Accepted Manuscript Extracorporeal photopheresis in steroid-refractory acute or chronic graft-versus-host disease: results of a systematic review of prospective studies Iman Abu-Dalle , Tea Reljic , Taiga Nishihori , Ahmad Antar , Ali Bazarbachi , Benjamin Djulbegovic , Ambuj Kumar , Mohamed A. Kharfan-Dabaja PII:

S1083-8791(14)00315-2

DOI:

10.1016/j.bbmt.2014.05.017

Reference:

YBBMT 53471

To appear in:

Biology of Blood and Marrow Transplantation

Received Date: 7 April 2014 Accepted Date: 19 May 2014

Please cite this article as: Abu-Dalle I, Reljic T, Nishihori T, Antar A, Bazarbachi A, Djulbegovic B, Kumar A, Kharfan-Dabaja MA, Extracorporeal photopheresis in steroid-refractory acute or chronic graftversus-host disease: results of a systematic review of prospective studies, Biology of Blood and Marrow Transplantation (2014), doi: 10.1016/j.bbmt.2014.05.017. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

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Extracorporeal photopheresis in steroid-refractory acute or chronic graft-versus-host disease: results of a systematic review of prospective studies

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Iman Abu-Dalle1,*, Tea Reljic2,*, Taiga Nishihori3,4, Ahmad Antar1,5, Ali Bazarbachi1,5, Benjamin Djulbegovic2,3,6, Ambuj Kumar2, Mohamed A. Kharfan-Dabaja3,4

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1. Department of Internal Medicine, American University of Beirut Medical Center, Beirut, Lebanon 2. Center for Evidence Based Medicine, University of South Florida College of Medicine, Tampa, FL, USA 3. Department of Oncologic Sciences, University of South Florida College of Medicine, Tampa, FL, USA 4. Department of Blood and Marrow Transplantation, Moffitt Cancer Center, Tampa, FL, USA 5. Division of Hematology-Oncology, American University of Beirut Medical Center, Beirut, Lebanon 6. Department of Malignant Hematology, Moffitt Cancer Center, Tampa, FL, USA

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*IA-D and TR contributed equally to this manuscript The authors declare no relevant financial conflicts of interest in relation to this manuscript

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Abstract number of words=217 Manuscript number of words (including headings)=2786 Number of tables=1 Number of figures=5 Number of references =49

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Corresponding author: Mohamed A. Kharfan-Dabaja, M.D. Department of Blood and Marrow Transplantation Moffitt Cancer Center 12902 Magnolia Drive, FOB-3 Tampa, FL Phone: 1-813-745-8248 Fax: 1-813-745-8468 E-mail: [email protected]

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ABSTRACT Acute and chronic GVHD remains major obstacles for successful allogeneic hematopoietic cell transplantation. Extracorporeal photopheresis modulates immune

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cells such as alloreactive T cells and dendritic cells, and improves GVHD target organ function(s) in steroid-refractory GVHD patients. We performed a systematic review to evaluate the totality of evidence regarding the efficacy of ECP for treatment of acute

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and chronic steroid-refractory or steroid-dependent GVHD. Nine studies, including one randomized controlled trial, met inclusion criteria with a total of 325 subjects. In pooled

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analyses, ORR were 0.69 (95%CI: 0.34-0.95) and 0.64 (95%CI: 0.47-0.79) for acute and chronic GVHD, respectively. In acute GVHD organ-specific responses, ECP resulted in highest ORR for cutaneous with 0.84 (95%CI: 0.75-0.92) followed by gastrointestinal with 0.65 (95%CI: 0.52-0.78). Similar response rates were seen in

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chronic GVHD involving skin and gastrointestinal tract. Conversely, ORR for chronic GVHD involving the lungs was only 0.15 (95%CI: 0-0.5). In chronic GVHD, grade 3-4 adverse events were reported at 0.38 (95%CI: 0.06-0.78). ECP-related mortality rates

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were extremely low. Rates of immunosuppression discontinuation were 0.55 (95%CI: 0.40-0.70) and 0.23 (95%CI: 0.07-0.44) for acute and chronic GVHD, respectively. In

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summary, albeit limited by numbers of available studies, pooled analyses of prospective studies demonstrate encouraging responses following ECP treatment in acute and chronic GVHD after failing corticosteroids. Further research efforts are needed to improve organ-specific responses.

KEYWORDS Extracorporeal photopheresis, graft-versus-host disease, acute, chronic 2

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INTRODUCTION Allogeneic hematopoietic cell transplantation (allo-HCT) remains the only known curative therapeutic modality for various hematologic malignancies and blood disorders

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(1-7). The efficacy of allo-HCT is limited, however, by development of acute and/or chronic graft-versus-host disease (GVHD), which is associated with substantial

morbidity and contributes significantly to the non-relapse mortality (NRM) associated

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with hematopoietic cell allografting (8-11). Higher incidences of acute and chronic

GVHD are observed following increased use of unrelated donors, especially with HLA-

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mismatching, as well as use of G-CSF mobilized peripheral blood stem cells, among other reasons (12-15).

Therapy for acute and/or chronic GVHD relies primarily on administration of corticosteroids, namely prednisone at a starting dose of 1-2 mg/kg (16). Unfortunately, a

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significant number of patients (approx. 40-50%) do not respond or are unable to tolerate tapering of prednisone dose below 0.5 mg/kg/day (10, 17). In such cases, a second-line therapy is generally added (18-20); but, at the present time no particular immune

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suppressive agent or therapy is considered a standard option in this setting (21).

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There is a prevailing consensus, among transplant physicians, to offer patients with steroid-refractory acute or chronic GVHD participation in clinical trials whenever possible. In cases of ineligibility to participation or unavailability of such trials, the choice of second-line therapy is largely based on physician preference, familiarity with a particular treatment option or institutional standard operating procedures.

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Extracorporeal photopheresis (ECP), also known as extracorporeal photochemotherapy, involves ex vivo exposure of mononuclear cells obtained by apheresis to a photosensitizing agent, 8-methoxypsoralen, and ultraviolet A (UVA) light

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followed by re-infusion of the treated cells to the patient (22-30). The precise

mechanism(s) of ECP in the setting of acute and/or chronic GVHD is not clearly understood. Various possible mechanisms to explain GVHD (acute or chronic)

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responses following ECP have been described including normalization of CD4+/CD8+ lymphocyte populations and decrease in circulating dendritic cells (CD80+ and CD123+),

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among others (31-33).

