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Extracorporeal photopheresis versus alternative treatment for chronic graft-versus-host disease after haematopoietic stem cell transplantation in paediatric patients

  1. Marcus Weitz1,*,
  2. Brigitte Strahm2,
  3. Joerg J Meerpohl3,
  4. Dirk Bassler4

Editorial Group: Cochrane Childhood Cancer Group

Published Online: 25 FEB 2014

Assessed as up-to-date: 11 MAR 2013

DOI: 10.1002/14651858.CD009898.pub2


How to Cite

Weitz M, Strahm B, Meerpohl JJ, Bassler D. Extracorporeal photopheresis versus alternative treatment for chronic graft-versus-host disease after haematopoietic stem cell transplantation in paediatric patients. Cochrane Database of Systematic Reviews 2014, Issue 2. Art. No.: CD009898. DOI: 10.1002/14651858.CD009898.pub2.

Author Information

  1. 1

    University of Tuebingen, Department of Pediatrics, Tübingen, Germany

  2. 2

    University Medical School Freiburg, Pediatric Hematology and Oncology Centre for Pediatrics and Adolescent Medicine, Freiburg, Germany

  3. 3

    Medical Center - University of Freiburg, German Cochrane Centre, Freiburg, Germany

  4. 4

    University Children's Hospital, Department of Neonatology, Tuebingen, Germany

*Marcus Weitz, Pediatric Nephrology, University Children's Hospital, Steinwiesstrasse 75, Zurich, 8032, Switzerland. marcus.weitz@kispi.uzh.ch.

Publication History

  1. Publication Status: New
  2. Published Online: 25 FEB 2014

SEARCH

 

Background

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. Contributions of authors
  12. Declarations of interest
  13. Differences between protocol and review
  14. Index terms
 

Description of the condition

Haematopoietic stem cell transplantation (HSCT) is a curative treatment option for children with haematological malignancies, haemoglobinopathies, immune deficiencies and inborn errors of metabolism (Diaconescu 2005; Gaziev 2010; Kennedy-Nasser 2006; Peters 2003; Rappeport 2011; Walters 2000; Walters 2005). Chronic graft-versus-host disease (cGvHD) is considered one of the major complications following HSCT, limiting its wider application (Billingham 1966; Ferrara 2004; Sullivan 2004). cGvHD was traditionally defined by manifestation after 100 days following HSCT (Gilman 2000). Several advances in the practice of HSCT (including different haematopoietic stem cell sources, intensity of conditioning regimen, immunosuppression and donor lymphocyte infusions) resulted in a more time variable presentation of cGvHD (Bunin 2008; Eapen 2004). Presently, cGvHD is described according to its pattern of presentation: 1. following HSCT as a progression from acute graft-versus-host disease (aGvHD) (progressive form); 2. as a recurrence after a disease-free interval (quiescent form); and 3. without a history of aGvHD (de novo form) (Shulman 1988). The US National Institutes of Health (NIH) developed a diagnosis and scoring system defining cGvHD based on specific clinical signs and histopathology rather than time of onset after HSCT (Filipovich 2005; Jagasia 2009). The NIH global severity score uses the numerical scoring system for individual organs to calculate a summary scale according to the number and severity of organs involved. This provides a more clinically informative and discriminating severity measure for use in clinical trials and as an indicator of the need for systemic immunosuppressive treatment (Arai 2010).

The incidence of cGvHD varies between 6% and 65%, depending on the transplant procedure and disease-specific variables (Meisel 2007; Rocha 2000; Zecca 2002). Well-known risk factors for developing cGvHD are precedent aGvHD, stem cell donor, the preparative regimen, prophylactic procedures and the underlying disease (Flowers 2011; Rocha 2000; Zecca 2002). The exact pathogenesis of cGvHD remains unclear. Several studies demonstrated the role of T cells in the development of cGvHD (De Bueger 1993; Higman 2004; Mutis 1999). Increased levels of non-specific antibodies in people with cGvHD and response to B-cell-depleting antibodies suggest that B cells play a role (Allan 2007; Zhang 2006). Moreover, a co-ordinated T-cell B-cell interaction to minor histocompatibility alloantigens seems to account for the manifestation of cGvHD (Miklos 2005). Soluble inflammation-associated factors are also involved in the pathogenesis of cGvHD (Fujii 2008; Lin 2003). Other pathogenetic suggestions include a defective negative selection of autoreactive T cells due to thymic damage, aberrant production of transforming growth factor-beta and activation of platelet-derived growth factor receptor, as well as deficiency of CD8+ cells (Martin 2008; Toubai 2008). Clinical manifestations of cGvHD are separated into more inflammatory, acute type features (erythematous rash, mucositis, diarrhoea, transaminitis and pulmonary infiltrates) as opposed to more fibrotic, chronic characteristics (sclerotic and lichen planus-like skin changes, fasciitis, sicca syndrome, oesophageal strictures and bronchiolitis obliterans) (Flowers 2002; Higman 2004). The most commonly affected organs, isolated or in combination, are the skin and oral cavity, with over 70% involvement for both, followed by eyes, liver, lungs, gastrointestinal tract and musculoskeletal system (Atkinson 1990; Beredjiklian 1998; Chosidow 1992; Cooke 2009; Dudek 2003; Filipovich 2005; Janin 1994; Lee 2003; Melin-Aldana 2007; Pavletic 2005; Sullivan 1981; Treister 2005).

Both cGvHD and treatment of cGvHD lead to significant morbidity and mortality in children; however, outcome reports for cGvHD are mostly based on adult retrospective studies with a five-year overall survival rate of 60% to 90% in the low-risk range, 40% to 75% in the intermediate-risk range, and 10% to 60% in the high-risk range, using the previous grading and scoring system (Akpek 2003; Cahn 2005; Couriel 2006; Lee 2003; Shimada 2005). cGvHD accounts for 54% of deaths in adults two years after transplantation among the non-relapse-related deaths (Higman 2004; Horowitz 2004; Wingard 2002). The only available study with a larger cohort in children reports an overall six-year disease-free survival of 68% in the presence of cGvHD (Zecca 2002). According to reports in adults, immunosuppressive therapy is still required in 50% of people five years after the diagnosis of cGvHD (Stewart 2004).

 

Management options

As aGvHD also has a significant impact on the pathogenesis of cGvHD, prophylaxis to prevent GvHD plays a major role (Ram 2009). Prevention is based on T-cell inhibition including the following strategies: inhibition of T-cell activation and function (calcineurin inhibitor), inhibition of T-cell proliferation (methotrexate, mycophenolate mofetil) and elimination of T cells (alemtuzumab, anti-thymoglobulin) (Shah 2007; Storb 1986). The majority of children undergoing HSCT receive GvHD prophylaxis, starting before transplantation and typically continuing for up to six months after transplantation (Barrett 2008).

