GVHD remains the major impediment to broader application of allogeneic haematopoietic SCT. It can be prevented completely, but at the expense of other complications, rejection, relapse or delayed immune reconstitution. No optimal prevention or treatment method has been defined. This is reflected by enormous heterogeneity in approaches in Europe. Retrospective comparisons between different policies, although warranted, do not give definite answers. In order to improve the present situation, an European Group for Blood and Marrow Transplantation and the European LeukemiaNet working group has developed in a Delphi-like approach recommendations for prophylaxis and treatment of GVHD in the most common allogeneic transplant setting, transplantation from an HLA-identical sibling or unrelated donor for standard risk malignant disease. The working group proposes these guidelines to be adopted as routine standard in transplantation centres and to be used as comparator in systematic studies evaluating the advantages and disadvantages of practices differing from these recommendations.
GVHD remains one of the main obstacles to broader application of allogeneic haematopoietic SCT (HSCT). Once established, GVHD is difficult to treat. It can be prevented by selected methods, but often at the expense of an increased risk of relapse, rejection or delayed immune reconstitution.1, 2, 3 Hence, no optimal or even satisfactory prevention and treatment method can be defined. To advance our knowledge and define optimal approaches, correct information on the value of different strategies and methods in GVHD prevention and treatment is essential. Comparative retrospective analyses fail in this regard. GVHD prevention and treatment techniques are poorly standardized. Methods may seem superficially similar, but details may differ markedly. This has been documented by two surveys of the European Group for Blood and Marrow Transplantation (EBMT), 15 years apart.4, 5 It remains open whether different methods yield similar or divergent outcomes.
There are standards and guidelines for the indications of allogeneic and autologous HSCT,6 for the use of donors,7, 8 for the prevention and treatment of infectious complications,9, 10, 11 and for quality management.12 The recommendations have yielded documented impacts and improved outcome.12 It is now time to arrive at similar widely accepted guidelines for some of the transplantation techniques. GVHD represents such a topic. Standardization of the prevention and management of GVHD is warranted. For that purpose a joint working group of the EBMT and the European LeukemiaNet (ELN) has been established.
The working group gives recommendations following the guidelines of the international accrediting organizations JACIE and FACT. According to their principles, all centres are mandated to have institutional guidelines for GVHD prevention and treatment. Centres are now invited to follow the present EBMT/ELN recommendations. They, however, remain free to apply institutional guidelines. If they prefer to do so, they should evaluate their strategy in relation to the recommended practice and define how this is carried out. Controlled trials to develop different components of GVHD prevention and treatment strategies are strongly encouraged, and it is proposed that the present standard procedures should serve as a comparator.
The spectrum of allogeneic transplantation settings is wide. In most instances, there is no well-documented best approach for GVHD prophylaxis or treatment. As the first step, the present recommendations apply for the most common allogeneic transplant setting, HSCT for standard risk malignant disease in adult patients using an HLA-matched sibling or unrelated donor and BM or peripheral blood as stem cell source. A recommendation for cord blood transplantation is also presented. There are divergent views concerning paediatric transplantations, mismatched family donor (haploidentical) transplantations and mismatched unrelated donor transplantations, and this document does not include recommendations for such transplantations. They are planned to follow at a later time point. In the meantime, institutional guidelines should be established and followed.
The consensus working group consisted of 24 members, representatives of the working parties and working groups of EBMT and ELN as well as other experienced transplant physicians and experts in clinical GVHD.
The aim of the consensus process was to produce recommendations for standard practice in the prevention and treatment of GVHD in transplantations from a matched sibling (including a 1 Ag-mismatched family donor, 9/10 Ag matched) or matched unrelated (10/10 or higher Ag or allele match) donor for standard risk malignant disease in adult patients as defined by the EBMT current practice document.6 Disease states with the highest risk of relapse where maximal utilization of the graft-versus-malignancy effect might be used at an increased risk of GVHD were excluded.