With the exception of one randomized controlled trial (RCT) (30), published data evaluating the efficacy of ECP for the treatment of steroid-refractory, steroid-dependent, or steroid-intolerant acute and/or chronic GVHD is limited to non-randomized single-

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institution prospective trials, retrospective data, or small case series (22-29, 34). These studies describe varying, and at times conflicting, results regarding the overall and organ-specific responses. Accordingly, we performed a systematic review to evaluate

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the totality of evidence regarding the efficacy or lack thereof of ECP for the treatment of

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steroid-refractory or steroid-dependent acute or chronic GVHD. METHODS

Literature search

A comprehensive literature search was undertaken using Medline/PubMed and Cochrane collaboration for prospective studies published from inception until March 5, 2013. The search was conducted using search strategy described in Appendix 1. 4

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Relevant references within each reviewed manuscript or review were scanned to identify other potentially relevant (and eligible) studies. No search limits were applied.

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Inclusion criteria Only prospective interventional trials (RCT or observational) evaluating the efficacy of ECP for treatment of steroid-refractory or steroid-dependent acute or chronic GVHD

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were eligible. Moreover, a minimum number of 5 subjects were required without any age restriction. Single case reports, and studies addressing ECP as preventive therapy

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were excluded in this analysis.

Study selection, quality assessment, and data extraction All retrieved articles were scanned for relevance initially on title and abstract followed by full text readings by two independent authors (I A-D and AA) in consultation with

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other authors (TR and MAK-D). Disagreements were resolved by consensus. Two independent authors (IA-D and AA) extracted data from all studies using a standardized data extraction form. Data were collected on patient characteristics, clinical outcomes

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(benefits and harms), adverse events, and methodological quality of all included

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studies. A third author (TR) verified data prior to analysis. Methodological quality of included randomized controlled trials was assessed using the Cochrane tool for assessment of bias(35) and for non-comparative cohort studies using the NewcastleOttawa scale modified for single-arm cohort (36). Data analysis and statistical methods

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Proportion was calculated for each outcome and trials which had similar definitions in terms of study design, patients, intervention, control, and outcomes were summarized and pooled (37). Methods by Stuart et al. (38) were used to transform the proportions

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into a quantity suitable for random-effects pooling. The pooled proportion was then calculated as a back-transform of the weighted mean of transformed proportions, using the random-effects model (38). Heterogeneity was tested using the I2 test (38). An I2

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above 30% was considered moderate heterogeneity and above 60% was considered high heterogeneity. Meta-analyses were performed using StatsDirect version 2.7.8 (39).

RESULTS Identification of eligible studies

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This systematic review is reported according to the PRISMA guidelines (40).

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Initial search yielded 378 references of which 330 were excluded for reasons described in Figure 1. A full text review of the 48 remaining manuscripts excluded an additional 39 references for various reasons illustrated in figure 1. Nine studies (RCT=1,

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non-RCT=8) enrolling a total of 325 subjects were included in this systematic review.

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Randomized controlled trial One RCT enrolling 47 patients (25 steroid-dependent, 5 steroid-refractory, and 17 steroid-intolerant) on standard therapy and 48 patients (28 steroid-dependent, 7 steroidrefractory, and 13 steroid-intolerant) on ECP treatment arm were identified (30). This study showed that ECP was well tolerated and resulted in a higher proportion of patients with chronic GVHD to achieve ≥50% reduction of corticosteroids (by week 12 post-ECP treatment) and ≥25% decrease in total skin score (compared to baseline) 6

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(8.3% vs. 0%, p=0.04) (30). Superiority of ECP was also observed in various extracutaneous organs affected with chronic GVHD, namely ocular (30% vs. 7%, p=0.04), oral mucosa (53% vs. 27%, p=0.06) (30). Methodological quality of this study

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was adequate (Appendix 2). Observational studies

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Eight observational studies enrolled a total of 228 patients. Six of the 8 studies

(n=176) included subjects with steroid-refractory or steroid-dependent acute or chronic

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GVHD (22-24, 26, 27, 29). The remaining 2 studies (n=52) included subjects with steroid-intolerant GVHD in addition to steroid-refractory or steroid-dependent cases (25, 28). One study evaluated the role of ECP therapy as treatment of viral reactivation, specifically cytomegalovirus (n=2/15) and Epstein-Barr virus (n=4/15) in association with

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steroid-refractory GVHD (n=15/15) (29). ECP was used for treatment of acute GVHD in 113 and for chronic GVHD in 115 subjects. Overall methodological quality of studies

OUTCOMES

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was moderate (Appendix 2, Table 1).

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Characteristics of the studies included in this analysis are summarized in Table 1.Our analysis did not exclude patients with steroid-intolerant GVHD because the postECP treatment outcomes reported in pertinent studies (25, 28) did not discriminate outcomes for each specific indication (i.e steroid-intolerant or steroid-refractory). Moreover, in one study, it was impossible to ascertain the precise number of subjects with steroid-intolerant GVHD (25). We analyzed outcomes of ECP therapy based on benefits (overall response and organ-specific response) and harms (any grade 3/4 7

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adverse events and ECP-related mortality) in patients treated for acute or chronic GVHD. Whenever possible, data were also analyzed based on organ-specific responses. We also analyzed ability to discontinue immunosuppresive therapies after

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initiation of ECP. Benefits

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Overall response

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For acute GVHD

Data on overall response rate (ORR) were extracted from 6 studies (54 patients) (22, 23, 26-29). The pooled proportion of ORR for ECP in various organs using the random effects was 0.69 (95%CI=0.34, 0.95) (Figure 2A). There was high heterogeneity between studies (I2=87%). Data on complete response (CR) were extracted from 5

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studies (101 patients) (22, 23, 27-29). The pooled proportion of CR in various organs was 0.53 (95% CI=0.31, 0.74). There was high heterogeneity between studies (I2=76%).