The clinical management of people with cGvHD is complicated due to the variability of disease manifestation, clinical course, infectious complications and treatment-related toxicity (Flowers 2002). Therefore, treatment of cGvHD in children is highly variable, and, due to lack of paediatric studies, mostly based on the experience in adults. In people with mild cGvHD and high-risk malignancies where a graft-versus-leukaemia effect gains importance, topical therapy should be considered (Filipovich 2005). Drug therapy for mild cGvHD mostly includes locally applied immunosuppressive agents (steroids and calcineurin inhibitors) for the affected organ (skin, eyes, oral cavity and lungs) (Jacobsohn 2010). In contrast, moderate-to-severe cGvHD is mostly treated with systemic steroids (Filipovich 2005; Salmasian 2010). Prednisone is usually tapered (alternate day) for the next two to three months (Sullivan 1988a). Some reports suggest better response rates and fewer corticosteroid complications when adding a calcineurin inhibitor (ciclosporin, tacrolimus) to systemic steroids (Koc 2002; Sullivan 1988b; Vogelsang 2001). Regarding the effect of corticosteroids on the growth and development of children and the mean duration of therapy of three years for people with cGvHD, the management of a daily calcineurin inhibitor with alternate day prednisone is considered standard for the treatment of cGvHD (Koc 2002; Sullivan 1988a). This therapeutic regimen yielded an objective response in more than 50% of people (Sullivan 1988a; Sullivan 1988b).

In cases where there is no response to therapy within four weeks, second-line treatment is mostly considered (Jacobsohn 2010). There are various salvage therapies including general immunosuppressants (mycophenolate mofetil, methotrexate, sirolimus, thalidomide, pentostatin and hydroxychloroquine) and monoclonal antibodies (rituximab) (Akpek 2001; Bolanos-Meade 2008; Busca 2000; Cutler 2006; Fraser 2007; Gilman 2006; Goldberg 2003; Jacobsohn 2009; Johnston 2005; Lopez 2005; Martin 2009; Mookerjee 1999; Vogelsang 1992).

 

Description of the intervention

Extracorporeal photopheresis (ECP), an immunomodulatory therapy, may play a role in the treatment of cGvHD. During ECP, peripheral mononuclear cells are collected ex vivo by leukapheresis, incubated with the photoactive and photosensitising drug 8-methoxypsoralen (8-MOP), exposed to ultraviolet-A (UV-A) light and then re-infused into the patient without any side effects to other organs (Bethea 1999; Girardi 2002; Heald 1989). Psoralen occurs naturally in the seeds of the furocoumarin family of plants and its exposure to UV-A light (wavelength 200 to 350 nm) facilitates the intercalation of psoralen with deoxyribonucleic acid (DNA), leading to the formation of both monofunctional and bifunctional adducts, which results in programmed cell death (apoptosis) of the majority of cells (Yoo 1996). Initially, the patients received psoralen orally prior to the leukapheresis (Bethea 1999). However, the oral application results in an inconstant absorption of the drug and considerable gastrointestinal side effects (Brickl 1984). The now generally used ex vivo method, with the incubation of the collected cells in a bag, significantly reduces the exposure of the patient to 8-MOP (Schooneman 2003).

ECP has been successfully applied in the treatment of cutaneous T-cell lymphoma since the 1980s (Edelson 1987). Following this observation, the method has been implemented for a wider spectrum of immunologically mediated diseases such as systemic scleroderma, autoimmune disorders, solid organ rejection, and acute and chronic GvHD (Szodoray 2010). In the paediatric setting, many authors report a response rate of 33% to 93% to ECP as second-line treatment in steroid-resistant cGvHD (Foss 2005; Messina 2003; Smith 1998; Sniecinski 1994). People with steroid-refractory cGvHD that responds to ECP have a higher five-year survival rate compared with non-responders (96% versus 85%) (Perotti 2010). Adverse reactions are uncommon (less than 0.003%), transient and mild (nausea, hypotension, dizziness, cytopenia, skin infection at site of venous access and abnormal clotting to heparin) (Kanold 2003). Moreover, ECP is not associated with increased risk of systemic infections and relapse of malignant disease (Dall'Amico 2002; Hackstein 2009; Scarisbrick 2008).

 

How the intervention might work

The mechanisms of action of ECP are not completely understood. It has been shown that the procedure induces apoptosis in mononuclear white blood cells (Voss 2010). However, only a small percentage of the peripheral mononuclear cells is treated and, therefore, an immunomodulatory effect of the apoptotic cells is hypothesised (Heshmati 2003). One suspected mechanism is that apoptotic T-cell fragments presented by dendritic cells induce an anti-idiotypic T-suppressor activity, or downregulate a pre-existing T-cell response, and in this way generate a tolerogenic response and modulate cytokine production (Bladon 2006; Legitimo 2007; Xia 2009). In summary, the postulated mechanisms involved include 1. reduced stimulation of effector T cells, 2. deletion of effector T cells, 3. induction of regulatory T cells, 4. increase of anti-inflammatory cytokines (i.e. tumour necrosis factor-beta, interleukin-10), and 5. reduction of proinflammatory cytokines (interleukin-1beta, interleukin-6, and tumour necrosis factor-alpha) (Fimiani 2004). On the basis of this hypothesis, photopheresis seems to downregulate the T-cell alloreactivity that plays the central role in the pathogenesis of GvHD after HSCT (Lamioni 2005; Maeda 2005).

 

Why it is important to do this review

cGvHD remains one of the major challenges for transplant-related morbidity and mortality after stem cell transplantation in paediatric patients. All conventional therapies including established first-line therapy have considerable side effects and probably increase the risk of infections and relapse of malignant disease. Therefore, it is essential to develop new therapeutic approaches for the selective immune control of cGvHD without generalised immunosuppression-related complications (infections and pharmacological toxicity issues) (Wolff 2011).

ECP seems to be an effective immunomodulatory therapy with very mild, if any, side effects and, therefore, may be a promising alternative for improving morbidity and mortality in children with cGvHD.

 

Objectives

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. Contributions of authors
  12. Declarations of interest
  13. Differences between protocol and review
  14. Index terms

To evaluate the effectiveness and safety of ECP for the management of cGvHD in children and adolescents after HSCT.

 

Methods

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. Contributions of authors
  12. Declarations of interest
  13. Differences between protocol and review
  14. Index terms
 

Criteria for considering studies for this review

 

Types of studies

We intended to consider randomised controlled trials (RCTs) for this review if they assessed any clinical outcome as described in the Types of outcome measures section. For medical reasons (e.g. we did not consider cGvHD a stable condition), we aimed to include only trials with a parallel group design. We excluded studies restricted to adults (over 18 years of age). For studies including both children and adults, we planned to include studies if children represented more than 50% of participants in the study.

