Treatment and unmet needs in steroid-refractory acute graft-versus-host disease

Abstract

Acute graft-versus-host disease (aGVHD) is a common complication of allogeneic hematopoietic stem cell transplantation (alloHCT) and is a major cause of morbidity and mortality. Systemic steroid therapy is the first-line treatment for aGVHD, although about half of patients will become refractory to treatment. As the number of patients undergoing alloHCT increases, developing safe and effective treatments for aGVHD will become increasingly important, especially for those whose disease becomes refractory to systemic steroid therapy. This paper reviews current treatment options for patients with steroidrefractory aGVHD and discusses data from recently published clinical studies to outline emerging therapeutic strategies.

Independent human mesenchymal stromal cell-derived extracellular vesicle preparations differentially affect symptoms in an advanced murine Graft-versus-Host-Disease model

“…In GvHD, donor immune cells attack and destroy previously healthy tissues of the recipient. Severe acute GvHD (aGvHD) is associated with a high mortality, with only 25-40% of patients with grade III aGvHD and 1-2% of patients with grade IV aGvHD surviving more than two years (Malard et al, 2020).…”

“…There is no accepted second-line treatment for steroid refractory GvHD. This is because most studies, which analysed the efficacy of other compounds as GvHD therapy, are retrospective, singlearmed or have produced inconsistent results (Malard et al, 2020). Thus, in view of the constantly growing number of alloSCTs (Passweg et al, 2020), the heavy burden of the disease and the lack of effective anti-GvHD therapies novel treatment strategies for steroidrefractory GvHD are urgently needed.…”

Tolerance to Bone Marrow Transplantation: Do Mesenchymal Stromal Cells Still Have a Future for Acute or Chronic GvHD?

“…Treatments that have fewer data available and are therefore considered to be third-line treatment options include alemtuzumab (anti-CD52 receptor antibody) which induces T cell and B cell depletion; pentostatin (a potent inhibitor of adenosine deaminase, the purine salvage enzyme involved in the irreversible deamination of adenosine and deoxyadenosine) and inhibitors of lymphocyte proliferation such as mycophenolate mofetil (MMF) (5,13). Most recently, abatacept, a fusion protein that selectively inhibits T cell co-stimulation by binding to CD80/CD86 on APCs and blocking CD28-mediated signaling has been proposed (14).…”

“…Other recent proposed biological drugs or treatments have been introduced, whose development is based on the known pathogenesis of aGvHD, but are still in the early clinical phases of development. These include fecal microbiota transplant to reestablish the microbiota balance through infusion of a fecal suspension from a healthy donor into a patient's gastrointestinal tract, an anti CD3/CD7 immunotoxin to depletes T and NK cells, and finally vedolizumab, a mAb blocking the a4b7 integrin present on the surface of T lymphocytes and which inhibits their gastro-intestinal localization (5,13). Figure 1 summaries the major mechanisms of the drugs, shown in red, currently used for aGvHD treatment.…”

Interplay Between the Intestinal Microbiota and Acute Graft-Versus-Host Disease: Experimental Evidence and Clinical Significance

“…Treatment protocols can also be challenging because therapeutic options are limited, response rates for corticosteroids are only approximately 50%, and response durations are typically brief (6,7). In addition, several drugs are reported to be effective in patients not responding to corticosteroids, but most data are unconvincing, and combination therapies tried to date have yielded modest or no benefit over corticosteroids alone (10)(11)(12). Because of the small number of results from well-designed, large-scale, clinical studies, there is considerable variability in dealing with aGVHD worldwide, which leads to updated consensus recommendations that still have problems (13).…”