The role of concomitant extracorporeal photopheresis for the treatment of chronic graft-versus-host disease after allogeneic haematopoietic stem cell transplantation
This is the protocol for a review and there is no abstract. The objectives are as follows:
To compare the efficacy of GvHD standard treatment with GvHD standard treatment and additional extracorporeal photopheresis for chronic GvHD after allo-SCT.
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Description of the condition
Allogeneic haematopoietic (blood-forming) stem cell transplantation (allo-SCT) is an important and potentially curative treatment modality for many haematological malignancies such as relapsed or chemotherapy-refractory leukaemia/lymphoma or multiple myeloma. Its success is largely based on the immunological effect of foreign donor cells (allogeneic cells) against the underlying disease, where donor cells eradicate or control remaining tumour cells. Allo-SCT may also be used in non-malignant haematological disorders such as aplastic anaemia or primary immunodeficiencies to replace a defective haematopoesis (Bensinger 2001; Baron 2004; Copelan 2006). Since the first allo-SCT has been performed in the 1960s, transplant numbers steadily increased. Approximately 23,000 allo-SCT were performed in Europe in 2009 (Gratwohl 2009).
Following a conditioning regimen usually consisting of chemotherapy (and radiotherapy), the patient receives bone marrow or peripheral blood stem cells from an unrelated or related donor to replace the recipient's haematopoietic system. The donor has to be fully or at least partially matched for certain tissue antigens (Human Leukocyte Class I and Class II antigens) to prevent graft rejection and to reduce graft-versus-host disease (GvHD) (Petersdorf 2001a; Petersdorf 2001b).
Different conditioning strategies are used to allow engraftment of the foreign cells and further reduce tumour burden. Classic myeloablative conditioning consists of high-dose chemotherapy with or without total body irradiation. Reduced-intensity conditioning strategies were developed more recently (Cremer 2011). These strategies are less toxic and allow patients with advanced age or co-morbidities to receive an allo-SCT. Reduced-intensity conditioning is thought to be associated with a reduction of graft-versus-host reactions and infectious complications but with an increased risk of relapse. Main risk factors for transplant-related morbidity and mortality are conditioning toxicity, graft failure, infectious complication and, in particular, acute and chronic GvHD (Jenq 2010; Pollack 2009; Gooley 2010).
GvHD is caused by allo-reactive T-cells attacking healthy recipient tissues. It can be divided into an acute and a chronic form. While acute GvHD by traditional definition occurs within the first 100 days after transplantation, chronic GvHD develops after day+100. With the introduction of RIC and donor lymphocyte infusions the time course has shifted and the classification is now mainly based on the distinct clinical features (Filipovich 2005; Vigorito 2009). While there was significant progress with respect to supportive and anti-infective co-medication within the last decade, GvHD remains the biggest barrier to successful allo-SCT. More than 25% of transplant related deaths are caused by GvHD (Westin 2011; Wolf 2012). Important risk factors for GvHD are human leukocyte incompatibilities (Speiser 1996), but also the conditioning regimen (Goldman 1988), sex mismatch (female graft, male host) (Weisdorf 1991), age (Weisdorf 1991), prior allo-immunisation, source of cells (Gluckman 2004), CMV (cytomegalovirus) status and genetic predisposition (Dickinson 2004; Leather 2004) are to be considered.
Acute GvHD occurs in 10% to 80% of allo-SCT patients and usually affects skin, liver and the gastrointestinal tract (Blazar 2012; Deeg 2007; Przepiorka 1995). The pathophysiology of acute GvHD is thought to consist of three phases. During recipient conditioning organ epithelial surfaces are damaged resulting in a pro-inflammatory environment and activation of antigen-presenting cells which in a second step activate donor T-cells after transplantation. These donor T-cells then dominate the effector phase of the immune response and cause skin exanthema, inflammation of the bile ducts or diarrhoea (Ferrara 2009; Paczesny 2009).