 

Types of participants

We planned to include children and adolescents under 18 years of age who underwent HSCT therapy with presence of cGvHD, independent of the underlying disease and donor source. We planned to consider all stages and grades of cGvHD, independent of the type of organ involvement.

 

Types of interventions

For the purpose of this review, we considered systemic steroids with or without calcineurin inhibitors as standard treatment as first-line therapy and considered all other treatment as second-line therapy of cGvHD.

The following comparisons for ECP for cGvHD after HSCT were conceivable.

  1. ECP versus standard treatment in paediatric patients with cGvHD as first-line treatment.
  2. ECP plus standard treatment versus standard treatment alone in paediatric patients with cGvHD as first-line treatment.
  3. ECP versus standard treatment in paediatric patients with steroid-/calcineurin-inhibitor-refractory cGvHD (second-line treatment).
  4. ECP plus standard treatment versus standard treatment alone in paediatric patients with steroid-/calcineurin-inhibitor-refractory cGvHD (second-line treatment).

These comparisons constituted four separate groups and we anticipated analysing them separately.

 

Types of outcome measures

 

Primary outcomes

  1. Response to ECP treatment (defined as either classical response rates (i.e. number of people in complete or partial remission) or percentage of achieved reduction in either NIH score (Filipovich 2005; Jagasia 2009), scales of Akpek and Lee (Akpek 2001; Lee 2003), or steroid-tapering under therapy with ECP (defined as number of people with at least 25% reduction in steroid dose).

 

Secondary outcomes

  1. Overall survival (defined as the time to death from any cause, starting at the day of HSTC).
  2. Failure-free survival (defined as progression of GvHD, expressed as change in NIH score or intensification of treatment, or both).
  3. Adverse events.
  4. Quality of life.
  5. Cost of intervention per month including length of hospital stay in days, number of outpatient attendances, direct medical resource use, direct medical costs, indirect medical resource use or costs and patient out-of-pocket expenses.

 

Search methods for identification of studies

We applied no language restrictions.

 

Electronic searches

We searched the following electronic databases: the Cochrane Central Register of Controlled Trials (CENTRAL) (Issue 9, 2012); MEDLINE/PubMed (1945 to 12 September 2012); and EMBASE (Ovid) (1980 to 12 September 2012).
The search strategies for the different electronic databases (using a combination of controlled vocabulary and text words) are shown in Appendix 1; Appendix 2; and Appendix 3.

 

Searching other resources

 

Conference proceedings

We did an electronic search of the conference proceedings of the following societies:

  • International Society for Paediatric Oncology (SIOP) (2007 to 2012).
  • American Society of Clinical Oncology (ASCO): Journal of Clinical Oncology (1995 to 2012).
  • American Society of Hematology (ASH): Blood (2001 to 2012).
  • American Society of Blood and Marrow Transplantation: Biology of Blood and Marrow Transplantation (1990 to 2012).
  • European Group for Blood and Marrow Transplantation (EBMT): Bone Marrow Transplantation (2000 to 2012).

We searched the reference lists of relevant articles and review articles.

 

Electronic search in databases of ongoing trials

We searched the following clinical trials registries for ongoing or recently completed trials, and for locating potential links to other related databases and resources on 12 September 2012.

We also contacted selected experts in the field to request information on unpublished studies that involved ECP in cGvHD.

 

Data collection and analysis

 

Selection of studies

One review author (MW) screened all titles and abstracts of the references identified by the search strategies for relevance. We only excluded citations that were clearly irrelevant at this stage. We considered citations as irrelevant that included only adults, were animal studies, did not describe cGvHD and that used stem cell sources other than haematopoietic. Two review authors (MW, DB) independently screened the remaining titles, excluded all irrelevant publications and recorded details of the studies together with the reasons for exclusion. We resolved any disagreement on the eligibility of studies through discussion and consensus. We obtained full-text versions of all potentially relevant papers. Two review authors (MW, DB) independently screened these manuscripts, identified potentially relevant studies and assessed eligibility of studies for inclusion. We resolved any disagreements on the eligibility of studies through discussion and consensus.

 

Data extraction and management

  1. We planned to extract data using a data extraction form developed by the review authors, and one of the review authors (MW) would transcribe the data into Review Manager 5 (RevMan 2011). Another review author (JM) was to verify all data entry for discrepancies. We planned to resolve any disagreement on data extraction and management issues through discussion and consensus, or if necessary through a third review author (DB or BS). We planned to request missing data from the original investigators.
  2. Two review authors (MW, JM) would have completed the 'Characteristics of included studies' table. Study characteristics would have included place of publication, date of publication, population characteristics, setting, detailed nature of intervention, detailed nature of comparator and detailed nature of outcomes. A key purpose of these data was to define unexpected clinical heterogeneity in included studies independently from analysis of results.
  3. Two review authors (MW, JM) intended to carefully record reasons why an included study did not contribute data on a particular outcome and to consider the possibility of selective reporting of results on particular outcomes.

 

Assessment of risk of bias in included studies

Two review authors (MW, DB) planned to assess independently each included study for risk of bias using the definitions for the different risk of bias items as stated in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011): random sequence generation, allocation concealment, blinding of participants and personnel, blinding of outcome assessment, incomplete outcome data, selective reporting and any other potential threats to validity (Higgins 2011; Kjaergard 2001; Moher 1998; Schulz 1995). We also planned to assess the risk of bias for blinding of outcome assessors and incomplete outcome data separately for each outcome. We aimed to consider a trial as having a low risk of bias if all domains were assessed as adequate. We planned to consider a trial as having a high risk of bias if one or more domain was assessed as inadequate or unclear. We wanted to report the 'Risk of bias' table as part of the table of 'Characteristics of included studies' table and present a 'Risk of bias' summary figure that would detail all of the judgements made for all included studies in the review (Higgins 2011). For each included study, we planned to assess selective reporting bias by comparing the methods and results section of the individual studies. We wanted to resolve any disagreements on the assessment of risk of bias through discussion and consensus, or if necessary through a third review author (JM or BS) and to explore the impact of the level of bias through undertaking sensitivity analyses (see Sensitivity analysis).

 

Measures of treatment effect

We planned to analyse extracted data using Review Manager 5 (RevMan 2011)

We planned to extract hazard ratios (HRs) with their 95% confidence intervals (CIs) for time-to-event outcomes, such as mortality. If HRs were not provided, we intended to use the indirect estimation methods described in Parmar 1998 and Williamson 2002 to calculate them. As an alternative, we intended to use the proportions of participants with the respective outcomes measured at certain time points to calculate risk ratios (RRs).

We planned to express results for binary outcomes as RRs with 95% CIs as measures of uncertainty. For continuous outcomes, we planned to express the results as mean differences (MDs), with 95% CIs as measures of uncertainty.