The concept was based on the predominant current practice in European centres as documented by the recent EBMT survey5 and developed as a Delphi-like approach. Four members of the group (TR, AG, DN and TdW) produced a questionnaire with 60 items on the prophylaxis and treatment of GVHD. Each point presented one proposal and a choice for approval or disapproval, with space for comments and an alternative proposal. The responses were returned to the co-ordinator of the process (TR). Approval by more than two-thirds of the participants was regarded as provisional consensus in each cycle. If a sufficient consensus was not reached regarding an item, it was revised according to the feedback and recirculated among the participants for approval or disapproval. In some cases, two or three alternatives were offered. Altogether three rounds were needed to reach a provisional consensus in all items. On the first round, a provisional consensus was reached in 47 (78%) of the 60 items and on the second round in all but 1 item (98%). The remaining issue was resolved in the third round. A report of the provisional consensus recommendations with discussion was produced, and the final consensus was reached by the acceptance of the document by all participants.
Table 1 shows the consensus recommendations. They are split into four parts, prevention of GVHD in transplantations with standard myeloablative conditioning, prevention of GVHD in transplantations with reduced intensity conditioning (RIC), treatment of acute GVHD and treatment of chronic GVHD. Drugs are specified in detail, concerning their total dose per day, time and criteria for initiation of treatment, mode of application, duration of treatment, and time and criteria for dose adaptation or withdrawal. In contrast, recommendations do not specify brand names, except for the anti-T-cell agents. In case of ambiguities of dosing and application, the drug insert was used as reference.
The aim to produce recommendations for standard practice in the prevention and treatment of GVHD in the most common types of allogeneic HSCT was approved by all the experts invited to participate in this consensus process. The initial responses to the baseline proposal for the recommendations demonstrated the well-known great variability in the practices of different centres, reflecting the scarcity of scientific evidence to support many of the applied policies. Unsurprisingly the final consensus recommendations were not in complete accordance with the practice in any of the institutions represented by the panellists. However, with the described process it was possible to produce a set of consensus recommendations, with more than one alternative presented for a limited number of issues only.
The present document was based on the opinions of a large group of experienced transplant physicians. It was supported by scientific evidence when available, the prevailing practice in European centres as reported in a recent survey,5 and the personal experience of the panellists. In some cases, the mostly limited available evidence from studies and the dominating practice in EBMT centres were not in line; the panellists took both aspects into consideration. It was not within the scope of this report to review the literature on all the presented issues. The scientific evidence or the absence of evidence in the treatment of GVHD has been recently presented by the sister organization ASBMT.13 The parts that raised most discussion during the process are commented on. The working group acknowledges that the recommendations are inevitably arbitrary in many aspects. Modifications will be necessary based on individual factors, and additional targeted treatment measures may be needed depending on the manifestations of GVHD. Despite these aspects, the consensus panel proposes these guidelines to be used as the basic routine protocol.
Major points in the discussion concerned the role of tacrolimus as compared with CsA in the GVHD prophylaxis, the dosing of MTX and the use of leucovorin rescue, the role, brand and dosing of antithymocyte globulin (ATG) as well as the role of mycophenolate mofetil (MMF) in the prophylaxis in transplantations with RIC.
CsA and tacrolimus were regarded as roughly equivalent in GVHD prophylaxis. However, as tacrolimus is used by fewer centres in Europe than CsA5 and as most panellists did not have sufficient experience with tacrolimus, no further recommendations of the use of this drug were included.
Initially there was moderate variation in the opinions of many details in the use of CsA. Following the prevailing practice in Europe, in this consensus proposal the recommended day of the start of administration is day –1. An earlier start to ascertain adequate blood concentrations at the time of transplantation was advocated by some participants, but it was not considered essential by the majority. The presented recommendation of the initial dose of 3 mg/kg/day given as two i.v. bolus infusions represents the most widely used dosing at European centres. Evidence showing a reduced relapse rate with lower cyclosporine doses3 led to a proposal for a lower initial dose by some participants. The proposed conversion factor when switching from i.v. to oral administration varied between 1 and 3. Consensus was clear that the dose should be adapted according to toxicity and/or drug levels.
