Treatment of refractory intestinal acute GvHD using multipotent mesenchymal stromal cells (MMSC)
Contact: Dr. Darya Dubnyak
Accepted 20 September 2016
Allogeneic hematopoietic stem cell transplantation (allo-HSCT) in patients with hematological malignancies is frequently accompanied by severe complications. E.g., acute graft versus host disease (aGvHD) is common in recipients of peripheral stem cells or bone marrow, thus being among the main reasons of increased mortality or suboptimal life quality during post-transplant period. The aim of this study was to assess efficacy of multipotent mesenchymal stromal cells (MMSCs) in patients with refractory clinical forms of aGvHD with affection of gastrointestinal tract (GIT).
Patients and methods
One-hundred-eighty allo-HSCT have been performed at the National Research Center of Hematology (Moscow) between November 2012 and June 2016. Fifteen cases of refractory aGvHD with GIT involvement have been diagnosed. We studied efficacy of MMSC application as a second-line therapy for such GvHD cases: fifteen patients with refractory aGvHD and GIT involvement participated in the study, including eight males and 7 females, at a median age of 40 (21 to 57 years old). Eight patients were admitted with acute myeloid leukemia (AML), and five patients were treated for acute lymphoid leukemia (ALL). Patients with myelodysplastic syndrome (n=1), and chronic myeloid leukemia (n=1) were also included. Two patients underwent myeloablative conditioning regimen versus 13 cases with reduced intensity conditioning regimen. In 10 cases, peripheral blood stem cells have been used. Twelve patients were subjected to unrelated allo-HSCT (matched, 8, mismatched, 4). Three patients underwent allo-HSCT from related donors (matched, 2; mismatched, 1). We used different immunossupressive therapy as a preventive treatment of GvHD: MMF+CSA+MTX (n=9), CSA+MMF (n=3), MMF+post-translant cyclophosphamide on +3,4 day (n=1), post-translant cyclophosphamide on +3,+4 (n=1). In case of unrelated donor, ATG was added to the therapy. GvHD was established on an average of day +54 after HSCT. Six patients were diagnosed with aGVHD of gastrointestinal tract, 3 patients, with aGVHD affecting GIT and skin; two patients, with aGVHD of GIT and liver; four patients had aGVHD with GIT, liver and skin involvement. The most patients suffered from severe form of GvHD (grade 2 was confirmed in 1 case, grade 3, in 8 cases, grade 4, in 6patients).
We administered prednisolone at the dose of 2mg/kg, as upfront therapy,. In 2 cases only partial response was achieved. We did not achieve any response to prednisolone in 12 patients. One patient with refractory form GvHD died due to malignancy progression. Fourteen patients who failed to respond for the first-line therapy were subjected to the second-line treatment. The therapy was started at an average of 14 days (8 to 58) since the diagnosis of aGvHD. In thirteen patients, MMSC were applied at 1…3 doses (1 dose =1x106/ kg MSCs) weekly. In one patient, ATG was administrated as a second-line therapy, however, without any response. In 2 of 13 patients, a “full” response to MMSC therapy was achieved. Moreover, we have got a partial response in 5 patients and did not observe any response in 6 patients. Four patients died from further GvHD progression accompanied by infectious complications. One patient further developed a chronic form of GvHD. In 7 cases, we tried a third-line therapy of aGvHD, with average onset time of 29 (17 to 97 days) since the aGvHD diagnosis. Different therapies were use in these cases. E.g., MMSC were applied in one patient with a partial response to therapy; ATG was injected in 2 patients without clinical effect. Usage of methotrexate in three patients brought a partial effect only in one case case and was entirely ineffective in two cases. Infliximab injection in 1 patient was also without effect. Three patients from the “third-line” group further died from progressing GvHD. A next-line therapy was tried in four patients who failed to respond to previous treatment. Tacrolimus was administered in 1 case, ATG, in 1 patient, rituximab, in 2 cases. These patients died from further GvHD progression and concomitant infectious complications. The three-year overall survival was 17.7%. Conclusions: At present, there is no precise concept for treatment of refractory aGvHD. Our study has shown that the second-line therapy with MMSC may be effective in 57% of the patients with severe aGvHD complicated by GIT affection . Moreover a “full” response was achieved in 14% of the cases. We didn’t observe any differences of efficacy in terms of MMSC source, i.e., if the same or another donor should be recruited. Third-line and subsequent therapies were proven to be entirely ineffective.
Refractory gvhd, intestinal, mesenchymal stem cells, intestinal, hematopoietic stem cell transplantation
Accepted 20 September 2016