EBMT GvHD Summit 2019 | Treatment of acute GvHD based on the EBMT–ELN working group recommendations

Acute graft-versus-host disease (aGvHD), as defined by the Mount Sinai Acute GvHD International Consortium (MAGIC) of the European Society for Blood and Marrow Transplantation (EBMT), is a serious complication of hematopoietic stem cell transplantation (HSCT).³ To date, corticosteroids are the accepted first-line treatment. However, in many patients steroid resistance or steroid dependence may develop.

On Saturday 18 May 2019, at the 1st EBMT GvHD Summit, Warsaw, PL, Olaf Penack from Charité, Berlin, DE, presented an educational talk about the recommendations of the EBMT– European Leukemia Net (ELN) consensus working group regarding the treatment of aGvHD.

The recommendations were produced by a task force of 5 experts and build on consensus statements from 20 EBMT and ELN working group members as well as other transplant experts in the field. GvHD Hub steering committee members Mohamed Mohty, Robert Zeiser, Hildegard Greinix, Arnon Nagler and Grezegorz Basak, were part of the working group. The recommendations were based on the current standard of practice throughout European hematology centers, utilizing a Delphi-like approach (≤ 80% approval of a method led to consensus).

The working group is dedicated to improve compliance with the EBMT–ELN recommendations in everyday clinical practice, in order to reduce heterogeneity in GvHD management and support optimal procedures. The end goal is to further improve the outcomes of allogeneic transplantations throughout Europe.

First-line treatment of aGvHD

• Systemic treatment is initiated for aGvHD grade II or higher is 2 mg/kg/day methylprednisolone or 2-2.5 mg/kg/day prednisone equivalent.
  • The dose should not be reduced for the first 7 days and tapering of the dose should be done slowly
    • In case of response, the dose should be reduced to 10% of the initial dose within 4 weeks
  • Early treatment with higher dose of steroids for ≥ grade II aGvHD does not improve response rates as no significant difference was seen between 2 or 10 mg/kg/day methyl-prednisolone, in terms of overall survival⁴
    • A meta-analysis of 7 randomized trials found a 14% survival decrease in patients when additional immunomodulating agents were administered¹
  • Grade II aGvHD, with isolated skin or upper gastrointestinal manifestations, can be treated with lower steroid doses of 1 mg/kg/day prednisone or methylprednisolone⁵
  • A randomized trial showed no benefit of treating grade I aGvHD¹

Second-line treatment of aGvHD

• Steroid resistance as defined by the EBMT- National Institutes of Health (NIH) and the Center for International Blood and Marrow Transplant Research (CIBMTR) Task Force:
  • progression in any organ within 3-5 days after treatment with >2m/Kg/day of prednisone equivalent
  • or failure to improve within 5-7 days of treatment initiation
  • or incomplete response after more than 28 days of immunosuppressive treatment including steroids
• Second-line therapy should be initiated when steroid resistance or dependence occurs and should follow institutional guidelines
• Patients who are refractory to corticosteroids have poor prognosis and there is currently no standard second-line treatment for these patients
  • Studies have assessed several treatment strategies in the last couple of years and current practice is to use one of the following; alemtuzumab, alpha1-antitrypsin, basiliximab, cellular therapies (mesenchymal cells, regulatory T-cells) daclizumab, extracorporal photopheresis, fecal microbiota transplantation, Janus kinase  inhibitors, methotrexate, mycophenolate mofetil, pentostatin, rabbit antithymocyte globulin, sirolimus, and vedolizumab.
• The best treatment strategy for patients with steroid refractory aGvHD is to enroll them in clinical trials or to administer best available therapy

Olaf Penack concluded by stating that a “high level of consensus (≥95%) was reached in all statements as well as a good basis of these implementations was given”. Based on a follow up survey after release of the latest guidelines, Doctor Penack stated that he is expecting difficulties regarding the standardized clinical implementation.