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Responses based on acute GVHD organ-specificity (cutaneous, gastrointestinal, and hepatic) were as follows: pooled ORR for cutaneous in 5 studies (103 patients) was

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0.84 (95%CI=0.75, 0.92), gastrointestinal in 5 studies (45 patients) was 0.65 (95%CI=0.52, 0.78), and hepatic in 5 studies (38 patients) was 0.55 (95%CI=0.35, 0.74) (Figure 3A, 3B, and 3C). Overall heterogeneity between studies was low I2=22%, 0%, and 27% respectively. For chronic GVHD

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ORR data were extracted from 5 studies (87 patients) (22, 23, 25, 26, 28). The pooled proportion of ORR for ECP in various organs using the random effects was 0.64 (95%CI=0.47, 0.79) (Figure 2B). There was high heterogeneity between studies

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(I2=64%). Data on CR were extracted from 5 studies (87 patients) (22, 23, 25, 26, 28). The pooled proportion of CR in various organs was 0.26 (95% CI=0.05, 0.55). There was high heterogeneity between studies (I2=88%).

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Responses based on chronic GVHD organ-specificity (cutaneous, gastrointestinal,

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hepatic, oral mucosa, musculoskeletal, and pulmonary) were as follows: pooled ORR for cutaneous in 4 studies (70 patients) was 0.71 (95%CI=0.57, 0.84), gastrointestinal in 2 studies (9 patients) was 0.62 (95%CI=0.21, 0.94), hepatic in 3 studies (45 patients) was 0.58 (95%CI=0.27, 0.86), oral mucosa in 3 studies (32 patients) was 0.63 (95%CI=0.43, 0.81), musculoskeletal in 2 studies (9 patients) was 0.45 (95%CI=0.18,

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0.74), and pulmonary in 3 studies (12 patients) was 0.15 (95%CI=0, 0.50) (Figure 4A, 4B, 4C, and 4D). Heterogeneity between studies was moderate for cutaneous (I2=39%), oral mucosa (I2=34%), and pulmonary (I2=45%) GVHD and high for hepatic GVHD (I2=

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77%). There were too few studies for the outcomes of gastrointestinal and

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musculoskeletal GVHD to compute measure of heterogeneity. Harms

Any grade 3/4 adverse events For acute GVHD None of the included studies reported data on any grade 3/4 adverse events among patients with acute GVHD 9

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For chronic GVHD The pooled incidence of any grade 3/4 adverse events from 2 studies (53 patients)

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was 0.38 (95%CI= 0.06, 0.78) (24, 25). There were too few studies to estimate heterogeneity between studies. Seaton et al. reported severe complications in 5 of 28 subjects who received ECP for treatment of chronic GVHD: renal failure/sepsis=1, acute respiratory distress syndrome (ARDS) of unknown cause=1, pneumothorax/pleural

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effusion=1, ischemic heart disease=1, unspecified=1 (24). Moreover, Foss et al.

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described serious adverse events in 15 of 25 subjects treated with ECP, namely pneumonia=5, cytomegalovirus colitis=1, gastrointestinal bleeding=1, urosepsis=1, linerelated complications=2 (line sepsis=1, deep venous thrombosis=1), unspecified=5 (25). ECP-related mortality

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For acute GVHD 4 studies (45 patients) (22, 23, 28, 29) reported data on incidence of ECP-related mortality. No deaths were reported as a result of ECP use. Moreover, 4 studies (75 patients) reported data on incidence of ECP-related mortality for chronic

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GVHD (22-24, 28). One death on one study was attributed to sepsis and idiopathic ARDS, among other reasons (24). The other three studies reported no treatment related

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deaths among patients with chronic GVHD. Discontinuation of immunosuppressive therapy (ies) Acute GVHD

The pooled rate of discontinuation of immunosuppressive therapies, including corticosteroids, from 3 studies (36 patients) was 0.55 (95%ci=0.40, 0.70) (23, 28, 29)

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(Figure 5A). There was no heterogeneity between studies (I2=0%). These studies did not report the median time-to-discontinuation of immunosuppressive therapies.

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Chronic GVHD Similarly, the pooled rate of discontinuation of immunosuppressive therapies,

including corticosteroids, from 3 studies (54 patients) was 0.23 (95%CI=0.07, 0.44) (23,

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25, 28) (Figure 5B). The heterogeneity between studies was high (I2=68%). Again, these studies did not report the median time-to-discontinuation of immunosuppressive

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therapies.

LIMITATIONS

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We identified several limitations associated with this analysis. For instance, while all included studies referred to steroid-refractory or intolerant patients, the definition of these terms varied across the studies (see Appendix 2, Table 2). Moreover, there was a

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lack of uniform criteria when defining overall responses. Four of the studies included in this analysis defined overall response as 50% or greater response in at least one site or

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organ involved (23, 25, 26, 28). Other studies defined response in the presence of at least 50% improvement in clinical signs (29) or 50% or better improvement in measurable parameters of GVHD such as surface area involved, liver enzyme values, volume of diarrhea, or improvement in pulmonary function tests (22). Moreover, studies differed in regards to frequency, tapering schedule, and length of the prescribed ECP therapy (22, 24, 26, 27, 29, 41). Additional sensitivity or subgroup analyses could not be performed for assessment of heterogeneity due to small number of included studies. 11

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ECP can be performed with two different methods which differ in the context of mononuclear cell collection and UVA irradiation. For example, Therakos devices provide mononuclear cell collection with a discontinuous or continuous flow method and

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then UVA irradiation in one-step method (or in-line procedure). On the other hand, COBE devices are used for automated mononuclear cell collection, then UVA irradiation is operated manually (off-line procedure or two-step method). There have been no

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head-to-head comparisons of ECP methods, which pose a limitation when analyzing the

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data in aggregate.

DISCUSSION

This represents the first comprehensive systematic analysis of treatment outcomes

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of ECP in corticosteroid-refractory acute or chronic GVHD in both pediatric and adult population. Through the comprehensive literature search, we identified 9 studies including one RCT totaling over 300 subjects included in the analysis. We analyzed the

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outcomes of ECP treatment for both beneficial and harmful endpoints in acute and chronic GVHD, and data were summarized in pooled analyses. With the exception of 2

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single-arm studies (25, 28) which included 52 subjects with steroid-intolerant acute or chronic GVHD, the remaining 6 single-arm studies included 176 subjects only with steroid-refractory or steroid-dependent acute or chronic GVHD (22-24, 26, 27, 29). Unfortunately, it was not possible to ascertain specific outcomes for subjects treated for steroid-intolerant acute or chronic GVHD due to inability to determine the number of subjects treated for this particular indication or the corresponding post-ECP treatment

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outcomes. We found that ORR for steroid-refractory/dependent/intolerant acute GVHD in all organs approached 70% pooling 6 different studies. This pooled overall response rate is quite intriguing and appears favorable in comparison to other pharmacologic

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interventions commonly utilized in the setting of second-line systemic therapy for acute GVHD where no single treatment emerges as an accepted standard of care (21).