The incidence of chronic GvHD varies in different studies between 28% to 100% (Bensinger 2001). Mortality and morbidity after allo-SCT is highly influenced by chronic GvHD (Socie 1999). Chronic GvHD usually evolves from a prior acute GvHD. Only 20% to 30% of chronic GvHDs occur without a preceding acute GvHD or after prior acute GvHD has resolved. The clinical picture of chronic GvHD is mainly reflected by skin, mouth and eye changes as well as chronic inflammation of liver, gut and lungs. Chronic GvHD shows similarities with multisystemic autoimmune diseases such as Sjogrens syndrome or systemic sclerosis (Lee 2003). Additionally, immunosuppression, involution of thymic epithelium, loss of germinal centres in lymph nodes (Ghayur 1990), reduced B-cell proliferation, reduced antibody responses, defects in CD4+ cell numbers and function as well as increased suppressor T-cell activity (Ferrara 1991) may appear. All these factors along with the therapeutic use of immunosuppressants constitute a significant risk of infection.
Description of the intervention
Corticosteroids with or without calcineurin inhibitors are the standard first line therapy for both acute and chronic GvHD and to date there is no proof for a benefit of any other combination therapy (Bacigalupo 2004; Deeg 2007; Wolff 2010). In a number of patients variable effectiveness of second line agents such as sirolimus, pentostatin or mycophenolate has been demonstrated mostly in early-phase non-randomised trials (Bolaños-Meade 2004; Wolff 2011). The same holds true for an arsenal of antibodies directed against inflammatory molecules or immune cells (Ratanatharathorn 2003). The prognosis for patients not responding to steroids is poor (Westin 2011). Escalation of immunosuppression in the case of steroid-refractoriness promotes lethal infectious complications as well as relapse by concomitant suppression of graft-versus-tumour effects.
In the 1970s, oral psoralen combined with UVA light (PUVA) was first used to treat psoriasis (Parish 1974) and in 1979 Gilchrist demonstrated PUVA efficacy in treating cutaneous T-cell lymphoma (Gilchrest 1979). To date it still has its use in the treatment of various skin conditions including cutaneous T-cell lymphoma (Morison 2004). However, it was observed that PUVA therapy applied to the skin only showed an effect as long as the disease was limited to the skin. As many cutaneous T-cell lymphoma patients progress to systemic disease with circulating lymphoma cells in the blood, PUVA-treatment of the blood was considered an analogue therapeutic concept.
Extracorporal photopheresis treatment consists of a combination of leukapheresis and UVA irradiation of the collected buffy coat after addition of 8-methoxypsoralene. After the blood from a patient's peripheral or central vein is separated in the leukapheresis process, the plasma and the red cells are returned to the patient. The remaining mononuclear cells are mixed with 8-methoxypsoralene. Upon UVA irradiation in a photoactivation chamber these photoactivated cells are then returned to the patients. Depending on device, blood flow rates and irradiation times the whole procedure takes one to four hours and it is usually administered on two consecutive days, once up to four times a week according to treatment protocols (Marshall 2006; Scarisbrick 2008).
Extracorporal photochemotherapy has been shown to induce partial and full remissions in systemic cutaneous T-cell lymphoma (Edelson 1987); in 1988, the U.S. Food and Drug Administration (FDA) authorised the use of extracorporal photopheresis as the first selective immunotherapy for cancer (Heshmati 2003).
In the 1990s, extracorporal photopheresis has been increasingly used to treat a number of other T-cell mediated diseases such as autoimmune diseases, graft rejection after solid organ transplantation and acute/chronic GvHD after haematopoietic stem cell transplantation (Andreu 1995; Barr 1998; Greinix 1998; McKenna 2006; Rosetti 1996). Since then, numerous phase II clinical studies indicated efficacy especially in steroid-refractory acute and chronic GvHD with response rates ranging from 25% to 80% (Baird 2009). In chronic GvHD extracorporal photopheresis is now considered an established second line treatment option (Wolff 2011).