 

Unit of analysis issues

Since, for medical reasons, we only included parallel group randomised trials, unit of analysis issues related to cross-over and cluster randomised trials were not relevant for this systematic review. In the context of ECP, "body-part randomisation" and "body part analyses" did not make sense, so related issues do not need to be discussed here. In cases of parallel group designs with three or more treatment groups, we planned to divide the control group into several parts, so that the total number added up to the original size of the group.

 

Dealing with missing data

We planned to contact original investigators for missing data regarding study selection, data extraction and risk of bias assessment. To optimise the strategy for dealing with missing data, we intended to conduct an intention-to-treat analysis, which would have included all participants who did not receive the assigned intervention according to the protocol, as well as those who were lost to follow-up. If unsuccessful, we wanted to address the potential impact of missing data on the findings of the review in the 'Discussion' section.

 

Assessment of heterogeneity

We planned to assess statistical heterogeneity using the I2 statistic (Higgins 2002; Higgins 2003). This measure describes the percentage of total variation across studies that is caused by heterogeneity rather than by chance (Higgins 2003). The values of I2 lie between 0% and 100%. We planned to use a simplified categorisation of heterogeneity with the following categories: low (I2 less than 30%); moderate (I2 between 30% and 60%) and high (I2 more than 60%) (Deeks 2011).

If moderate or high heterogeneity had been detected, we intended to explore clinical heterogeneity by examining differences between groups as detailed below (Subgroup analysis and investigation of heterogeneity).

 

Assessment of reporting biases

We minimised the likelihood of publication bias by using a comprehensive search strategy without language restrictions and we also searched trial registries. In addition to the evaluation of reporting bias, as described in the Assessment of risk of bias in included studies section, we planned to assess reporting bias by constructing a funnel plot where a sufficient number of studies had been identified (i.e. at least 10 studies included in a meta-analysis). When there were fewer studies, the power of these tests would be too low to distinguish chance from real asymmetry (Sterne 2011).

 

Data synthesis

For future updates, we will conduct meta-analyses of pooled data from all contributing studies using Review Manager 5(RevMan 2011). We intended to use a fixed-effect model as primary analysis. If we had found high clinical, methodological or statistical heterogeneity (I2 more than 50%), we would, as a secondary analysis, have used a random-effects model and reported results from both models. We planned to summarise studies in cases where pooling of results was not possible.

 

Subgroup analysis and investigation of heterogeneity

We planned to assess clinical heterogeneity by examining differences due to:

  • underlying disease;
  • type of haematopoietic stem cell source;
  • age of children at HSCT;
  • age at start of ECP;
  • type of conditioning regimen;
  • type of GvHD prophylaxis regimen; and
  • degree of human leukocyte antigen (HLA) compatibility (matched sibling donor versus matched unrelated donor versus mismatched unrelated donor.

 

Sensitivity analysis

We planned to investigate the robustness of our results through a sensitivity analysis on the basis of risk of bias of the included studies by defining the following groups:

  • low risk of bias (adequate sequence generation and allocation concealment; successful blinding of all participants, care providers and outcome assessors; incomplete outcome data for less than 20% of participants; no selective reporting or other sources of bias);
  • high risk of bias (not adequate sequence generation and allocation concealment; not adequate blinding of all participants, care providers and outcome assessors; incomplete outcome data for more than 20% of participants; selective reporting or other sources of bias);
  • unclear risk of bias (rating of unclear risk of bias in at least one of these seven categories).

We intended to perform sensitivity analyses for each risk of bias item separately.

 

Results

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. Contributions of authors
  12. Declarations of interest
  13. Differences between protocol and review
  14. Index terms
 

Description of studies

See: Characteristics of excluded studies; Characteristics of ongoing studies tables.

 

Results of the search

We perfomed the search on 12 September 2012. The initial search yielded 68 articles including three duplicates in CENTRAL, MEDLINE/PubMed and EMBASE (Ovid) (Figure 1). After title and abstract screening, we excluded 53 of the unique articles, as the intervention was not ECP.

 FigureFigure 1. Identification of potentially eligible studies.

We screened 12 full texts but we found only one RCT. However, this RCT was not eligible for inclusion in the review (see Excluded studies). We found another 11 studies by searching the references of the full-texts articles. These additional articles were not eligible and were excluded following full-text screening. Reasons for exclusion were as follows:

  • 13 were case report/case series;
  • four were reviews reporting case reports/case series;
  • four were prospective, not randomised, not controlled clinical trials;
  • one was a retrospective case series;
  • one was an RCT including less than 50% of children.

The search of the trial registers and conference proceedings identified no eligible studies. We contacted two experts in the field, which did not yield any studies.

 

Included studies

We found no RCTs meeting the inclusion criteria for this review.

 

Excluded studies

We found one RCT, which we excluded since the study population did not meet our inclusion criteria (less than 50% were children with cGvHD). We excluded observational data from 21 non-randomised controlled trials/case series.

See: Characteristics of excluded studies table.

 

Risk of bias in included studies

We found no studies meeting the inclusion criteria for this review. For that reason, the assessment of risk of bias was not applicable.

 

Effects of interventions

We found no studies meeting the inclusion criteria for this review. For that reason the effectiveness and safety of ECP for the management of cGvHD in children and adolescents after HSCT remains unclear.

 

Discussion

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. Contributions of authors
  12. Declarations of interest
  13. Differences between protocol and review
  14. Index terms

cGvHD remains one of the major challenges for transplant-related morbidity and mortality after HSCT in paediatric patients. ECP represents an alternative second-line treatment option in paediatric patients with cGvHD after HSCT. However, there are no data from RCTs available to support or refute treatment with ECP in children with cGvHD after HSCT. Therefore, this systematic review cannot establish whether such a treatment is effective in paediatric patients with cGvHD after HSCT.