Our analysis highlights varying organ-specific responses in accordance with other

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studies which provide insights on most appropriate target organs for ECP therapy. With

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regard to acute GVHD, ECP appears particularly useful in skin GVHD with a pooled ORR of 0.84 (95%CI: 0.75-0.92) followed by gastrointestinal GVHD. A similar pattern of organ-specific response was observed in chronic GVHD. Of note, ECP therapy did not yield meaningful responses in chronic pulmonary GVHD.

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ECP was first established as a promising therapy for cutaneous T cell lymphoma (42), and the seminal work by Edelson et al. led to the FDA approval for this modality for this disease. ECP is an apheresis-based therapy where approximately 5 x 109

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transplant recipient leukocytes are treated with a photoactivatable 8-methoxypsoralen, followed by exposure to approximately 1.5 J/cm2 of UVA and reinfusion of treated

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leukocytes to recipients in a closed-loop system (43). ECP effectively induces cell death on most of the treated leukocytes within 24 to 48 hours (44, 45). Infusion of EPC-treated cells (i.e., apoptotic cells) in this context appears to be cleared by antigen presenting cells which apparently leads to immune modulation and immune tolerance induction (43). There are several potential mechanisms of tolerance induction by apoptotic cells in GVHD reviewed by Peritt et al. including inhibition of proinflammatory cytokines, increased production of anti-inflammatory cytokines, suppressed effector T cell 13

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stimulation, elimination of effector T cells, and induction of regulatory T cells (43). Most recently, the induction of monocyte to dendritic cell maturation in the context of ECP was evaluated and the important role of dendritic cells in the mechanism of ECP is

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being increasingly recognized (33, 46).

ECP is an effective non-pharmacologic modality for patients with steroid-refractory GVHD with relatively low risk of infections and other toxicities as demonstrated in this

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analysis. ECP can be combined with other pharmacologic immunosuppression and a

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combination therapy may also offer potential for better GVHD control. Taken together, Blood and Marrow Transplant Clinical Trial Network (BMT CTN) originally designed a phase 2 randomized multicenter study evaluating the role of ECP + prednisone + sirolimus against the standard immunosuppressive therapy for glucocorticoids + calcineurin inhibitor for the upfront treatment of chronic GVHD (protocol 0801).

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Unfortunately, the ECP component of the trial was closed due to slow accrual (http://www.clinicaltrials.gov/ct2/show/NCT01106833). One important question remains unanswered in the transplant community whether the place for ECP may be expanded

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to an upfront treatment setting for GVHD. This will need to be addressed in future

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multicenter clinical trials.

Therapeutic Recommendations Based on our current systematic review of available evidence on prospective studies, the following recommendations regarding the use of ECP for patients with steroid-refractory GVHD may be considered in line with recommendations or guidelines set forth by professional societies (21, 47, 48). 14

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In adults as well as in the pediatric setting, ECP is an effective treatment modality for corticosteroid-refractory acute GVHD. ECP will likely be more beneficial to those with skin involvement. Treatment response for acute GVHD involving visceral organs may be

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expected in over half of patients. Of note, ECP’s steroid-sparing effects would be

desirable for these immunosuppressed patients and potentially preserving the putative graft-versus-tumor effect.

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For chronic GVHD, ECP can be considered for steroid-refractory disease in both adult and pediatric age groups. Organ-specific response appears to be higher in

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cutaneous, gastrointestinal, hepatic, and oral mucosa. Response in musculoskeletal chronic GVHD is expected to be less than 50% (though the number of treated patients for this particular indication is limited). Our analysis hints to a very limited role of ECP on pulmonary chronic GVHD (49).

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ECP is considered relatively safe with very limited toxicities. Careful patient assessment for eligibility to ECP procedure and close monitoring while on ECP therapy by transfusion medicine and/or transplant physicians is still required. Particular attention

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is necessary considering the rapidly changing clinical status of GVHD patients, focusing on hemodynamic compromise and renal functions. Hematologic parameters including

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anemia and thrombocytopenia ought to be optimized with transfusions support prior to initiation of therapy.

There is no consensus on the optimal ECP schedule. A commonly used schedule may start with three times per week, and then decrease frequency to a twice a week schedule as tolerated. For responders, it may be continued twice per week every 2 to 4

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weeks until maximum response. Following the usual clinical practice, GVHD response should be assessed weekly for acute GVHD and every 1-2 months for chronic GVHD.

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CONCLUSION

ECP is an effective therapeutic modality for corticosteroid-refractory acute and

chronic GVHD. It yields varying organ-specific responses favoring cutaneous, followed

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by gastrointestinal and hepatic. Favorable safety profiles of ECP allow its applicability to immunosuppressed allograft recipients. ECP appears to facilitate reduction of

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pharmacologic immunosuppression including corticosteroids. Further research is needed to elucidate the precise mechanism of ECP and to improve treatment

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outcomes.

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Table 1. Characteristics of single-arm included studies

Smith et al. 1998

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Patient age (years) Median (range) 29 (5.7-53)

Primary disease

Donor source

GVHD Type

Organ(s)

CML, acute leukemia, aplastic anemia, MDS

MRD= 17

Acute=6

Various

Mismatched related donor=1

Chronic=18

23

10.3 (5.4-18.1)

Leukemia, thalassemi a major, severe aplastic anemia

MRD=12 Mismatched related donor=1

28

34 (18-51)

AML, ALL, CML, MM

MRD=19

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Seaton et al. 2003

25

42 (18-59)

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MUD=9

Foss et al. 2005

AML, ALL, CLL, CML, NHL

Acute grade III-IV=9

MRD=17

Steroid refractory GVHD†

Immunothera py prior to ECP

ECP treatment

CSA, ATG, PUVA

ECP system: TherakosUvar XTS

Regimen: aGVHD: received 2-3 procedures/week

Various

Steroid refractory GVHD†

CSA, TAC, THAL,PUVA, azathioprine

Chronic Limited=1 Extensive=27

Chronic Extensive=25

Various

Various

Steroid refractory GVHD†

MMF, MTX, CSA, TAC, CTX, PUVA, azathioprine

Steroid refractory or steroid intolerant†

MMF, CSA, TAC, pentostatin, plaquenil

Steroid refractory or

MMF, MTX, CSA, TAC,

MUD=8

Garban et al. 2005

27

aGVHD: 40 (23-63)