How the intervention might work
The mechanism of action of extracorporal photopheresis can be characterised by a modulation of the immune system resulting in a to some extent selective immunosuppression of allo-reactive T-cells (Marshall 2006). A pivotal event after photopheresis treatment is the induction of apoptosis (a form of controlled cell death) in treated white blood cells. Apoptotic cells have been shown to modulate the immune response in different ways. The clearance of apoptotic cells by antigen-presenting cells in the absence of danger signals has been demonstrated to increase the production of anti-inflammatory cytokines and decrease the production of pro-inflammatory cytokines (Savill 2002). Moreover, allo-activated human T-cells are more prone to undergo apoptosis than non-activated T-cells (Hannani 2010; Holtick 2012). Some studies also suggest that extracorporal photopheresis can directly modulate dendritic cells or the dendritic cell ratio favouring plasmacytoid over monocytoid dendritic cell profiles as well as a decrease in antigen responsiveness (Gerner 2009; Gorgun 2002; Holtick 2008). Other possible effects on dendritic cells include monocyte stimulation and enhanced generation of immature dendritic cells (Berger 2002; Craciun 2002; Spisek 2006).
Furthermore, animal experiments demonstrated the induction of regulatory T-cells after extracorporal photopheresis treatment. These cells might be able to selectively inhibit GvHD reactions without affecting graft-versus-tumour activity (Edinger 2003; Gatza 2008; Maeda 2005). Accordingly, clinical and experimental data demonstrate that extracorporal photopheresis modulates the immune response without increase of relapse and infection rates which are important deleterious side effects of conventional immunosuppressants (Fefer 2004; Suchin 1999).
Why it is important to do this review
Extracorporal photopheresis is a complex and expensive treatment option. A systematic review or meta-analysis considering additional extracorporal photopheresis for the treatment of chronic GvHD is lacking. By focusing on randomised controlled trials (RCTs) and systematically analysing their reliability and validity we seek to eliminate the limitations of individual trails and gain more evidence regarding clinical benefit as well as therapy related risks of extracorporal photopheresis. We will then summarise the results in a meta-analysis and therefore possibly re-evaluate the treatment options in chronic GvHD.
To compare the efficacy of GvHD standard treatment with GvHD standard treatment and additional extracorporeal photopheresis for chronic GvHD after allo-SCT.
Criteria for considering studies for this review
Types of studies
We will accept only RCTs for this review and include full-text, abstract publications and unpublished data, if sufficient information is available. We will exclude quasi-randomised trials and cross-over trials.
Types of participants
We will consider patients (≥16) with clinically confirmed chronic GvHD (Filipovich 2005) after allo-SCT, without gender or ethnicity restriction. We will consider newly diagnosed patients and those with relapsed and resistant disease as eligible for participation.
Types of interventions
We will exclude studies containing PUVA-treatment as part of the intervention.
Types of outcome measures
GvHD response rates
Disease-free survival with regard to the underlying malignancy
Relapse rate of the underlying malignancy
Adverse events: incidence of CTC grade III and IV events & events precluding ECP-treatment
Duration of systemic immunosuppressive treatment
Steroid dosage (cumulative or peak dosage)
Quality of life if measured with validated instruments
Search methods for identification of studies
We will adopt search strategies from those suggested in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). To reduce language bias we will apply no language restriction.
The search will cover:
Cochrane Central Register of Controlled Trials (CENTRAL), The Cochrane Library, latest issue (Appendix 1);
MEDLINE (from 1948 to present) (Appendix 2).
Searching other resources
We will search the following conference proceedings of the following societies if they are not included in CENTRAL:
American Society of Hematology from 2007 to present;
European Hematology Association from 2007 to present;
European Group of Bone Marrow Transplantation from 2007 to present;
American Society of Bone Marrow Transplantation from 2007 to present.