We limited the search strategy to children and adolescents under 18 years of age. However, we found one RCT that assessed the efficacy of ECP in cGvHD in mainly adults (> 50%). This randomised controlled, single-blinded trial investigated the effect of ECP on the cutaneous manifestation of cGvHD in people with failed corticosteroid treatment following HSCT (Flowers 2008). People were eligible in case of 1. corticosteroid refractoriness defined as lack of response or disease progression after administration of a least 1 mg/kg of methylprednisolone equivalent, 2. corticosteroid-dependency after more than 10 mg of methylprednisolone equivalent to control skin manifestation, and 3. corticosteroid intolerance due to intolerable adverse effects. Steroids had to be applied in a stable dose for at least two weeks prior to randomisation and had to be maintained on the same dose level for the first six study weeks (with the exception of reduction due to adverse side effects). Immunosuppressants such as tacrolimus, mycophenolate and ciclosporin A were accepted as concomitant medication if they had been introduced at least four weeks before randomisation. Discontinuation of these agents during the study period was only permitted for safety reasons. The primary objective of the study was the median percentage change of total skin score (TSS) at week 12 compared with the pretreatment value. Secondary objectives included 1. the proportion of participants with at least 25% improvement in TSS, 2. 50% or greater reduction in daily steroid dose compared with the baseline dose, or 3. improvement of at least 25% in TSS in conjunction with steroid-sparing at weeks 12 and 24. Skin assessments were performed on alternate weeks up to study week 12 and afterwards on alternate weeks up to study week 24. Participants were randomised with a block scheme in a 1:1 ratio to the conventional therapy arm (49 participants) or to the conventional therapy arm combined with ECP (50 participants). Conventional therapy consisted of corticosteroids and other immunosuppressive agents in refractory participants. ECP was administered three times during week one, and then twice weekly on consecutive days during weeks two to 12. Responding participants could continue ECP treatment until week 24 following the schedule of two treatments every week. Ten participants (four in the study group, six in the control group) withdrew consent prior study week 12. Four participants died due to multiple organ failure, cardiac failure and infection. The changes in TSS from baseline until week 12 between the ECP group (-14.5%) and the control group (-8.5%) were not statistically different. However, ECP-treated participants had a 50% or greater reduction in the total daily dose of corticosteroids. At week 12, the percentage of participants experiencing both a 50% or greater reduction in daily corticosteroid dose and a 25% or greater improvement in the TSS was higher in the ECP group (8%) than the control group (0%). Regarding TSS, 40% of the participants in the ECP group had a complete or partial skin response compared with 10% in the control group. Current clinical practice guidelines already recommend consideration of ECP as second-line therapy option in adults and paediatric patients with cGvHD based on the available and partially limited evidence (Wolff 2011).

Apart from this RCT in mainly adults, the search strategy identified 21 non-randomised, paediatric studies including several case reports, case series and observational studies that suggest a benefit of ECP in pediatric patients with cGvHD. We identified one major non-randomised, non-controlled prospective study including children with acute (33 participants) and chronic (44 participants) GvHD resistant to conventional immunosuppressive therapy (Messina 2003). Depending on the original disorder and haematopoietic stem cell source, immunosuppressive prophylaxis consisted either of 1. ciclosporin A alone, 2. short-term methotrexate plus rabbit anti-thymoglobulin (ATG) or 3. ciclosporin A combined with steroids. People with cGvHD and skin involvement were assessed according to the extent of skin surface involved (ESS in %) and skin severity score (SSS) in monthly intervals. The clinical stage in people with organ involvement was graded for each organ and then combined to an overall grade following published criteria (Ferrara 1991; Przepiorka 1995; Sullivan 1991). Resistance to conventional immunosuppressive therapy after complete remission was defined as lack of clinical stabilisation or improvement after treatment with prednisolone at a dosage of 2.5 mg/kg for at least seven days and no response to at least two lines of alternative immunosuppressive treatment options (such as ciclosporin A or tacrolimus). The median Lansky/Karnofsky performance score at the start of the ECP was 60% (range 30% to 90%). Photopheresis was carried out on two consecutive days weekly for the first month, every two weeks for the second and third month, followed by monthly intervals for at least three months. Clinical evaluation of the participants was done at months one, two, three and six after initiation of ECP. Complete response was defined as clinical stage 0 or I, partial response as improvement greater than 50% and no response as stable or progressive disease or improvement less than 50%. For the participants with cGvHD, the median Lansky/Karnofsky score improved from 60% to 90% (range 60% to 100%). About 59% of the participants had an overall improvement evaluated according to organ involvement. The median improvement in ESS and SSS scores was 26% and 8 points, respectively. At the end of ECP treatment, 44% of participants had a complete response; 29% a partial response; 5% no response; and 10 participants died due to complication of GvHD, infection or relapse of the primary disease. Participants with cGvHD responding to ECP had a significantly better five-year overall survival of 96.1% (95% CI 88.7% to 100%) compared with non-responders with 58.4% (95% CI 34.5% to 82.4%).

These studies provide only limited evidence for the efficacy of ECP in pediatric patients with cGvHD after HSCT and, therefore, should not solely be used to establish recommendations in pediatric patients. It is questionable if insights gained from data of the RCT performed in a predominant adult population can be transferred to children (Flowers 2008). Further evaluation in controlled trials, preferably in RCTs, including cost-effectiveness analyses is urgently needed. However, performing RCTs in this age group will be challenging due to the limited number of children, the variable disease presentation and the lack of well-defined response criteria. International multicentre trials with appropriate funding will be needed to study the efficacy of ECP in cGvHD in children after HSCT. There is no ongoing prospective RCT investigating the efficacy of ECP in people with cGvHD after HSCT to help to define the role of ECP in treatment of cGvHD in children and adolescents.

 

Authors' conclusions

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. Contributions of authors
  12. Declarations of interest
  13. Differences between protocol and review
  14. Index terms

 

Implications for practice

There is no randomised evidence for the use of extracorporeal photopheresis (ECP) in paediatric patients with chronic graft-versus-host disease (cGvHD) after haemopoietic stem cell transplantation (HSCT). During the course of this review, we have identified case reports, case series and observational studies. Thus, ideally, ECP should be applied in paediatric patients in the context of randomised controlled trials (RCTs) only and international efforts should be undertaken to set up such a study. There is no high-quality evidence to support the use of ECP in people with steroid-refractory cGvHD.

 
Implications for research

Future RCTs will need the incorporation of  1. reliable and validated scoring systems to assess disease manifestations, 2. well-defined response criteria and 3. relevant outcome measures including overall survival, failure-free survival, adverse effects, quality of life, long-term effects and cost-effectiveness analyses. Furthermore, the efficacy of ECP may depend on the affected organ system and a subgroup analysis according to disease manifestation will help to clarify this issue. Furthermore the type of photopheresis procedure should be specified. Once the value of ECP is established, comparative trials defining the advantages and disadvantages of the various ECP regimens should be considered while keeping in mind that the performance of such RCTs is very challenging and may incorporate methodological design issues for rare diseases. If treatment decisions based on clinical grounds in favour of ECP are made, patients should carefully be monitored for beneficial and harmful effects and efforts should be made to share this information with other clinicians, for example by setting up registries for paediatric patients that are treated with ECP.

 

Acknowledgements

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. Contributions of authors
  12. Declarations of interest
  13. Differences between protocol and review
  14. Index terms

We would like to thank Edith Leclercq, the Trials Search Co-ordinator of the Childhood Cancer Group, for developing and running the search strategies in the different databases and the editorial base of the Cochrane Childhood Cancer Group for their helpful comments on our protocol and review.

