Updated consensus of the EBMT | Prophylaxis and management of post-transplant GvHD

Methods used to prevent and treat graft-versus-host disease (GvHD) vary worldwide due to a lack of consensus on best practice and availability of different therapies. In 2014, the European Society of Blood and Marrow Transplantation (EBMT) and European LeukemiaNet (ELN) published guidelines on how to manage GvHD in standard-risk sibling (9/10 human leukocyte antigen [HLA]-matched) or matched unrelated donor (MUD; 10/10 HLA-matched) allogeneic hematopoietic stem cell transplant (allo-HSCT).¹ The guidelines specifically focus on adult patients receiving allo-HSCT to treat a hematological malignancy with bone marrow (BM) or peripheral blood (PB) as the stem cell source.²

Recently, these guidelines were updated, based on evidence from trials, meta-analyses, systematic reviews published post-2014, and expert opinions on debated topics. This article summarizes the changes to these guidelines. The following transplant settings were not included in the recommendations: pediatric, haploidentical, and mismatched unrelated donor transplant.²

Thirty-eight statements on the topics of GvHD prophylaxis, drug management, and treatment of acute GvHD (aGvHD) and chronic (cGvHD) were created by five experts (termed the ‘task force’). An EBMT GvHD management recommendation panel of 20 experts was subsequently established, and the statements underwent a consensus process by Delphi consensus protocols. Altogether, a 100% (20/20) consensus was reached on 29 recommendations, and 95% (19/20) consensus was reached on the remaining nine recommendations.²

Recommendations are classified within four consensus evidence groups, modified from the National Comprehensive Cancer Network (NCCN) definitions (Table 1).

Table 1. Categories of evidence²

Key updates²

• Broader use of rabbit anti-T-lymphocyte globulin (rATG)
• Lower steroid doses for Grade 2 aGvHD with isolated skin or gastrointestinal (GI) manifestations
• Fluticasone, azithromycin, and montelukast (FAM) for bronchiolitis obliterans syndrome
• New treatment options for steroid-refractory (SR) aGvHD and cGvHD

Prophylaxis of GvHD²

• Patients undergoing MUD allo-HSCT and patients undergoing matched-related donor (MRD) allo-HSCT who are at a high risk of GvHD should receive ATG
• Prophylaxis with the calcineurin inhibitors cyclosporin or tacrolimus was considered equivalent
• For patients receiving myeloablative conditioning (MAC) prior to allo-HSCT, the panel recommended methotrexate (MTX) + a calcineurin inhibitor
• In common practice, the panel recommend a mycophenolate mofetil (MMF) regimen for patients receiving non-MAC and reduced intensity conditioning (RIC)

A summary of recommendations made by the panel for GvHD prophylaxis are shown in Table 2.

Table 2. Recommendations for GvHD prophylaxis²

GvHD; graft-versus-host disease; MAC, myeloablative conditioning; MMF, mycophenolate mofetil; MRD, matched related donor; MTX, methotrexate; MUD, matched unrelated donor; PB, peripheral blood; rATG, rabbit anti-thymocyte globulin; RIC, reduced intensity conditioning

Drug management during prophylaxis²

• Level of evidence for this section is low
• Target serum concentration of cyclosporin depends on the dosing schedule and transplant setting (Table 3)
• Cyclosporin or tacrolimus duration of prophylaxis: 6 months (Table 3)
  • Dose tapering should be adjusted based on individual patient risk of relapse, T-cell chimerism and whether the patient has, or does not have, GvHD
• Evidence was insufficient to recommend sirolimus as prophylaxis
• ATG dose and duration shown in Table 3
  • No recommendations on timing of rATG administration are given based on a lack of evidence

Table 3. Recommendations for drug management during GvHD prophylaxis²

aGvHD, acute graft-versus-host disease; BM, bone marrow; cGvHD, chronic graft-versus-host disease; GvHD, graft-versus-host disease; IV, intravenous; MAC, myeloablative conditioning; MRD, matched related donor; MTX, methotrexate; MUD, matched unrelated donor; rATG, rabbit anti-thymocyte globulin; RIC, reduced intensity conditioning

aGvHD treatment²

• Systemic treatment should be given for Grade ≥ 2 aGvHD
• Grade 2 aGvHD with isolated skin or upper GI manifestations: treat with lower steroid doses (Table 4)
• Choice of second-line therapy for SR GvHD:
  • Little data are available to compare options
  • No standard second-line treatment exists
  • Options are shown in Table 4
  • Patients should be enrolled on clinical trials where possible
• aGvHD with GI involvement: non-absorbable oral steroids (Table 4) in addition to systemic corticosteroids

Table 4. Treatment of aGvHD²

aGvHD, acute graft-versus-host disease; CR, complete response; GI, gastrointestinal; MMF, mycophenolate mofetil; MTX, methotrexate; rATG, rabbit anti-thymocyte globulin; SR, steroid refractory 

cGvHD treatment²

• First-line treatment for newly diagnosed cGvHD: steroids
• Severe cGvHD: addition of another immunosuppressant to reduce steroid use
• No standard second-line treatment for cGvHD
  • Follow institutional guidelines
  • Enroll patients in clinical trials where possible
  • Most widely used second-line treatment, in addition to corticosteroids, are shown in Table 5

Table 5. Treatment recommendations for cGvHD²

cGvHD, chronic graft-versus-host disease; FAM, fluticasone, azithromycin, and montelukast; MMF, mycophenolate mofetil; MRD, minimal residual disease; mTOR, mammalian target of rapamycin

Limitations

• Conflicting evidence within publications
• In SR aGvHD, novel agents have been added to the available treatment options, however none have been compared to existing second-line treatment options
• Cord blood transplant recommendations have not been updated due to a decline in the number of cord blood transplants in Europe
• Despite the common use of post-transplant cyclophosphamide in MRD and MUD allo-HSCT, no formal recommendation has been given in this review due to a lack of long-term outcome data

Conclusion

The updated guidelines established a high level of consensus (≥ 95%) in recommendations for the prevention and treatment of GvHD. However, it is likely that, as with the 2014 recommendations, implementation into clinical practice will not be standardized and adherence will vary. The authors plan to conduct an audit following the circulation of these amended guidelines to best understand any barriers to implementation and understand if clinicians are able to adhere to them.