both the closed (one-step) system with Therakos UVAR XTS™ device and the open (two-step) system with a cell separator and a UV-A irradiator have been used [Table 1] and [Table 3].
Table 3: International guidelines on the use of extracorporeal photopheresis as second-line therapy on patients with chronic graft-versus-host disease

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Second, the definition of steroid-refractory and steroid-dependent cGVHD varied between investigators, so it was hard to define the indications of choosing ECP as second-line therapy. For example, the definition of steroid-refractory cGVHD were not concordant: in the article by Smith et al.,[23] steroid-refractory GVHD patients were defined as patients with GVHD who failed to respond to standard drug therapy with steroids, cyclosporine, monoclonal antibodies, and antithymocyte globulin. In contrast, Garban et al.[27] defined cGVHD as resistant to immunosuppressive therapy when the disease did not improve under corticosteroids given at a minimum dose of 2 mg/kg body weight/day for at least 1 month. The British Photodermatology Group and the UK Skin Lymphoma Group come to a consensus where steroid refractory cGVHD was defined as patients not responding to a minimum of 4 weeks of standard primary therapy with prednisolone at a dose of 1 mg/kg body weight/day.[35] It would be highly desirable if a uniform definition was found by the scientific community in the future. The absence of uniform criteria for the assessment of cGVHD is also a problem. Moreover, the precision of pooled effective size is affected by the small sample size of the included studies. Therefore, we had to choose the random-effects model for the entire study to increase power and precision regardless of heterogeneity. Only one RCT was identified during our literature search. Thus, evidence of the efficacy of ECP remained insufficient. The beneficial effect of ECP should be further tested in the context of multicenter trials with a large number of patients to document its effect.

Future directions

Further elucidation of the mechanism of action in ECP for the treatment of cGVHD will be a promising opportunity in future research. ECP is thought to control GVHD in part through direct induction of lymphocyte apoptosis, but its effects on the immune system beyond apoptosis remain poorly characterized. A recent basic study demonstrated that the immune response evoked by ECP treatment may be governed by the state of the antigen-presenting cells and the maturation signals present in the patient at the time of therapy.[36] Altered maturation of DCs and indirect modulation of T-cell reactivity seem to be another important mechanism.[16],[37] Greinix et al.[38] reported furthermore on the role of B-cells as antigen-presenting cells in GVHD altered by ECP. Further studies will be required to address the underlying mechanisms. Understanding the mechanisms will help us to improve treatment for patients with steroid-refractory cGVHD. Another task is the conduction of prospective randomized clinical ECP trials to assess the proper place of ECP in cGVHD prophylaxis and treatment.

In conclusion, this study suggests that ECP is a safe, effective, and well-tolerated treatment for cGVHD resistant to conventional treatment. It offers the possibility of reducing or discontinuing steroids or other immunosuppressive therapies. In the future, more mechanisms of action in ECP will be elucidated leading to a better standardization of treatment strategies. Larger, high-quality, multicenter, and randomized controlled clinical trials will be carried out.

Financial support and sponsorship

This work was supported by the National Natural Science Foundation of China (Grant No. 81170492, 81370673), National High Technology Research and Development Program 863 of China (Grant No. 2012AA022703), National Key Basic Research Program 973 of China (Grant No. 2010CB732404), Key Medical Projects of Jiangsu Province (Grant No. BL2014078) and Key Discipline of Jiangsu Medicine (2011–2015).

Conflicts of interest

Prof. Michael Schmitt received a grant from Therakos Ltd., for a local ECP registry. All other authors have no conflicts of interest.

 
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    Figures

  [Figure 1], [Figure 2], [Figure 3], [Figure 4]
 
 
    Tables

  [Table 1], [Table 2], [Table 3]


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