Therapy response of glucocorticoid-refractory acute GVHD of the lower intestinal tract

Abstract

Acute graft-versus-host disease (aGVHD) is a major life-threatening complication of allogeneic hematopoietic cell transplantation. While most studies report therapy-response of aGVHD including a cumulative grade of skin, liver and intestinal tract manifestations, there is a lack of information specifically on lower gastrointestinal tract aGVHD (GI-GVHD) therapy-response, which is highly relevant in light of novel therapies that target intestinal regeneration such as IL-22, R-spondin or GLP-2. Here we retrospectively analyzed patients who developed GI-GVHD over a 6-year period. A total of 144 patients developed GI-GVHD and 82 (57%) were resistant to glucocorticoid-therapy (SR). The most commonly used second-line therapy was ruxolitinib (74%). Overall and complete response (CR) to ruxolitinib on day 28 were 44.5% and 13%, respectively. SR-GVHD patients experienced a lower 5-year overall survival (OS) (34.8 vs 53.3%, p = 0.0014) and higher incidence of 12-months non-relapse-mortality (39.2 vs 14.3%, p = 0.016) compared to glucocorticoid-sensitive patients. SR-GI-GVHD patients, that achieved a CR on day 28 after ruxolitinib start, experienced a higher OS compared to non-CR patients (p = 0.04). These findings indicate that therapy response of SR-GI-GVHD to different immunosuppressive approaches is still low, and that novel therapies specifically aiming at enhanced intestinal regeneration should be tested in clinical trials.

Salvage Therapy Using Mesenchymal Stromal Cells “MSC-FFM” For a Severe Gastrointestinal Steroid-Refractory Acute Graft-Versus-Host Disease in a 12-Year-Old Boy with Sickle Cell Disease

“…aGvHD is a much-dreaded complication following HSCT. A GI-GvHD represents an even greater therapeutic challenge with a very guarded prognosis [3,4,[23][24][25][26][27].…”

“…The number of transplants worldwide is increasing annually [1]. However, despite well-conducted prophylaxis, Graft-versus-Host Disease (GvHD) remains a major complication of transplantation, affecting 20-80% of patients [2][3][4]. Acute Graft-versus-Host Disease (aGvHD) is graded according to the Glucksberg criteria [5].…”

“…Studies show that gastrointestinal aGvHD is usually given the most severe grade, and it is linked to very high rates of non-relapse mortality [3]. Treating gastrointestinal GvHD (GI-GvHD) is a major challenge because of the imbalances in fluids and electrolytes caused by secretory diarrhea and the risks of bleeding and infection inherent among immunosuppressed and often thrombocytopenic patients [3]. GI-GvHD is also associated with malnutrition, which represents a further significant and independent risk factor for mortality.…”

“…In addition to human leukocyte antigen matching, the severity of GvHD at presentation (Glucksberg grade) is the strongest predictor of resistance to corticosteroid therapy [7]. Indeed, 60-70% of cases with severe aGvHD at presentation (≥ grade III) are SR-aGvHD and associated with a high mortality rate, estimated at 80% at one year [3].…”

The road to refractory graft-versus-host disease is paved with good intentions

“…To date, clinical trials testing the use of additional small molecules or biologicals given in combination with glucocorticoids at the onset of acute GVHD have consistently failed to improve survival ( 3 – 5 ). Although the use of ruxolitinib as salvage for steroid-refractory acute GVHD is an important advance ( 6 ), the failure rate remains substantial, and patients with lower intestinal GVHD in particular fare poorly ( 7 ). Ever-increasing immune suppression has been trialed and does not work ( 8 ).…”