AML, acute

MRD=21

Acute grade III-IV=12

17

Various

cGVHD: initially received 2 consecutive procedures every 3 weeks; then intensified to 23/week ECP system: Cobe Spectra Regimen: aGVHD: 3 times/week, responding pts treated with 2 consecutive days at 2 week intervals x 3 months

Chronic Limited=2 Extensive= 12

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MUD=10

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MUD=6

Salvaneschi et al. 2001

Criteria for ECP initiation

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Total N

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Study, year

cGVHD: 2 consecutive days at 2 week intervals x 3 months ECP system: TherakosUvar XTS Regimen: cGVHD: 2 consecutive days every 2 weeks x 4 months then monthly ECP system: TherakosUvar XTS Regimen: cGVHD: 2 consecutive days every 2 weeks or once per week ECP system: Cobe Spectra

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59

40 (21-60)

MUD=6

steroid resistant†

Chronic Extensive= 15

Not reported

Acute grade II-IV=59

Various

chlorambucil

Steroid refractory or dependent GVHD

CSA

Steroid refractory or steroid intolerant GVHD†

MMF, pentostatin, inolimomab, RTX, TAC, THAL, azathioprine, infliximab, monoclonal Ab Not reported

Calore et al. 2008

27

15

14 (4-18)

9.6 (1.4-18.1)

AML, ALL, CML, severe aplastic anemia, NHL, other

Not reported

AML, ALL, NHL

MRD=9

Acute grade II-IV=12

Various

Chronic Limited=3 Extensive= 12

Acute grade II-IV= 15

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Kanold et al. 2007

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Greinix et al. 2006

leukemia, CML, MDS, MM, Fanconi’s anemia, solid tumor AML, ALL, CML, other

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cGVHD: 45 (14-62)

Various

95^

41 (16-67)^^

AML, ALL, CML, NHL, others

Related=31

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Flowers et al. 2008

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Mismatched =6

Unrelated=17

Chronic GVHD Limited=3 Extensive=45

Various

Steroid refractory or dependent GVHD or viral reactivation (EBV or CMV)**

Steroid refractory or dependent or intolerant

MMF, CSA, TAC

Regimen: 6 courses within 3 weeks, after 3 weeks treatment stopped if complete or no response, and continue 1 course per week if partial response ECP system: TherakosUvar XTS Regimen: aGVHD: 2 consecutive days every 1 to 2 weeks until improvement. In first 21 patients reduces to every 2 to 4 weeks until maximum response ECP system: Cobe Spectra Regimen: As per Andreu et al. (41)

ECP system: Cobe Spectra

Regimen: aGVHD: 2 consecutive days every week for the first month, every 2 weeks for the second and third month then monthly for at least 3 months ECP system: TherakosUvar Regimen: 3 times during week 1, then twice weekly (weeks 212. If response, continue 2 treatments every 4 weeks till week 24

Abbreviations: Ab, antibody; aGVHD, acute graft-versus-host disease; AML, acute myeloid leukemia; ALL, acute lymphoid leukemia; ATG, Antithymocyte globulin; cGVHD, chronic graft-versus-host disease; CLL, chronic lymphocytic leukemia ;CML, chronic myeloid leukemia; CSA, cyclosporine A; CTX,

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cyclophosphamide; ECP, extracorporeal photopheresis; GVHD, graft-versus-host disease; NHL, non-Hodgkin lymphoma; MDS, myelodysplastic syndrome; MM, multiple myeloma; MMF, mycophenolate mofetil; MRD: matched-related donors; MTX, methotrexate; MUD: matched-unrelated donors; PUVA, psoralen + UVA; RTX, Rituximab; TAC, Tacrolimus; THAL, thalidomide; EBV, Epstein-Barr virus; CMV, cytomegalovirus.

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** Study also reports on 16 acute GVHD patients with good response to steroids not included in this analysis ^ 48 received standard therapy plus ECP and 47 received standard therapy alone ^^patients who received ECP † might have received other therapies besides steroids prior to initiation of ECP

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LEGENDS FOR FIGURES: Figure 1. PRISMA flow diagram Abbreviations: ECP, extracorporeal photopheresis; GVHD, graft-versus-host disease; RCT,

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randomized controlled trial

Abbreviation: GVHD, graft-versus-host disease

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Figure 2. Overall response after ECP in acute (2A) and chronic (2B) GVHD

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Figure 3. Acute GVHD organ-specific response (cutaneous (A), gastrointestinal (B), and hepatic (C))

Abbreviation: GVHD, graft-versus-host disease

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Figure 4. Chronic GVHD organ-specific response (cutaneous (A), gastrointestinal (B), hepatic (C), and oral mucosa (D)

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Abbreviation: GVHD, graft-versus-host disease

Figure 5. Discontinuation of immunosuppressive therapy(ies) in acute (5A) and chronic

