Multipotent Mesenchymal Stromal Cells for Poor Graft Function after Allogeneic Hematopoietic Cell Transplantation:a Multicenter Prospective Study

Poor graft function (PGF) is a rare but serious complication of hematopoietic cell transplantation (HCT). Boost of CD34⁺stem cells could be a therapeutic option but is not always feasible nor successfull. Due to their hematopoietic support properties and immune regulatory effects, multipotent mesenchymal stromal cells (MSC) could be considered a good candidate to help restore bone marrow (BM) niches homeostasis and facilitate hematopoiesis after HCT. Here, we conducted a multicenter prospective study to evaluate the efficacy of MSC perfusion to improve PGF after HCT.

Thirty patients (median age 51y, range 11 to 70y) received a single IV administration of third-party donor BM-derived MSC (1-2 x 10 exp6/kg body weight) for PGF after allogeneic HCT (median 151 days after HCT, range 62- 430). PGF was defined as (1) at least one cytopenia (Hb < 80 g/L, absolute neutrophil count [ANC] <0.5 x 10exp9/L, platelet count <20 x 10exp9/L) and/or (2) transfusion dependence. Overall, 3 patients were treated for tri-, 17 for bi- (mainly platelets and red blood cells [RBC]) and 10 for mono- (mainly RBC) lineage cytopenia(s). Only 5/30 patients had isolated or combined severe neutropenia. All patients were screened for full-donor chimerism, absence of disease relapse and absence of any other identifiable cause of cytopenia at inclusion.

The primary endpoint was response at day +90 after MSC administration. A significant decrease in RBC and platelet transfusion requirements was observed at day + 90 after MSC (median monthly frequencies of 0 and 0 vs. 5 and 4 before MSC, respectively, p ≤0.001). An increase in ANC was also noted (median 2.500 at day 90 vs. 1.767 x 10exp9/L before MSC, p= 0.04), with 2/5 patients with severe neutropenia having recovered an ANC > 0.5 x 10exp9/L. At day 90 post-MSC, 51.8% (95% CI, 33 - 70.7%) of patients resolved at least one of their cytopenias (overall response, OR) and 40.7% (95% CI, 22.2 - 59.3%) achieved a complete haematological recovery (CR: ANC >0.5 x 10exp9/L and transfusion independence). Corresponding response rates increased at day 180, with 69.2% (95% CI, 51.5 - 86.9%) OR and 61.5% (95% CI, 42.8 - 80.2%) CR, respectively. Overall survival at 1 year post-MSC was 70% (95% CI, 53.6 - 86.3%), with all but one of the d90-responders being alive (1 death to relapse of hematological malignancy). No severe adverse event related to MSC administration was reported during the 1-year follow-up.

In conclusion, perfusion of BM-derived MSC from a third party donor appeared to be safe and to improve PGF after allogeneic HCT, although spontaneous amelioration cannot be excluded. Further (ideally comparative) studies are warranted to confirme our results.