Poor graft function (PGF) is a rare but serious complication of allogeneic hematopoietic cell transplantation (alloHCT). Due to their hematopoietic supporting properties and immune regulatory ...effects, multipotent mesenchymal stromal cells (MSC) could be considered a good candidate to help to restore bone marrow (BM) niches homeostasis and facilitate hematopoiesis after alloHCT.
We prospectively assessed the efficacy and safety of ex-vivo expanded BM-derived MSC from third-party donor in a series of 30 patients with prolonged severe cytopenia and PGF after alloHCT. This multicenter trial was registered at www.clinicaltrials.gov (#NTC00603330).
Within 90 days post-MSC infusion, 53% (95% CI, 35 - 71%) of patients improved at least one cytopenia (overall response, OR) and 37% (95% CI, 19 - 54%) achieved a complete hematological response (CR: absolute neutrophil count, ANC >0.5 x 10
/L, Hb > 80g/L and platelet count > 20 x 10
/L with transfusion independence). Corresponding response rates increased to 67% (95% CI, 50 - 84%) OR and 53% (95% CI, 35 - 71%) CR within 180 days after MSC infusion. A significant decrease in red blood cells and platelets transfusion requirement was observed after MSC (median of 30-days transfusion requirement of 0.5 and 0 from d90-120 post-MSC versus 5 and 6.5 before MSC, respectively, p ≤0.001). An increase in ANC was also noted by day +90 and +180, with 3/5 patients with severe neutropenia having recovered an ANC > 1 x 10
/L within the 90-120 days after MSC infusion. Overall survival at 1 year post-MSC was 70% (95% CI, 55.4 - 88.5), with all but one of the patients who achieved CR being alive. A single infusion of third-party MSC appeared to be safe, with the exception of one deep vein thrombotic event possibly related to the intervention.
In conclusion, a single i.v. infusion of BM-derived MSC from third party donor seemed to improve hematological function after alloHCT, although spontaneous amelioration cannot be excluded. Comparative studies are warranted to confirm these encouraging results.
Few studies thus far have compared head-to-head different non-myelooablative conditioning regimens for allogeneic hematopoietic cell transplantation (allo-HCT).
Here, we report the results of a phase ...II multicenter randomized study comparing non-myeloablative allo-HCT from HLA-identical siblings (n = 54) or from 10/10 HLA-matched unrelated donors (n = 40) with either fludarabine plus 2 Gy total body irradiation (Flu-TBI arm; n = 49) or 8 Gy TLI + anti-thymocyte globulin (TLI-ATG arm; n = 45) conditioning.
The 180-day cumulative incidences of grade II-IV acute GVHD (primary endpoint) were 12.2% versus 8.9% in Flu-TBI and TLI-ATG patients, respectively (P = 0.5). Two-year cumulative incidences of moderate/severe chronic GVHD were 40.8% versus 17.8% in Flu-TBI and TLI-ATG patients, respectively (P = 0.017). Five Flu-TBI patients and 10 TLI-ATG patients received pre-emptive DLI for low donor chimerism levels, while 1 Flu-TBI patient and 5 TLI-ATG patients (including 2 patients given prior pre-emptive DLIs) received a second HCT for poor graft function, graft rejection, or disease progression. Four-year cumulative incidences of relapse/progression were 22% and 50% in Flu-TBI and TLI-ATG patients, respectively (P = 0.017). Four-year cumulative incidences of nonrelapse mortality were 24% and 13% in Flu-TBI and TLI-ATG patients, respectively (P = 0.5). Finally, 4-year overall (OS) and progression-free survivals (PFS) were 53% and 54%, respectively, in the Flu-TBI arm, versus 54% (P = 0.9) and 37% (P = 0.12), respectively, in the TLI-ATG arm.
In comparison to patients included in the Flu-TBI arm, patients included in the TLI-ATG arm had lower incidence of chronic GVHD, higher incidence of relapse and similar OS.
The study was registered on ClinicalTrial.gov ( NCT00603954 ) and EUDRACT (2010-024297-19) .
A conditioning regimen for allogeneic hematopoietic cell transplantation (HCT) combining total lymphoid irradiation (TLI) plus anti-thymocyte globulin (ATG) has been developed to induce ...graft-versus-tumor effects without graft-versus-host disease (GVHD).
We compared immune recovery in 53 patients included in a phase II randomized study comparing nonmyeloablative HCT following either fludarabine plus 2 Gy total body irradiation (TBI arm, n = 28) or 8 Gy TLI plus ATG (TLI arm, n = 25).