We thank E. Merlin and the other reviewers for reading our review and for their helpful comments and suggestions.

The editorial base of the Cochrane Childhood Cancer Group is funded by Stichting Kinderen Kankervrij (KiKa).

 

Data and analyses

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. Contributions of authors
  12. Declarations of interest
  13. Differences between protocol and review
  14. Index terms

This review has no analyses.

 

Appendices

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. Contributions of authors
  12. Declarations of interest
  13. Differences between protocol and review
  14. Index terms
 

Appendix 1. Search strategy for Cochrane Central Register of Controlled Trials (CENTRAL)

1. ForStem cell transplantation the following text were used:

stem cell transplantation OR stem cell transplantations OR SCT OR hematopoietic stem cell transplantation OR HSCT OR peripheral blood stem cell transplantation OR peripheral stem cell transplantation OR PBSCT OR stem cell OR stem cells OR stem cell* OR bone marrow transplantation OR BMT OR hematopoietic stem cell mobilization OR hematopoietic stem cell mobilisation OR allograft OR allografts OR allograft* OR allogeneic transplantation OR allogeneic marrow transplantation OR allogen* OR homologous transplantation OR myeloablative therapy OR myeloablative agonist OR myeloablative agonists OR myeloablativ* OR mega therapy OR high-dose therapy OR high dose therapy OR stem cell rescue OR bone marrow rescue OR bone marrow grafting OR bone marrow cell transplantation OR cord blood stem cell transplantation OR placental blood stem cell transplantation OR umbilical cord stem cell transplantation

2. For Graft-versus-host disease the following text words were used:

graft versus host disease OR graft vs host disease OR chronic graft versus host disease OR chronic graft vs host disease OR acute graft versus host disease OR acute graft vs host disease OR GVHD OR cGVHD OR aGVHD OR graft versus leukemia OR graft vs leukemia OR homologous wasting disease OR graft versus host reaction OR graft vs host reaction

3. For Photopheresis the following text words were used:

photopheresis OR extracorporeal photopheresis OR Photopheresis, Extracorporeal OR Photochemotherapy, Extracorporeal OR ECP OR Extracorporeal Photochemotherapy OR Extracorporeal Photochemotherapies OR Photochemotherapies, Extracorporeal OR photochemotherapy OR photodynamic therapy OR photodynamic therapies OR phototherapy OR PDT OR phototherapies OR ultraviolet therapy OR ultraviolet therapies OR UVA-irradiation OR photoradiation OR ficusin OR psoralene OR psoralen OR psoralens OR 66-97-7 OR 8-methoxypsoralen OR 8-MOP OR 8MOP OR 8 MOP OR Methoxsalen OR 298-81-7 OR photochemical OR photochemicals OR photosensitizer* OR photosensitiser*

4. For Children the following text words were used:

infant OR infan* OR newborn OR newborn* OR new-born* OR baby OR baby* OR babies OR neonat* OR child OR child* OR schoolchild* OR schoolchild OR school child OR school child* OR kid OR kids OR toddler* OR adolescent OR adoles* OR teen* OR boy* OR girl* OR minors OR minors* OR underag* OR under ag* OR juvenil* OR youth* OR kindergar* OR puberty OR puber* OR pubescen* OR prepubescen* OR prepuberty* OR pediatrics OR pediatric* OR paediatric* OR peadiatric* OR schools OR nursery school* OR preschool* OR pre school* OR primary school* OR secondary school* OR elementary school* OR elementary school OR high school* OR highschool* OR school age OR schoolage OR school age* OR schoolage* OR infancy 

Final search 1 AND 2 AND 3 AND 4

The search was performed in title, abstract or keywords

 

Appendix 2. Search strategy for MEDLINE/PubMed

1. For Stem cell transplantation the following MeSH headings and text words was used: 

stem cell transplantation OR stem cell transplantations OR SCT OR hematopoietic stem cell transplantation OR HSCT OR peripheral blood stem cell transplantation OR peripheral stem cell transplantation OR PBSCT OR stem cell OR stem cells OR stem cell* OR bone marrow transplantation OR BMT OR hematopoietic stem cell mobilization OR hematopoietic stem cell mobilisation OR allograft OR allografts OR allograft* OR allogeneic transplantation OR allogeneic marrow transplantation OR allogen* OR homologous transplantation OR myeloablative therapy OR myeloablative agonist OR myeloablative agonists OR myeloablativ* OR mega therapy OR high-dose therapy OR high dose therapy OR stem cell rescue OR bone marrow rescue OR bone marrow grafting OR bone marrow cell transplantation OR cord blood stem cell transplantation OR placental blood stem cell transplantation OR umbilical cord stem cell transplantation  

2. For Graft-versus-host disease the following MeSH headings and text words was used: 

graft versus host disease OR graft vs host disease OR chronic graft versus host disease OR chronic graft vs host disease OR acute graft versus host disease OR acute graft vs host disease OR GVHD OR cGVHD OR aGVHD OR graft versus leukemia OR graft vs leukemia OR homologous wasting disease OR graft versus host reaction OR graft vs host reaction

3. For Photopheresis the following MeSH headings and text words was used: 

photopheresis OR extracorporeal photopheresis OR Photopheresis, Extracorporeal OR Photochemotherapy, Extracorporeal OR ECP[tiab] OR Extracorporeal Photochemotherapy OR Extracorporeal Photochemotherapies OR Photochemotherapies, Extracorporeal OR photochemotherapy OR photodynamic therapy OR photodynamic therapies OR phototherapy OR PDT[tiab] OR phototherapies OR ultraviolet therapy OR ultraviolet therapies OR UVA-irradiation OR photoradiation OR ficusin OR psoralene OR psoralen OR psoralens OR 66-97-7 OR 8-methoxypsoralen OR 8-MOP OR 8MOP OR 8 MOP OR Methoxsalen OR 298-81-7 OR photochemical OR photochemicals OR photosensitizer* OR photosensitiser*

4. For Children the following MeSH headings and text words was used: 

infant OR infan* OR newborn OR newborn* OR new-born* OR baby OR baby* OR babies OR neonat* OR child OR child* OR schoolchild* OR schoolchild OR school child OR school child* OR kid OR kids OR toddler* OR adolescent OR adoles* OR teen* OR boy* OR girl* OR minors OR minors* OR underag* OR under ag* OR juvenil* OR youth* OR kindergar* OR puberty OR puber* OR pubescen* OR prepubescen* OR prepuberty* OR pediatrics OR pediatric* OR paediatric* OR peadiatric* OR schools OR nursery school* OR preschool* OR pre school* OR primary school* OR secondary school* OR elementary school* OR elementary school OR high school* OR highschool* OR school age OR schoolage OR school age* OR schoolage* OR infancy OR schools, nursery OR infant, newborn  