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(5B) GVHD

Abbreviation: GVHD, graft-versus-host disease

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REFERENCES

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1. van Besien K. Allogeneic transplantation for AML and MDS: GVL versus GVHD and disease recurrence. Hematology Am Soc Hematol Educ Program 2013;2013:56-62. 2. Kharfan-Dabaja MA, Bazarbachi A. Hematopoietic stem cell allografting for chronic lymphocytic leukemia: a focus on reduced-intensity conditioning regimens. Cancer Control 2012;19:68-75. 3. Kunter G, Perkins JB, Pidala J, et al. Pharmacokinetically-targeted BU and fludarabine as conditioning before allogeneic hematopoietic cell transplantation for adults with ALL in first remission. Bone Marrow Transplant 2014;49:11-16. 4. Ayas M, Nassar A, Hamidieh AA, et al. Reduced intensity conditioning is effective for hematopoietic SCT in dyskeratosis congenita-related BM failure. Bone Marrow Transplant 2013;48:1168-1172. 5. Matos-Fernandez NA, Abou Mourad YR, Caceres W, Kharfan-Dabaja MA. Current status of allogeneic hematopoietic stem cell transplantation for paroxysmal nocturnal hemoglobinuria. Biol Blood Marrow Transplant 2009;15:656-661. 6. Peffault de Latour R, Porcher R, Dalle JH, et al. Allogeneic hematopoietic stem cell transplantation in Fanconi anemia: the European Group for Blood and Marrow Transplantation experience. Blood 2013;122:4279-4286. 7. Bacigalupo A, Socie G, Lanino E, et al. Fludarabine, cyclophosphamide, antithymocyte globulin, with or without low dose total body irradiation, for alternative donor transplants, in acquired severe aplastic anemia: a retrospective study from the EBMT-SAA Working Party. Haematologica 2010;95:976-982. 8. Przepiorka D, Weisdorf D, Martin P, et al. 1994 Consensus Conference on Acute GVHD Grading. Bone Marrow Transplant 1995;15:825-828. 9. Filipovich AH, Weisdorf D, Pavletic S, et al. National Institutes of Health consensus development project on criteria for clinical trials in chronic graft-versus-host disease: I. Diagnosis and staging working group report. Biol Blood Marrow Transplant 2005;11:945-956. 10. Deeg HJ. How I treat refractory acute GVHD. Blood 2007;109:4119-4126. 11. Lee SJ, Flowers ME. Recognizing and managing chronic graft-versus-host disease. Hematology Am Soc Hematol Educ Program 2008:134-141. 12. Anasetti C, Logan BR, Lee SJ, et al. Peripheral-blood stem cells versus bone marrow from unrelated donors. N Engl J Med 2012;367:1487-1496. 13. Allogeneic peripheral blood stem-cell compared with bone marrow transplantation in the management of hematologic malignancies: an individual patient data meta-analysis of nine randomized trials. J Clin Oncol 2005;23:5074-5087. 14. Jagasia M, Arora M, Flowers ME, et al. Risk factors for acute GVHD and survival after hematopoietic cell transplantation. Blood 2012;119:296-307. 15. Flowers ME, Inamoto Y, Carpenter PA, et al. Comparative analysis of risk factors for acute graft-versus-host disease and for chronic graft-versus-host disease according to National Institutes of Health consensus criteria. Blood 2011;117:3214-3219. 16. Mielcarek M, Storer BE, Boeckh M, et al. Initial therapy of acute graft-versus-host disease with low-dose prednisone does not compromise patient outcomes. Blood 2009;113:2888-2894. 17. Pidala J, Anasetti C. Glucocorticoid-refractory acute graft-versus-host disease. Biol Blood Marrow Transplant 2010;16:1504-1518.

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18. Kharfan-Dabaja MA, Mhaskar AR, Djulbegovic B, Cutler C, Mohty M, Kumar A. Efficacy of rituximab in the setting of steroid-refractory chronic graft-versus-host disease: a systematic review and meta-analysis. Biol Blood Marrow Transplant 2009;15:1005-1013. 19. Pidala J, Kim J, Roman-Diaz J, et al. Pentostatin as rescue therapy for glucocorticoidrefractory acute and chronic graft-versus-host disease. Ann Transplant 2010;15:21-29. 20. Hoda D, Pidala J, Salgado-Vila N, et al. Sirolimus for treatment of steroid-refractory acute graft-versus-host disease. Bone Marrow Transplant 2010;45:1347-1351. 21. Martin PJ, Rizzo JD, Wingard JR, et al. First- and second-line systemic treatment of acute graft-versus-host disease: recommendations of the American Society of Blood and Marrow Transplantation. Biol Blood Marrow Transplant 2012;18:1150-1163. 22. Smith EP, Sniecinski I, Dagis AC, et al. Extracorporeal photochemotherapy for treatment of drug-resistant graft-vs.-host disease. Biol Blood Marrow Transplant 1998;4:27-37. 23. Salvaneschi L, Perotti C, Zecca M, et al. Extracorporeal photochemotherapy for treatment of acute and chronic GVHD in childhood. Transfusion 2001;41:1299-1305. 24. Seaton ED, Szydlo RM, Kanfer E, Apperley JF, Russell-Jones R. Influence of extracorporeal photopheresis on clinical and laboratory parameters in chronic graft-versus-host disease and analysis of predictors of response. Blood 2003;102:1217-1223. 25. Foss FM, DiVenuti GM, Chin K, et al. Prospective study of extracorporeal photopheresis in steroid-refractory or steroid-resistant extensive chronic graft-versus-host disease: analysis of response and survival incorporating prognostic factors. Bone Marrow Transplant 2005;35:11871193. 26. Garban F, Drillat P, Makowski C, et al. Extracorporeal chemophototherapy for the treatment of graft-versus-host disease: hematologic consequences of short-term, intensive courses. Haematologica 2005;90:1096-1101. 27. Greinix HT, Knobler RM, Worel N, et al. The effect of intensified extracorporeal photochemotherapy on long-term survival in patients with severe acute graft-versus-host disease. Haematologica 2006;91:405-408. 28. Kanold J, Merlin E, Halle P, et al. Photopheresis in pediatric graft-versus-host disease after allogeneic marrow transplantation: clinical practice guidelines based on field experience and review of the literature. Transfusion 2007;47:2276-2289. 29. Calore E, Calo A, Tridello G, et al. Extracorporeal photochemotherapy may improve outcome in children with acute GVHD. Bone Marrow Transplant 2008;42:421-425. 30. Flowers ME, Apperley JF, van Besien K, et al. A multicenter prospective phase 2 randomized study of extracorporeal photopheresis for treatment of chronic graft-versus-host disease. Blood 2008;112:2667-2674. 31. Alcindor T, Gorgun G, Miller KB, et al. Immunomodulatory effects of extracorporeal photochemotherapy in patients with extensive chronic graft-versus-host disease. Blood 2001;98:1622-1625. 32. Goussetis E, Varela I, Tsirigotis P. Update on the mechanism of action and on clinical efficacy of extracorporeal photopheresis in the treatment of acute and chronic graft versus host disease in children. Transfus Apher Sci 2012;46:203-209. 33. Edelson RL. Mechanistic insights into extracorporeal photochemotherapy: Efficient induction of monocyte-to-dendritic cell maturation. Transfus Apher Sci 2013. 34. Couriel DR, Hosing C, Saliba R, et al. Extracorporeal photochemotherapy for the treatment of steroid-resistant chronic GVHD. Blood 2006;107:3074-3080. 35. Higgins JPT AD, Sterne JAC. Chapter 8: Assessing risk of bias in included studies. . In: Higgins JPT GS, ed. Cochrane Handbook for Systematic Reviews of Interventions Version 510: The Cochrane Collaboration; 2011. 36. Wells GA SB, O'Connell D, Peterson J, Welch V, Losos M, Tugwell P. The NewcastleOttawa Scale (NOS) for assessing the quality if nonrandomized studies in meta-analyses.; 2013. 22

