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Editorial Theme | Novel therapies for the treatment of GvHD

Feb 19, 2020

Graft- versus-host disease (GvHD) is a common and severe complication observed after allogenic hematopoietic stem cell transplant (allo-HSCT). 1GvHD can be acute (aGvHD) or chronic (cGvHD) depending on the onset and clinical manifestations. 2First-line treatment is based on corticosteroids, but prolonged use is associated with toxicities and development of resistance. Currently, there are only two approved treatments for GvHD: ruxolitinib, indicated for steroid resistant (SR) aGvHD, and ibrutinib, used in patients with cGvHD who have failed one or more lines of therapy. There is currently a strong unmet need for new GvHD treatment options, and many emerging treatments are being tested.

We have reported on the EBMT–ELN working group recommendations for the treatment of aGvHD that were presented at the 1st EBMT GvHD Summitin May 2019. These guidelines have been developed to improve the outcomes of patients with GvHD and are based on the current standard of practice in European hematology centers. Recently, an update of these guidelines has been published in Lancet Haematology. 3

The new GvHD Hub editorial theme will focus on novel therapies for the treatment of GvHD. Here are some highlights of the content that the GvHD Hub has previously covered on novel therapies.

Emerging treatment strategies for aGvHD

Immunomodulatory drugs:

  • Sirolimus is an mTOR inhibitor that impairs T-cell signaling. Results from the BMT CTN 1501phase II trial ( NCT02806947), designed to evaluate the difference in Day 28 complete response (CR)/partial response (PR) rates between sirolimus- and prednisone-treated patients with standard-risk aGvHD, demonstrated that sirolimus had similar efficacy to prednisone, with the advantage of avoiding steroid exposure and steroid-related toxicity whilst also improving quality of life
  • Mycophenolate mofetilis an immunosuppressive agent which selectively inhibits the synthesis of guanosine, an essential nucleotide for purine base synthesis in lymphocytes
  • Methotrexateis an immune system suppressant which inhibits T and B lymphocyte proliferation by inhibiting purine synthesis. Methotrexate is an antimetabolite to folate, which is required for purine and pyrimidine base biosynthesis
  • Pentostatinis a potent inhibitor of adenosine deaminase and interferes with RNA synthesis and DNA processing in rapidly dividing cells. It leads to lymphocytopenia and suppresses CD4 helper T cells

Protease inhibitor:

  • Alpha-1 antitrypsinis a protease inhibitor, used for the treatment of SR GvHD 4, that has demonstrated efficacy in patients with high-risk gastrointestinal SR GvHD. It protects tissues from enzymatic breakdown induced by inflammatory cells

Monoclonal Antibodies:

  • Begelomab binds to the T-cell activation antigen CD26, preventing T-cell migration. A studyin 69 patients with GvHD, presented at the 45 thMeeting of the European Society for Blood and Marrow Transplantation (EBMT), indicated that this monoclonal antibody is active in SR aGvHD
  • Alemtuzumab targets CD52, a protein expressed on T and B lymphocytes and on some monocyte-derived dendritic cells. It has been demonstrated, in small studies, that alemtuzumab is effective in SR severe liver aGVHD 5and gastrointestinal aGVHD 6
  • Basiliximab, a chimeric monoclonal antibody, blocks the alpha-chain of the interleukin-2 (IL-2) receptor complex. A recent study demonstrated that basiliximab is effective as treatment for SR aGvHD in pediatric patients after haploidentical hematopoietic stem cell transplant 7

Adoptive cell therapy:

  • Mesenchymal stromal cells (MSCs) are pluripotent stem cells that can inhibit B-cell and T-cell activation. MSCs may be a possible novel strategy for the treatment of SR aGvHD. A retrospective study, analyzing a cohort of 60 patients with SR aGvHD who had received MSCs, showed that clinical responses at Week 1 following MSC treatment may be a feasible early predictor of clinical outcome

Cellular photoimmunotherapy:

Microbiome restoration:

  • Fecal microbiota transplantation (FMT) from a healthy individual into a sick recipient appears to be a promising treatment option for patients who do not respond or progress after an initial response to a first-line standard GvHD treatment.

