Editorial theme | Novel therapies for the treatment of GvHD

Graft-versus-host disease (GvHD) is a common and severe complication observed after allogenic hematopoietic stem cell transplant (allo-HSCT).¹ GvHD can be acute (aGvHD) or chronic (cGvHD) depending on the onset and clinical manifestations.² First-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 Summit in 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 1501 phase 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 mofetil is an immunosuppressive agent which selectively inhibits the synthesis of guanosine, an essential nucleotide for purine base synthesis in lymphocytes
• Methotrexate is 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
• Pentostatin is 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 antitrypsin is a protease inhibitor, used for the treatment of SR GvHD⁴, 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 study in 69 patients with GvHD, presented at the 45^th Meeting 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 aGVHD⁵ and gastrointestinal aGVHD⁶
• 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 transplant⁷

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:

• Extracorporeal photopheresis (ECP) uses ultraviolet A radiation to treat lymphocytes and is safe and effective for the treatment of aGvHD

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^th Congress 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:

• Mycophenolate mofetil
• Pentostatin demonstrated activity in patients with SR cGvHD⁸

Kinase inhibitors:

• Baricitinib, a JAK1 and 2 inhibitor, interferes with the JAK-STAT signaling pathway in lymphocytes. It is currently being tested in 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 Jagasia discussed 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:

• Extracorporeal photopheresis (ECP) uses ultraviolet A radiation to treat lymphocytes and is safe and effective for the treatment of cGvHD

Over the last 15 years, the field of cGvHD has evolved, with the development of novel treatments that 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?