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37. DerSimonian R, Laird N. Meta-analysis in clinical trials. Control Clin Trials 1986;7:177188. 38. Stuart A, Ord K. Kendall's advanced theory of statistics: Wiley; 1994. 39. StatsDirectLtd. StatsDirect statistical software. England; 2011. 40. Moher D, Liberati A, Tetzlaff J, Altman DG. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. Bmj 2009;339:b2535. 41. Andreu G, Leon A, Heshmati F, et al. Extracorporeal photochemotherapy: evaluation of two techniques and use in connective tissue disorders. Transfus Sci 1994;15:443-454. 42. Edelson R, Berger C, Gasparro F, et al. Treatment of cutaneous T-cell lymphoma by extracorporeal photochemotherapy. Preliminary results. N Engl J Med 1987;316:297-303. 43. Peritt D. Potential mechanisms of photopheresis in hematopoietic stem cell transplantation. Biol Blood Marrow Transplant 2006;12:7-12. 44. Maeda A, Schwarz A, Kernebeck K, et al. Intravenous infusion of syngeneic apoptotic cells by photopheresis induces antigen-specific regulatory T cells. J Immunol 2005;174:59685976. 45. Lamioni A, Parisi F, Isacchi G, et al. The immunological effects of extracorporeal photopheresis unraveled: induction of tolerogenic dendritic cells in vitro and regulatory T cells in vivo. Transplantation 2005;79:846-850. 46. Berger C, Hoffmann K, Vasquez JG, et al. Rapid generation of maturationally synchronized human dendritic cells: contribution to the clinical efficacy of extracorporeal photochemotherapy. Blood 2010;116:4838-4847. 47. Pierelli L, Perseghin P, Marchetti M, et al. Extracorporeal photopheresis for the treatment of acute and chronic graft-versus-host disease in adults and children: best practice recommendations from an Italian Society of Hemapheresis and Cell Manipulation (SIdEM) and Italian Group for Bone Marrow Transplantation (GITMO) consensus process. Transfusion 2013;53:2340-2352. 48. Wolff D, Schleuning M, von Harsdorf S, et al. Consensus Conference on Clinical Practice in Chronic GVHD: Second-Line Treatment of Chronic Graft-versus-Host Disease. Biol Blood Marrow Transplant 2011;17:1-17. 49. Lucid CE, Savani BN, Engelhardt BG, et al. Extracorporeal photopheresis in patients with refractory bronchiolitis obliterans developing after allo-SCT. Bone Marrow Transplant 2011;46:426-429.

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Literature search of PubMed and Cochrane library

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(N=378)

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Excluded (N=330) 244 - Not a clinical study 26 - Not involving ECP 42 - Did not enroll patients with steroid refractory GVHD 18 - Other

Full text review

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(N=48)

Studies included in systematic review 1 RCT 8 Single-arm studies

Figure 1. PRISMA flow diagram

Excluded (N=39) 7 - Not a clinical study 2 - Not involving ECP 11 - Duplicate publication of included studies 13 - Retrospective 6 - Less than 5 patients with steroid refractory/intolerant-GVHD

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Smith, 1998

0.00 (0.00, 0.46) 0.78 (0.40, 0.97)

Smith, 1998

0.33 (0.13, 0.59)

Salvaneschi, 2001

0.64 (0.35, 0.87)

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Salvaneschi, 2001

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Proportion meta-analysis plot [random effects]

Proportion meta-analysis plot [random effects]

0.75 (0.43, 0.95)

Kanold, 2007

0.83 (0.52, 0.98)

Garban, 2005

0.87 (0.60, 0.98)

Calore 2008

1.00 (0.78, 1.00)

Kanold, 2007

0.73 (0.45, 0.92)

combined

0.64 (0.47, 0.79)

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Garban, 2005

combined 0.00

0.25 0.50 0.75 1.00 proportion (95% confidence interval)

0.0

2B.

0.64 (0.43, 0.82)

0.2

0.4 0.6 0.8 1.0 proportion (95% confidence interval)

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2A.

0.69 (0.34, 0.95)

Foss 2005

Figure 2: Overall response after ECP in acute (2A) and chronic (2B) GVHD

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Proportion meta-analysis plot [random effects]

Proportion meta-analysis plot [random effects]

0.89 (0.52, 1.00)

Salvaneschi, 2001

0.60 (0.15, 0.95)

Garban, 2005

0.75 (0.43, 0.95)

Garban, 2005

0.60 (0.15, 0.95)

Greinix 2006

0.80 (0.67, 0.89)

Greinix 2006

Kanold, 2007

1.00 (0.69, 1.00)

Kanold, 2007

Calore 2008

0.92 (0.64, 1.00)

Calore 2008

0.71 (0.42, 0.92)

combined

0.84 (0.75, 0.92)

combined

0.65 (0.52, 0.78)

0.6 0.8 1.0 1.2 proportion (95% confidence interval)

Proportion meta-analysis plot [random effects]

0.333 (0.008, 0.906)

Garban, 2005

0.000 (0.000, 0.842)

Greinix 2006

0.609 (0.385, 0.803)

Kanold, 2007

0.667 (0.299, 0.925)

0.00

3C.

0.2

0.83 (0.36, 1.00)

0.4 0.6 0.8 1.0 proportion (95% confidence interval)

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1.000 (0.025, 1.000)

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combined

0.0

3B.

0.60 (0.32, 0.84)

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Salvaneschi, 2001

Calore 2008

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0.4

3A.