At the 24 thCongress of the European Hematology Association (EHA), Florent Malard, Hospital Saint-Antoine, Paris, FR, talked to the GvHD Hub about the use of fecal microbiota transplantation in the context of GvHD treatment

Florent Malard | EHA 2019 | How can we better utilize FMT in patients undergoing stem cell transplantation?

Emerging treatment strategies for cGvHD

Immunomodulatory drugs:

Kinase inhibitors:

  • Baricitinib, a JAK1 and 2 inhibitor, interferes with the JAK-STAT signaling pathway in lymphocytes. It is currently being testedin an ongoing phase I/II study in patients with cGvHD that have not responded to therapy
  • KD025 is an orally available selective Rho-associated protein kinase (ROCK) 2 inhibitor. At the 61st ASH Annual Meeting, Madan Jagasiadiscussed the mechanism of action of KD025 treatment and explained that some patients may benefit from prolonged exposure to KD025

Madan Jagasia | ASH 2019 | Is sustained treatment with KD025 required for cGvHD control?

Proteasome inhibitors:

  • Bortezomib blocks the activation of NF-κB, which is critical for the inflammatory process. It has been shown to be effective in the treatment of cGvHD ( NCT01672229)
  • Ixazomib is a selective inhibitor of the 20S proteasome. In a phase II trial ( NCT02513498), ixazomib demonstrated low treatment failure at 6 months in the setting of advanced cGVHD

Cellular photoimmunotherapy:

Over the last 15 years, the field of cGvHD has evolved, with the development of novel treatmentsthat are more effective and less toxic. At the 61st ASH Annual Meeting, Steven Pavletic talked about ongoing clinical trials and new drugs for the treatment of cGvHD, such as JAK inhibitors and ROCK inhibitors.

Steven Pavletic | ASH 2019 | What is new in chronic GvHD?

  1. Jacobsohn D.A. &  Vogelsang G.B. Acute graft versus host disease. Orphanet J Rare Dis. 2007 Sep 4; 2:35. DOI: 10.1186/1750-1172-2-35
  2. Ramachandran V. et al. Review of graft-versus-host disease. Dermatol Clin. 2019 Oct; 37(4):569–582. DOI: 10.1016/j.det.2019.05.014
  3. Penack O. et al. Prophylaxis and management of graft versus host disease after stem-cell transplantation for haematological malignancies: updated consensus recommendations of the European Society for Blood and Marrow Transplantation. Lancet Haematol. 2020 Feb; 7(2):e157–e167. DOI: 10.1016/S2352-3026(19)30256-X
  4. Marcondes A.M. et al. Response of steroid-refractory acute GvHD to α1-antitrypsin. Biol Blood Marrow Transplant. 2016 Sep; 22(9):1596–1601. DOI: 10.1016/j.bbmt.2016.05.011
  5. Schub N. et al. Therapy of steroid-refractory acute GVHD with CD52 antibody alemtuzumab is effective. Bone Marrow Transplant. 2011 Jan; 46(1):143–147. DOI: 10.1038/bmt.2010.68
  6. Meunier M. et al. Alemtuzumab for severe steroid-refractory gastrointestinal acute graft-versus-host disease. Biol Blood Marrow Transplant. 2014 Sep; 20(9):1451–1454. DOI: 10.1016/j.bbmt.2014.05.031
  7. Tang F.F. et al. Basiliximab as treatment for steroid-refractory acute graft-versus-host disease in pediatric patients after haploidentical hematopoietic stem cell transplantation. Biol Blood Marrow Transplant. 2020 Feb; 26(2):351–357. DOI: 10.1016/j.bbmt.2019.10.031
  8. Jacobsohn D.A. et al. Phase II study of pentostatin in patients with corticosteroid-refractory chronic graft-versus-host disease. J Clin Oncol. 2007 Sep 20; 25(27):4255–4261. DOI: 10.1200/JCO.2007.10.8456