The classical dosing of MTX, given in combination with CsA, is 15 mg/m2 on day +1 and 10 mg/m2 on days +3, +6 and +11 (ref. 14). In recent years, many centres have omitted the last dose, possibly in part reflecting the developing role of ATG. There are also other, less commonly used versions, which slightly differ from the classical schedule both in timing and dosing. The initial opinions of the inclusion of the last dose of the classical schedule were almost even. The panel concluded that it recommends the four-dose schedule and omission of the last dose in case of any significant toxicity (World Health Organization grade II or higher).
The use of leucovorin rescue has varied in European centres. In the recent EBMT survey5, approximately half of the centres reported using leucovorin, and practically all of them had their own schedule of administration differing from each other in dosing, timing and/or route of administration. The panel reached a consensus in recommending the use of leucovorin rescue and proposed a schedule based on study evidence.15, 16
The recommendation about the inclusion of ATG in transplantations from an unrelated donor was decided to remain conditional. There is evidence to show improved quality of life and reduction of GVHD with the addition of ATG, without compromising survival.17, 18 The two predominant ATG brands, ATG Fresenius and Thymoglobulin, are both widely used. ATG preparations differ significantly from each other in their effects.19, 20, 21, 22, 23 A minority of centres use alemtuzumab instead of ATG. The dosing and timing of ATG administration in European centres vary, and there is no strong scientific evidence on which to base detailed recommendations. The consensus panel includes both brands in its recommendations, but renounced to include alemtuzumab because of quantitatively more limited use in Europe.5 The recommended doses and timing of administration of ATG follow the most widely applied practices.5, 24 The dose of ATG Fresenius is lower than the registration dose (20 mg/kg on 3 days).
The group presents recommendations separately for transplantations with RIC. The spectrum of reduced intensity or reduced toxicity conditioning regimens is wide and the separation from myeloablative conditioning sometimes arbitrary.25 Therefore, it was not possible to produce recommendations for the whole field. In this document, the RIC recommendations apply to regimens with markedly reduced cytotoxicity mainly relying on the graft-versus-malignancy effect, such as the very low-dose TBI containing protocols.26, 27 In RIC transplantations, MMF is widely used instead of MTX in combination with a calcineurin inhibitor for GVHD prophylaxis. However, there is no convincing evidence in the literature to support the superiority of MMF over MTX in these transplantations. In the present document, the recommendation of the use of MMF in RIC transplantations is based on the prevailing policy in Europe. This issue should be addressed in a prospective trial. ATG is conditionally proposed as a component of the prophylactic regimen, but it was pointed out that this may increase the risk of rejection when minimally intensive regimens are used, and interference with the graft-versus-malignancy effect and potentially increased risk of relapse might be a concern. Therefore, ATG should be avoided when using minimally intensive conditioning.
The details of the current use of MMF are variable. The recommendations present the most widely used practice. The proposed numbers of daily doses varied between one and four, the latter taking into account the short half-life of the drug. Also, an earlier start than the presented day +1 was proposed. The initial opinions about the duration of MMF prophylaxis varied as well.
T-cell depletion was not included in the recommendations. The use of T-cell depletion in Europe in the setting in question is limited,5 and there is no widely applied standard approach.
Initially, there was marked variability in the opinions about the GVHD prophylaxis in cord blood transplantation, reflecting uncertainty of an optimal approach. There are no data to base recommendations on evidence. A majority favoured the combination of CSA and MMF as shown in Table 1, which also became the consensus recommendation. Some opinions in favour of adding corticosteroid or ATG were presented.