In comparison with TBI patients, TLI patients had a similarly low 6-month incidence of grade II-IV acute GVHD, a lower incidence of moderate/severe chronic GVHD (P = 0.02), a higher incidence of CMV reactivation (P < 0.001), and a higher incidence of relapse (P = 0.01). While recovery of total CD8(+) T cells was similar in the two groups, with median CD8(+) T-cell counts reaching the normal values 40 to 60 days after allo-HCT, TLI patients had lower percentages of naïve CD8 T cells. Median CD4(+) T-cell counts did not reach the lower limit of normal values the first year after allo-HCT in the two groups. Furthermore, CD4(+) T-cell counts were significantly lower in TLI than in TBI patients the first 6 months after transplantation. Interestingly, while median absolute regulatory T-cell (Treg) counts were comparable in TBI and TLI patients, Treg/naïve CD4(+) T-cell ratios were significantly higher in TLI than in TBI patients the 2 first years after transplantation.
Immune recovery differs substantially between these two conditioning regimens, possibly explaining the different clinical outcomes observed (NCT00603954).
The prognosis of steroid-refractory acute graft-versus-host disease (aGVHD) remains poor and better treatments are urgently needed. Multipotent mesenchymal stromal cell (MSC)-based therapy emerged as ...a promising approach but response rates were highly variable across studies. We conducted a multicenter prospective study assessing the efficacy of 1-2 infusion(s) of cryopreserved, third-party donor bone marrow-derived MSCs for treating grade II-IV steroid-refractory or -dependent aGVHD in a series of 33 patients. MSCs were produced centrally and distributed to 8 hospitals throughout Belgium to be infused in 2 consecutive cohorts of patients receiving 1-2 or 3-4 × 10
MSCs/kg per dose, respectively. All patients received MSCs as the first rescue therapy after corticosteroids, with the exception for one patient who received prior treatment with mycophenolate mofetil (that was still ongoing by the time of MSC therapy). In these conditions, MSC therapy resulted in at least a partial response in 13 patients (40.6%) at day 30 and in 15 patients (46%) within 90 days after first MSC infusion. The corresponding complete response rates were 21.6% (7 patients) and 30% (10 patients), respectively. Only 5 patients achieved a sustained complete response, lasting for at least 1 month. The 1-year overall survival was 18.2% (95% CI: 8.82-37.5%). Higher response and survival rates were observed among patients receiving 3-4 × 10
MSCs/kg for first infusion, as compared with patients receiving 1-2 × 106 MSCs/ kg. Response and survival with MSC therapy for SR/SD-aGVHD remains to be optimized.
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.
Selleslag:Celyad: Other: Clinical trial research (no honoraria recieved); Novartis: Consultancy, Honoraria, Speakers Bureau.
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Background. Allogeneic hematopoietic cell transplantation (allo-HCT) following nonmyeloablative conditioning is increasingly used as treatment for hematological malignancies in older patients or ...those with comorbidities. One of the most widely used nonmyeloablative conditioning associates fludarabine (90 mg/m² total dose) and 2 Gy total body irradiation (TBI) (Flu-TBI). This regimen can be safely performed in an outpatient setting but is associated with a relatively high incidence of graft-versus-host disease (GVHD). In an effort to prevent GVHD, the Stanford group have developed another nonmyeloablative conditioning that combines total lymphoid irradiation (TLI, 8 Gy total dose) with ATG (7.5 mg/kg Thymoglobulin® total dose) (TLI-ATG). As these 2 conditioning regimens have not been compared head to head, the Belgian Hematological Society (BHS)-transplantation committee initiated a phase II multicenter randomized study comparing nonmyeloablative allo-HCT with PBSC with either Flu-TBI (TBI arm) or TLI-ATG (TLI arm), and postgrafting immunosuppression with tacrolimus and mycophenolate mofetil. Here, we report the final analysis of the study.
Methods. Patients were randomized 1/1 between TBI or TLI arm. Main inclusion criteria consisted of hematological malignancies not rapidly progressing, age ≤ 75 years of age, and having a HLA-identical sibling donor or 10/10 HLA-matched related or unrelated donors who is fit to donate PBSC. The primary endpoint was the 6-month incidence of grade II-IV acute GVHD.
Results. 107 patients were randomized in the TBI (n=55) or TLI (n=52) arms between January 2008 and March 2011 in one of the 9 participating centers. Thirteen patients (6 in the TBI and 7 in the TLI arm) were excluded from the analyses because they did not meet the inclusion criteria at the time of the start of the conditioning (disease relapse before the start of the conditioning (n=5), ineligible for further irradiation (n=3), donor refusal to give PBSC (n=2), HLA-mismatched donor (n=2), and poor performance status (PS) precluding transplantation (n=1)). One patient randomized in the TBI arm received the TLI conditioning (and was analyzed in intention to treat in the TBI arm). Thus, the analysis includes data from 94 patients randomized to the TBI (n=49) or TLI (n=45) arm. The 2 groups were well balanced. Median follow-up for surviving patients was 45 (range, 19-65) months. The 180-day cumulative incidences of grade II-IV acute GVHD were 12.2% versus 8.9% in TBI and TLI patients, respectively (P=0.5). Two-year cumulative incidences of moderate/severe chronic GVHD were 40.8% versus 17.8% in TBI and TLI patients, respectively (P=0.017). Four-year cumulative incidences of relapse/progression were 22% and 50% in TBI and TLI patients, respectively (P=0.017). The difference remained statistically significant in multivariate analysis (HR=2.3, P=0.02). Four-year cumulative incidences of nonrelapse mortality were 24% and 13% in TBI and TLI patients, respectively (P=0.5). Finally, 4-year overall (OS) and progression-free survivals (PFS) were 53% and 54%, respectively, in the TBI arm, versus 54% (P=0.9) and 37% (P=0.12), respectively, in the TLI arm.
