Prospective phase II clinical trial of autologous haematopoietic stem cell transplant for treatment refractory multiple sclerosis

Background Autologous haematopoietic stem cell transplantation (AHSCT) has been explored as a therapeutic intervention in multiple sclerosis (MS) over the last two decades; however, prospective clinical trials of the most common myeloablative conditioning regimen, BEAM, are limited. Furthermore, patient selection, optimal chemotherapeutic regimen and immunological changes associated with disease response require ongoing exploration. We present the outcomes, safety and immune reconstitution (IR) of patients with active, treatment refractory MS. Methods This study was a single-centre, phase II clinical trial of AHSCT for patients with active relapsing remitting (RRMS) and secondary progressive MS (SPMS). Patients underwent AHSCT using BEAM (carmustine, etoposide, cytarabine, melphalan)+antithymocyte globulin chemotherapeutic regimen. Outcomes The primary outcome was event-free survival (EFS); defined as no clinical or radiological relapses and no disability progression. Multiparameter flow cytometry was performed for evaluation of post-transplant IR in both MS and lymphoma patients receiving the same chemotherapy regimen. Results Thirty-five patients (20 RRMS, 15 SPMS) completed AHSCT, with a median follow-up of 36 months (range 12-66). The median Expanded Disability Status Scores (EDSS) was 6 (2-7) and patients had failed a median of 4 (2-7) disease modifying therapies. 66% failed treatment with natalizumab. EFS at 3 years was 60%, (70% RRMS). Sustained improvement in EDSS was seen in 15 (44%) of patients. There was no treatment-related mortality. A sustained rise in CD39 + T regulatory cells, immunosuppressive CD56 hi natural killer cells and ablation of proinflammatory mucosal-associated invariant T cells was seen for 12 months following AHSCT in patients with MS. These changes did not occur in patients with lymphoma receiving the same chemotherapy for AHSCT. Conclusions The EFS in our MS cohort is significantly greater than other high-efficacy immunosuppressive therapies and similar to other AHSCT studies despite a more heavily pretreated cohort. Trial registration number ACTRN12613000339752

Long-term Culture of Autologous Transplanted Bone-marrow for Acute Myeloid-leukemia - Evidence for An In-vitro Hematopoietic Defect and Lack of Correlation With the Speed of Engraftment

Haematological recovery after autologous bone marrow transplantation (BMT) for acute myeloid leukaemia (AML) is often delayed and available laboratory assays cannot accurately predict speed of engraftment. By using the long-term bone marrow culture (LTBMC) method, we attempted to define the haemopoietic defect underlying this slow engraftment, and assessed the usefulness of LTBMC in predicting engraftment. Cryopreserved bone marrow (BM) harvested from three different groups (AML autografts, n = 18; autografts for non-leukaemic diseases, n = 23; normal donors, n = 10) were cultured and their growth was compared and correlated with the speed of engraftment. In the AML autografts, non-adherent and adherent progenitor production was significantly reduced compared with normal BM during the whole culture period (P < 0.01). None of the LTBMC parameters was found to correlate with engraftment after autologous BMT. The nonleukaemic autografts showed progenitor production intermediate between normal and AML autografts. Their progenitor content at the end of the culture period (reflecting the stem cell pool) was not statistically different from normal BM. In this group, most of the progenitor cell contents during LTBMC correlated with neutrophil (r(s) = -0.618 to -0.879, P < 0.01) and platelet (r(s) = -0.479 to -0.707, P < 0.02) recovery. The conclusion drawn from these results is that AML autografts are defective in their ability to sustain in vitro haemopoiesis, but this in vitro defect does not correlate with the slow haemopoietic recovery after autologous BMT. In contrast, LTBMC of autografts for non-leukaemic diseases, whose defect affects the stem cell pool to a lesser extent than BM in AML correlates with the speed of engraftment