The overall approach to the first-line treatment of acute GVHD was rather uniform from the beginning, although some variability in the initial opinions was seen. The treatment should be initiated based only on clinical symptoms and signs, without the need of histological confirmation. Early treatment with rapid withdrawal in case of non-confirmation was considered as less critical than delaying treatment to confirm acute GVHD. Although treatment in an early phase is in principle logical, the panel decided to recommend grade II or higher as indication for initiating the treatment. The dose of 1 mg/kg/day for early cases was advocated by some members, but as 2 mg/kg/day is the widely used practice and supported by trial evidence in comparison with a higher dose (10 mg/kg)28 this dose is presented as the consensus recommendation.
Non-absorbable oral steroid treatment (budesonide 9 mg/day) is recommended along with systemic therapy in the case of gastrointestinal GVHD. Budesonide and beclomethasone are both being used for gastrointestinal GVHD; they have different pharmacological characteristics and might have different effects on upper or lower gastrointestinal tract GVHD. There are no comparative studies to date; hence budesonide is recommended in the absence of a prospective trial.
The definition of corticosteroid resistance has been quite variable. The panel agreed on the definition of the dose of 2 mg/kg/day given for 7 days without response. However, there is study evidence supporting response evaluation on day 5 (ref. 29), and the panel agreed that in case of clearly progressive GVHD corticosteroid resistance can be diagnosed on day 5. There are no data, in contrast, to show that a change in treatment on day 5 or earlier in case of progression will impact on the final outcome. Prospective studies might evaluate this issue.
The panel concluded that there is no established standard second-line treatment for acute GVHD.30 Careful monitoring and treatment of complications, while keeping the same treatment of cyclosporine and corticosteroids, remain a valid option. Institutional guidelines should be followed, and the patients should be treated in clinical trials as far as possible.
The working group recommends the evaluation of patients with chronic GVHD according to the NIH guidelines.31 However, the group acknowledges that these guidelines are still under clinical evaluation and not yet to be regarded as standard practice.
The treatment of newly diagnosed chronic GVHD is based on corticosteroids (first line) and calcineurin inhibitors, the details depending on the clinical history and the past and ongoing treatment.32 The panel acknowledges that with the variability of the manifestations of chronic GVHD the details of the treatment are bound to vary to some extent; therefore the present recommendations include only the main lines. The time needed to evaluate the response to first-line treatment is recommended to be at least 1 month. This is essential for the planning of second-line treatment trials. However, occasional patients with truly worsening manifestations during the first weeks may need earlier re-evaluation of the treatment. For cases of insufficient response, there is no standard second-line treatment at present. Careful monitoring and treatment of complications, while keeping the same treatment of cyclosporine and corticosteroids, remain a valid option. A large variety of second-line treatments has been used.5, 33 The patients should be treated in clinical trials when possible.
The aim of the present recommendations is to establish a standard practice to create a platform for developing the procedures of the prophylaxis and treatment of GVHD in the most common types of allogeneic HSCT. They present the consensus of a large group of experienced transplant physicians, based on scientific evidence where available, prevailing practice in European centres and personal experience. The present consensus process has again demonstrated the lack of solid scientific support for a large proportion of the procedures used in GVHD prevention and management. The panel proposes that these guidelines be adopted as the routine standard in transplantation centres and used as comparator in systematic studies evaluating the advantages and disadvantages of practices differing from these recommendations. Such studies should be actively promoted. Thereby, the strategies and procedures could be developed based on scientific documentation, the heterogeneity in GVHD management policies could be reduced, optimal procedures could be identified, and, hopefully, the outcome of allogeneic transplantations would become improved.
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The authors declare no conflict of interest.
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Ruutu, T., Gratwohl, A., de Witte, T. et al. Prophylaxis and treatment of GVHD: EBMT–ELN working group recommendations for a standardized practice. Bone Marrow Transplant 49, 168–173 (2014). https://doi.org/10.1038/bmt.2013.107
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