Conclusions. In comparison to patients included in the TBI arm, patients included in the TLI arm had lower incidence of chronic GVHD, higher incidence of relapse and similar OS. The study was registered on ClinicalTrial.gov (NCT00603954).
Beguin:Genzyme / Sanofi: Research Funding. Baron:Genzyme / Sanofi: Honoraria, Research Funding.
Histiocytoses are rare disorders with heterogeneous prognosis. BRAF(V600E) mutations have been observed in half of patients with Langerhans cell histiocytosis (LCH) and in 50% to 100% of patients ...with Erdheim-Chester disease (ECD) patients. We recently reported short-term efficacy of a BRAF inhibitor (vemurafenib) in three patients with multisystemic ECD.
Vemurafenib was given to eight patients with multisystemic ECD with CNS and/or cardiac involvement. All patients were refractory to first-line treatment and harbored a BRAF(V600E) mutation. Four patients also had LCH lesions. Positron emission tomography (PET) scan response at month 6 was used as the main evaluation criterion. Secondary evaluation criteria were comparison at baseline and at last visit of PET and of cardiovascular and cerebral infiltrations (computed tomography scan and magnetic resonance imaging MRI).
All patients were partial metabolic responders at 6 months of vemurafenib, and the median reduction in maximum standardized uptake value was 63.5% (range, 41.3% to 86.9%). Evaluation of cardiac and aortic infiltrations showed that seven patients had a partial response and one patient had stable disease according to surface measurements derived from RECIST criteria. The four patients with infratentorial CNS infiltration had an objective decrease of the lesions on MRI. All patients had an improvement of general symptoms and a persistent response to vemurafenib, with a median follow-up time of 10.5 months (range, 6 to 16 months). Skin adverse effects were frequent and severe.
Vemurafenib has an objective and sustained efficacy in BRAF(V600E)-mutated ECD as second-line therapy. In contrast to melanoma, no resistance has emerged to date after 6 to 16 months.
Objective
We undertook this study to examine microRNA (miRNA) expression across rheumatoid arthritis (RA) phenotypes, along with the effects and mechanisms of action of miRNA‐17‐5p (miR‐17).
Methods
...A miRNA array was performed in synovial tissue biopsied from patients with naive erosive RA (n = 3) and patients with nonerosive RA (n = 3). MicroRNA‐17 lipoplex was delivered intraarticularly in the murine collagen‐induced arthritis model. Clinical, histologic, and structural effects were studied over the course of arthritis. In‐depth studies of the mechanisms of action of miR‐17 were performed in primary RA fibroblast‐like synoviocytes (FLS) isolated from synovial tissue.
Results
Fifty‐five miRNAs including miR‐17 were reduced in erosive RA. The miR‐17 transfection into arthritic paws reduced the clinical inflammation score between day 2 and day 7 (2.8 versus 1.9; P = 0.03). Synovial B cell, T cell, macrophage, and polynuclear neutrophil infiltration was significantly reduced. Structural damage was also decreased, as shown by a reduction in the number of osteoclasts detected using tartrate‐resistant acid phosphatase staining (osteoclast surface/bone surface 32% versus 18%; P = 0.005) and erosion score by computed tomography analysis (2.9 versus 1.7; P = 0.023). Proinflammatory cytokines from the interleukin‐6 (IL‐6) family and IL‐1β expression were also significantly reduced, but tumor necrosis factor was not. MicroRNA‐17 directly targeted the 3′‐untranslated regions of STAT3 and JAK1. STAT3 and JAK1 messenger RNA (mRNA) and protein expression were reduced in RA FLS following miR‐17 transfection. STAT3 and JAK1 mRNA and activation of STAT3, as assessed by immunohistochemistry, were also reduced in injected paws (% stained area 93% versus 62%; P = 0.035).
Conclusion
We demonstrate an antiinflammatory and antierosive role of miR‐17 in vivo. This effect involves the suppression of the IL‐6 family autocrine‐amplifying loop through the direct targeting of JAK1 and STAT3.
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