5. ForRandomised controlled trials (RCTs)/clinical controlled trials (CCTs) the following MeSH headings and text words was used:

(randomized controlled trial[pt] OR controlled clinical trial[pt] OR randomized[tiab] OR placebo[tiab] OR drug therapy[sh] OR randomly[tiab] OR trial[tiab] OR groups[tiab]) AND humans[mh]

Final search: 1 AND 2 AND 3 AND 4 AND 5

[pt = publication type; tiab = title, abstract; sh = subheading; mh = MeSH term; * = zero to many characters; RCT = randomized controlled trial; CCT = controlled clinical trial]

 

Appendix 3. Search strategy for EMBASE (OVID)

1. For Stem cell transplantation the following Emtree terms and text words were used:

1. exp stem cell transplantation/
2. (stem cell transplantation or stem cell transplantations or SCT).mp.
3. exp hematopoietic stem cell transplantation/
4. (hematopoietic stem cell transplantation or HSCT).mp.
5. exp peripheral blood stem cell transplantation/
6. (peripheral blood stem cell transplantation or PBSCT).mp.
7. exp stem cell/
8. (stem cell or stem cells or stem cell$).mp.
9. exp bone marrow transplantation/
10. (bone marrow transplantation or BMT).mp.
11. exp stem cell mobilization/
12. (hematopoietic stem cell mobilization or hematopoietic stem cell mobilisation).mp.
13. exp allograft/
14. (allograft or allografts or allograft$).mp.
15. exp allotransplantation/
16. (allogeneic transplantation or allogeneic marrow transplantation).mp.
17. allogen$.mp.
18. homologous transplantation.mp.
19. myeloablative therapy.mp.
20. exp myeloablative agent/
21. (myeloablative agonist or myeloablative agonists).mp.
22. myeloablativ$.mp.
23. (mega therapy or high-dose therapy or high dose therapy).mp.
24. exp bone marrow rescue/
25. (stem cell rescue or bone marrow rescue).mp.
26. bone marrow grafting.mp.
27. bone marrow cell transplantation.mp.
28. exp cord blood stem cell transplantation/
29. (cord blood stem cell transplantation or placental blood stem cell transplantation or umbilical cord stem cell transplantation).mp.
30. or/1-29

2. For Graft-versus-host disease the following Emtree terms and text words were used:

1. exp graft versus host reaction/
2. (graft versus host disease or graft vs host disease).mp.
3. exp chronic graft versus host disease/
4. (chronic graft versus host disease or chronic graft vs host disease).mp.
5. exp acute graft versus host disease/
6. (acute graft versus host disease or acute graft vs host disease).mp.
7. (GVHD or cGVHD or aGVHD).mp.
8. exp graft versus leukemia effect/
9. (graft versus leukemia or graft vs leukemia).mp.
10. homologous wasting disease.mp.
11. (graft versus host reaction or graft vs host reaction).mp.
12. or/1-11

3. For Photopheresis the following Emtree terms and text words were used:

1. PUVA/
2. (photopheresis or extracorporeal photopheresis).mp.
3. (Extracorporeal Photochemotherapy or Extracorporeal Photochemotherapies or ECP).mp.
4. photochemotherapy.mp. or exp photochemotherapy/
5. exp photodynamic therapy/
6. (photodynamic therapy or photodynamic therapies).mp.
7. exp phototherapy/
8. (phototherapy or phototherapies or PDT).mp.
9. (ultraviolet therapy or ultraviolet therapies).mp.
10. exp ultraviolet radiation/ or exp ultraviolet A radiation/
11. UVA-irradiation.mp.
12. photoradiation.mp.
13. exp psoralen/
14. (ficusin or psoralene or psoralen or psoralens).mp.
15. 66-97-7.rn.
16. exp methoxsalen/
17. (8-methoxypsoralen or 8-MOP or 8MOP or 8 MOP or Methoxsalen).mp.
18. 298-81-7.rn.
19. (photochemical or photochemicals).mp.
20. exp photosensitizing agent/
21. (photosensitizer$ or photosensitiser$).mp.
22. or/1-21

4. For Children the following Emtree terms and text words were used:

1. infant/ or infancy/ or newborn/ or baby/ or child/ or preschool child/ or school child/
2. adolescent/ or juvenile/ or boy/ or girl/ or puberty/ or prepuberty/ or pediatrics/
3. primary school/ or high school/ or kindergarten/ or nursery school/ or school/
4. or/1-3
5. (infant$ or newborn$ or (new adj born$) or baby or baby$ or babies or neonate$ or perinat$ or postnat$).mp.
6. (child$ or (school adj child$) or schoolchild$ or (school adj age$) or schoolage$ or (pre adj school$) or preschool$).mp.
7. (kid or kids or toddler$ or adoles$ or teen$ or boy$ or girl$).mp.
8. (minors or minors$ or (under adj ag$) or underage$ or juvenil$ or youth$).mp.
9. (puber$ or pubescen$ or prepubescen$ or prepubert$).mp.
10. (pediatric$ or paediatric$ or peadiatric$).mp.
11. (school or schools or (high adj school$) or highschool$ or (primary adj school$) or (nursery adj school$) or (elementary adj school) or (secondary adj school$) or kindergar$).mp.
12. or/5-11
13. 4 or 12

5. For Randomised controlled trials (RCTs)/clinical controlled trials (CCTs) the following Emtree terms and text words were used:

1. Randomized Controlled Trial/
2. Controlled Clinical Trial/
3. randomized.ti,ab.
4. placebo.ti,ab.
5. randomly.ti,ab.
6. trial.ti,ab.
7. groups.ti,ab.
8. drug therapy.sh.
9. or/1-8
10. Human/
11. 9 and 10

Final search 1 and 2 and 3 and 4 and 5

[mp = title, abstract, subject headings, heading word, drug trade name, original title, device manufacturer, drug manufacturer name; sh = subject heading; ti,ab = title, abstract; / = Emtree term; $=zero or more characters ; RCT = randomized controlled trial; CCT = controlled clinical trial]

 

 

Contributions of authors

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. Contributions of authors
  12. Declarations of interest
  13. Differences between protocol and review
  14. Index terms

Marcus Weitz: conception, design and co-ordination of the review. Identifying potential studies meeting the inclusion criteria (both by initial screening of the titles and abstracts and by screening of the full-text articles), data management and interpretation of the data. Writing of the review and approval of the final version.
Joerg Meerpohl: methodological support, identifying potential studies meeting the inclusion criteria (both by initial screening of the titles and abstracts and by screening of the full-text articles), data management and interpretation, as well as general advice on the review. Approval of the final version.
Brigitte Strahm: interpretation of the data, clinical expertise, providing general advice on the review and approval of the final version.
Dirk Bassler: identifying potential studies meeting the inclusion criteria (both by initial screening of the titles and abstract and by screening of the full-text articles), data management and interpretation of data. Involvement in writing the review and approval of the final version.