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Salvaneschi, 2001

0.546 (0.350, 0.735)

0.25 0.50 0.75 1.00 proportion (95% confidence interval)

Figure 3: Acute GVHD organ-specific response (cutaneous (3A), gastrointestinal (3B), and Hepatic (3C))

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Proportion meta-analysis plot [random effects] Salvaneschi, 2001

Proportion meta-analysis plot [random effects]

0.83 (0.52, 0.98) 0.52 (0.30, 0.74)

Foss 2005

0.80 (0.59, 0.93)

Kanold, 2007

0.75 (0.43, 0.95)

combined

0.71 (0.57, 0.84)

Kanold, 2007

0.833 (0.359, 0.996)

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Seaton 2003

0.333 (0.008, 0.906)

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Foss 2005

0.0

0.2

4A.

0.4 0.6 0.8 1.0 proportion (95% confidence interval)

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combined

Proportion meta-analysis plot [random effects]

0.67 (0.30, 0.93)

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Salvaneschi, 2001

0.32 (0.15, 0.54)

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Seaton 2003

0.82 (0.48, 0.98)

combined 0.0

4C.

0.2

0.4

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Kanold, 2007

0.6

0.8

0.58 (0.27, 0.86)

0.0

4B.

0.2

0.4

0.6

0.8

1.0

proportion (95% confidence interval)

Proportion meta-analysis plot [random effects]

Salvaneschi, 2001

0.67 (0.35, 0.90)

Foss 2005

0.46 (0.19, 0.75)

Kanold, 2007

0.86 (0.42, 1.00)

combined

1.0

proportion (95% confidence interval)

0.619 (0.211, 0.944)

0.0

4D.

0.63 (0.43, 0.81) 0.2

0.4

0.6

0.8

1.0

proportion (95% confidence interval)

Figure 4: Chronic GVHD organ-specific response (cutaneous (4A), gastrointestinal (4B), Hepatic (4C), and oral mucosa (4D))

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Proportion meta-analysis plot [random effects]

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Proportion meta-analysis plot [random effects]

Salvaneschi, 2001

0.44 (0.14, 0.79)

Kanold, 2007

0.50 (0.21, 0.79)

Calore 2008

0.67 (0.38, 0.88)

Kanold, 2007

0.20 (0.04, 0.48)

combined

0.55 (0.40, 0.70)

combined

0.23 (0.07, 0.44)

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Foss 2005

5B.

0.0

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0.43 (0.18, 0.71)

0.08 (0.01, 0.26)

0.2 0.4 0.6 0.8 proportion (95% confidence interval)

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5A.

0.3 0.6 0.9 proportion (95% confidence interval)

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0.0

Salvaneschi, 2001

Figure 5: Discontinuation of immunosuppressive therapy (ies) in acute (5A) and chronic (5B) GVHD

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Appendix 1. Search strategy Dates of search: form inception to 05 March 2013 MEDLINE via PubMed

#1 "Photopheresis"[Mesh]

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#2 "Photochemotherapy"[Mesh] #3 "PUVA Therapy"[Mesh] #4 Photophere* #5 photochemo*

#7 (#1 OR #2 OR #3 OR #4 OR #5 OR #6) => treatment search #8 "Graft vs Host Disease"[Mesh]

#10 Graft versus Host #11 Graft v Host #12 GVHD #13 runt diseas* #14 homologous wasting diseas*

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#9 Graft vs Host

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#6 puva therapy

#15 (#8 OR #9 OR #10 OR #11 OR #12 OR #13 OR #14) => disease search

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#16 (#7 AND #15) => Final search strategy Cochrane CENTRAL

#1 MeSH descriptor: [Photopheresis]

#2 MeSH descriptor: [Photochemotherapy]

#4 photochemo* #5 puva therapy

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#3 Photophere*

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#6 #1 OR #2 OR #3 OR #4 OR #5 => treatment search #7 MeSH descriptor: [Graft vs Host Disease] #8 Graft vs Host

#9 Graft versus Host #10 Graft v Host #11 GVHD

#12 runt diseas* #13 homologous wasting diseas* #14 #8 OR #9 OR #10 OR #11 OR #12 OR #13 => disease search #15 #6 AND #14 => Final search strategy

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Appendix 2.

Table 1. Methodological quality of included studies

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Randomized controlled trials

Unclear

Attrition bias minimized Yes

Reporting bias minimized Yes

Detection bias minimized Yes Unclear Unclear Unclear Unclear Unclear Unclear Unclear

Follow-up time appropriate Unclear Yes Yes Yes Unclear Yes Yes Yes

Attrition bias minimized Yes Yes Yes Yes Yes Yes Yes Yes

Random sequence generation

Allocation concealment

Performance bias

Detection bias

Yes

Unclear

Unclear

Study

Representativeness of study sample

Ascertainment of exposure

Smith, 1998 Salvaneschi, 2001 Seaton, 2003 Foss, 2005 Garban, 2005 Greinix, 2006 Kanold, 2007 Calore, 2008

Yes No Yes No Yes No No No

Yes Yes Yes Yes Yes Yes Yes Yes

Demonstration outcome was not present at start Yes Yes Yes Yes Yes Yes Yes Yes

Study Flowers, 2008

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Non-comparative studies

Table 2. Definition of steroid-refractory graft versus host disease (GVHD) used in included studies

Smith, 1998 Salvaneschi, 2001 Seaton, 2003

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Foss, 2005

Definition Patients with GVHD who fail to respond to standard drug therapy with steroids, cyclosporine, monoclonal antibodies, and Antithymocyte globulin Not defined Patients refractory to conventional immunosuppressive treatment Refractory disease after being treated with steroids, cyclosporine A, tacrolimus, and/or mycophenolate mofetil Refractory to corticosteroids (2-3 mg/kg/day of prednisone for a minimum 5 days associated with either cyclosporine or cyclosporine + Mycophenolate mofetil) Not defined Absence of clinical and biologic improvement after at least 7 days of conventional treatment for acute GVHD or 2 months for chronic GVHD; or severe acute or chronic GVHD responding to treatment but with intolerance, as assessed on a case-by-case basis by a physician Patients experiencing a flare-up of acute GVHD during the tapering of methylprednisolone Lack of response or disease progression after at least 1 mg/kg of methylprednisolone equivalent

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Study

Garban, 2005 Greinix, 2006

Kanold, 2007

Calore, 2008 Flowers, 2008

Extracorporeal photopheresis in steroid-refractory acute or chronic graft-versus-host disease: results of a systematic review of prospective studies.

Acute and chronic graft-versus-host disease (GVHD) remain major obstacles for successful allogeneic hematopoietic cell transplantation. Extracorporeal...
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