We will electronically search the metaRegister of Controlled Trials (mRCT) (http://www.controlled-trials.com/mrct/)
We will also handsearch references of all identified trials, relevant review articles and current treatment guidelines.
Data collection and analysis
Selection of studies
After the first review of all titles and abstracts of the identified studies from the above sources, two authors (UH, RK) will independently reject all studies that are clearly ineligible. We will assess selected studies by using an eligibility form regarding study design and compliance with inclusion criteria (Higgins 2011). In case of doubt we will include full-text analysis and discuss eligibility with both authors to finalise a decision (preferably including studies rather than losing relevant data). According to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement, we will use a flow diagram to show numbers of identified records, excluded articles and included studies (Moher 2009).
Data extraction and management
Two authors (UH, RK) will independently extract data according to the Cochrane Handbook for Systematic Reviews of Interventions by using a standardised data extraction form containing the following items (Higgins 2011):
general information (author, title, source, publication date, country, language, duplicate publications);
quality assessments(sequence generation, allocation concealment, blinding (participants personnel outcome assessors), incomplete outcome data, selective outcome reporting, other sources of bias);
study characteristics (trial design, aims, setting and dates, source of participants, inclusion/exclusion criteria, comparability of groups, subgroup analysis, statistical methods, power calculations, treatment cross-overs, compliance with assigned treatment, length of follow-up, time point of randomisation);
participant characteristics (age, gender, ethnicity, number of participants recruited/allocated/evaluated, participants lost to follow-up, diagnosis and stage of GvHD, additional diagnosis of the underlying malignancy);
interventions (setting, type and composition of the GvHD-treatment, duration of follow-up);
outcomes (overall survival, GvHD response rates, disease-free survival, incidence of relapse and non-relapse mortality, adverse events, duration of systemic immunosuppressive treatment, steroid dosage, quality-of-life);
A meta-analysis will be performed in any case the data/studies are sufficiently appropriate.
Assessment of risk of bias in included studies
To assess the risk of bias in included studies we will use a questionnaire according to the recommendations in the Cochrane Handbook for Systematic Reviews of Interventions for the following criteria (Higgins 2011).
blinding (participants, personnel, outcome assessors);
incomplete outcome data;
selective outcome reporting;
other sources of bias.
The judgment of the authors (UH, RK) will involve an answer for each criteria, based on a three-point scale ("Yes" (low risk of bias), "No" (high risk of bias), "Unclear") and a summary description.
Measures of treatment effect
For binary outcomes we will calculate risk ratios (RRs) with 95% confidence intervals (CIs) for each trial. We will calculate continuous outcomes as standardised mean difference (SMD). For time-to-event outcomes we will extract the hazard ratio (HR) from published data according to Parmar 1998 and Tierney 2007.
Dealing with missing data
As suggested in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011), there are many potential sources of missing data which are to be taken into account: at study level; at outcome level; at summary data level; at individual level; at study-level characteristics (e.g. for subgroups analysis). Firstly, it is important to make the difference between "missing at random" and "not missing at random".
We will contact the original investigator to request missing data. If data are still missing, we will make explicit assumptions of any methods used; for example that the data are assumed missing at random or that missing values were assumed to have a particular value, such as a poor outcome.
Assessment of heterogeneity
We will assess heterogeneity of treatment effects between trials by using a Chi2 test with a significance level at P < 0.1. We will use the I2 statistic to quantify possible heterogeneity (I2 > 30% moderate heterogeneity, I2 > 75 % considerable heterogeneity) (Higgins 2011). We will explore potential causes of heterogeneity by sensitivity and subgroup analysis using meta-regression.
Assessment of reporting biases
In meta-analyses with at least 10 trials, we will explore potential publication bias by generating a funnel plot and we will statistically test by means of a linear regression test. We will consider P < 0.1 as significant for this test (Higgins 2011).