 

Declarations of interest

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. Contributions of authors
  12. Declarations of interest
  13. Differences between protocol and review
  14. Index terms

None.

 

Differences between protocol and review

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. Contributions of authors
  12. Declarations of interest
  13. Differences between protocol and review
  14. Index terms

None.

References

References to studies excluded from this review

  1. Top of page
  2. AbstractRésumé scientifique
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. Contributions of authors
  13. Declarations of interest
  14. Differences between protocol and review
  15. Characteristics of studies
  16. References to studies excluded from this review
  17. Additional references
Apisarnthanarax 2003 {published data only}
  • Apisarnthanarax N, Donato M, Korbling M, Couriel D, Gajewski J, Giralt S, et al. Extracorporeal photopheresis therapy in the management of steroid-refractory or steroid-dependent cutaneous chronic graft-versus-host disease after allogeneic stem cell transplantation: feasibility and results. Bone Marrow Transplantation 2003;31(6):459-65.
Balda 1996 {published data only}
  • Balda B, Konstantinov A, Starz H, Gneklow A, Heidemann P. Extracorporeal photochemotherapy as an effective treatment modality in chronic graft versus host disease. Journal of the European Academy of Dermatology and Venereology 1996;7:155-62.
Besnier 1997 {published data only}
  • Besnier DP, Chabannes D, Mahe B, Mussini JM, Baranger TA, Muller JY, et al. Treatment of graft-versus-host disease by extracorporeal photochemotherapy: a pilot study. Transplantation 1997;64(1):49-54.
Biagi 2000 {published data only}
  • Biagi E, Perseghin P, Buscemi F, Dassi M, Rovelli A, Balduzzi A. Effectiveness of extracorporeal photochemotherapy in treating refractory chronic graft-versus-host disease. Haematologica 2000;85(3):329-30.
Bisaccia 2011 {published data only}
  • Bisaccia E, Palangio M, Gonzalez J. Long-term extracorporeal photochemotherapy in a pediatric patient with refractory sclerodermatous chronic graft-versus-host disease. Transfusion and Apheresis Science 2011;45(2):187-90.
Child 1999 {published data only}
  • Child FJ, Ratnavel R, Watkins P, Samson D, Apperley J, Ball J, et al. Extracorporeal photopheresis (ECP) in the treatment of chronic graft-versus-host disease (GVHD). Bone Marrow Transplantation 1999;23(9):881-7.
D'Incan 2000 {published data only}
  • D'Incan M, Kanold J, Halle P, De Lumley L, Souteyrand P, Demeocq F. Extracorporeal photopheresis as an alternative therapy for drug-resistant graft versus host disease: three cases. Annales de Dermatologie et de Venereologie 2000;127(2):166-70.
Dall'Amico 1997 {published data only}
  • Dall'Amico R, Rossetti F, Zulian F, Montini G, Murer L, Andreetta B, et al. Photopheresis in paediatric patients with drug-resistant chronic graft-versus-host disease. British Journal of Haematology 1997;97(4):848-54.
Flowers 2008 {published data only}
  • Flowers ME, Apperley JF, van Besien K, Elmaagacli A, Grigg A, Reddy V, et al. A multicenter prospective phase 2 randomized study of extracorporeal photopheresis for treatment of chronic graft-versus-host disease. Blood 2008;112(7):2667-74.
Foss 2003 {published data only}
  • Foss FM. Extracorporeal photopheresis in the treatment of graft-vs-host disease. Journal of Cutaneous Medicine and Surgery 2003;7(4 Suppl):13-7.
Foss 2005 {published data only}
  • Foss FM, DiVenuti GM, Chin K, Sprague K, Grodman H, Klein A, 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 Transplantation 2005;35(12):1187-93.
Halle 2002 {published data only}
  • Halle P, Paillard C, D'Incan M, Bordigoni P, Piguet C, De Lumley L, et al. Successful extracorporeal photochemotherapy for chronic graft-versus-host disease in pediatric patients. Journal of Hematotherapy & Stem Cell Research 2002;11(3):501-12.
Kanold 2003 {published data only}
  • Kanold J, Paillard C, Halle P, D'Incan M, Bordigoni P, Demeocq F. Extracorporeal photochemotherapy for graft versus host disease in pediatric patients. Transfusion and Apheresis Science 2003;28(1):71-80.
Kanold 2005 {published data only}
  • Kanold J, Messina C, Halle P, Locatelli F, Lanino E, Cesaro S, et al. Update on extracorporeal photochemotherapy for graft-versus-host disease treatment. Bone Marrow Transplantation 2005;35(Suppl 1):S69-71.
Kanold 2007 {published data only}
Looks 1996 {published data only}
  • Looks A, Fuchs D, Rulke D, Lange D, Zintl F, Wollina U. Successful treatment of acute graft versus host disease after bone marrow transplantation in 16-year old girl with extracorporeal photopheresis. Onkologie 1996;7:155-62.
Messina 2003 {published data only}
Perotti 1999 {published data only}
  • Perotti C, Torretta L, Viarengo G, Roveda L, Bernuzzi S, Carbone S, et al. Feasibility and safety of a new technique of extracorporeal photochemotherapy: experience of 240 procedures. Haematologica 1999;84(3):237-41.
Peters 2000 {published data only}
  • Peters C, Minkov M, Gadner H, Klingebiel T, Vossen J, Locatelli F, et al. Statement of current majority practices in graft-versus-host disease prophylaxis and treatment in children. Bone Marrow Transplantation 2000;26(4):405-11.
Rossetti 1995 {published data only}
  • Rossetti F, Zulian F, Dall'Amico R, Messina C, Montini G, Zacchello F. Extracorporeal photochemotherapy as single therapy for extensive, cutaneous, chronic graft-versus-host disease. Transplantation 1995;59(1):149-51.
Rossetti 1996 {published data only}
  • Rossetti F, Dall'Amico R, Crovetti G, Messina C, Montini G, Dini G, et al. Extracorporeal photochemotherapy for the treatment of graft-versus-host disease. Bone Marrow Transplantation 1996;18(Suppl 2):175-81.
Salvaneschi 2001 {published data only}
Zecca 2000 {published data only}
  • Zecca M, Locatelli F. Management of graft-versus-host disease in paediatric bone marrow transplant recipients. Paediatric Drugs 2000;2(1):29-55.

Additional references

  1. Top of page
  2. AbstractRésumé scientifique
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. Contributions of authors
  13. Declarations of interest
  14. Differences between protocol and review
  15. Characteristics of studies
  16. References to studies excluded from this review
  17. Additional references
Akpek 2001
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