We will perform analyses according to the recommendations of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). We will use aggregated data for analysis. For statistical analysis, we will enter data into the Cochrane Collaboration's statistical software, Review Manager (Review Manager 2012). One author (RK) will enter the data and a second author (UH) will check for accuracy. We will perform meta-analyses using a fixed-effect model (for example, the generic inverse-variance method for survival data outcomes and Mantel-Haenszel method for dichotomous data outcomes). If appropriate, we will calculate the number needed to treat to benefit (NNT) and the number needed to treat to harm (NNH).
We will create 'Summary of findings' tables as suggested in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). Our prioritised endpoints in the 'Summary of findings' tables will be overall survival, GvHD response to treatment, incidence of relapse and non-relapse mortality.
Subgroup analysis and investigation of heterogeneity
We will assess heterogeneity of treatment effects between trials by using a Chi2 test with a significance level at P < 0.1. We will use the I2 statistic to quantify possible heterogeneity. On the following characteristics we will consider performing subgroup analyses, if appropriate:
We will perform sensitivity analyses on the following items:
the level of loss to follow-up at a fixed time-point (e.g. two years);
quality components, including full text publications/abstracts, preliminary results versus mature results.
We would like to thank the Cochrane Haematological Malignancies Group editors, affiliated consumers and members for critical advice, support and encouragement.
Appendix 1. Search strategy for CENTRAL (The Cochrane Library)
|#1||MeSH descriptor Graft vs Host Disease explode all trees|
|#2||MeSH descriptor Host vs Graft Reaction explode all trees|
|#3||(graft versus host*)|
|#6||(graft vs host*)|
|#9||(graft v host*)|
|#10||(graft-v host* )|
|#14||homologous wasting diseas*|
|#15||(#1 OR #2 OR #3 OR #4 OR #5 OR #6 OR #7 OR #8 OR #9 OR #10 OR #11 OR #12 OR #13)|
|#16||MeSH descriptor Photopheresis explode all trees|
|#18||(photochemotherap* or photo-chemotherap*)|
|#20||(#16 OR #17 OR #18 OR #19)|
|#21||(#15 AND #20)|
|#22||"accession number" near pubmed|
|#23||(#21 AND NOT #22)|
Appendix 2. Search strategy for MEDLINE (Ovid)
|1||GRAFT VS HOST DISEASE/|
|2||graft versus host$.tw,kf,ot.|
|3||graft vs host$.tw,kf,ot.|
|4||graft v host$.tw,kf,ot.|
|7||homologous wasting diseas$.tw,kf,ot.|
|11||(photochemotherap$ or photo-chemotherap$).tw,kf,ot.|
|14||8 and 13|
|15||randomized controlled trial.pt.|
|16||controlled clinical trial.pt.|
|25||23 and 24|
|26||14 and 25|
Contributions of authors
Udo Holtick: search strategy, development and writing of protocol, proofreading of the protocol, clinical expertise, content input
Raphael Knauss: development and writing of protocol, proofreading of the protocol, content input
Sebastian Theurich: clinical expertise
Hildegard Greinix: clinical expertise
Nicole Skoetz: administrative support, statistical and methodological advice, proofreading of the protocol
Michael von Bergwelt-Baildon: clinical expertise, content input, proofreading of the protocol
Christof Scheid: clinical expertise, content input, proofreading of protocol
Declarations of interest
Christof Scheid declared the following conflict of interest: honoraria from Therakos and serves as lead investigator for a clinical study sponsored by Therakos, travel/accommodations/meeting expenses by Janssen, Celgene, Novartis, Bristol Myers, Binding Site, payment for lectures including service on speakers bureaus provided by Janssen, Celgene, Novartis, Bristol Myers, binding site, as well as grants/grants pending by Pierre Fabre.
All other authors have no conflict of interest to declare.
Sources of support
Department I of Internal Medicine, Stem Cell Transplantation Program, University of Cologne, Germany, Not specified.