Linda Hamelin

Immunoablation and autologous haemopoietic stem-cell transplantation for aggressive multiple sclerosis: a multicentre single-group phase 2 trial.

BACKGROUND Strong immunosuppression, including chemotherapy and immune-depleting antibodies followed by autologous haemopoietic stem-cell transplantation (aHSCT), has been used to treat patients with multiple sclerosis, improving control of relapsing disease. We addressed whether near-complete immunoablation followed by immune cell depleted aHSCT would result in long-term control of multiple sclerosis. METHODS We did this phase 2 single-arm trial at three hospitals in Canada. We enrolled patients with multiple sclerosis, aged 18-50 years with poor prognosis, ongoing disease activity, and an Expanded Disability Status Scale of 3.0-6.0. Autologous CD34 selected haemopoietic stem-cell grafts were collected after mobilisation with cyclophosphamide and filgrastim. Immunoablation with busulfan, cyclophosphamide, and rabbit anti-thymocyte globulin was followed by aHSCT. The primary outcome was multiple sclerosis activity-free survival (events were clinical relapse, appearance of a new or Gd-enhancing lesion on MRI, and sustained progression of Expanded Disability Status Scale score). This study was registered at ClinicalTrials.gov, NCT01099930. FINDINGS Between diagnosis and aHSCT, 24 patients had 167 clinical relapses over 140 patient-years with 188 Gd-enhancing lesions on 48 pre-aHSCT MRI scans. Median follow-up was 6.7 years (range 3.9-12.7). The primary outcome, multiple sclerosis activity-free survival at 3 years after transplantation was 69.6% (95% CI 46.6-84.2). With up to 13 years of follow-up after aHSCT, no relapses occurred and no Gd enhancing lesions or new T2 lesions were seen on 314 MRI sequential scans. The rate of brain atrophy decreased to that expected for healthy controls. One of 24 patients died of transplantation-related complications. 35% of patients had a sustained improvement in their Expanded Disability Status Scale score. INTERPRETATION We describe the first treatment to fully halt all detectable CNS inflammatory activity in patients with multiple sclerosis for a prolonged period in the absence of any ongoing disease-modifying drugs. Furthermore, many of the patients had substantial recovery of neurological function despite their diseases aggressive nature. FUNDING Multiple Sclerosis Scientific Research Foundation.

Leading change: Retrospective evaluation of a nurse-led initiative in vascular access options for autologous stem cell transplant recipients ranging from Hickman catheters to peripherally inserted central catheters.

Central venous access is essential for patients undergoing autologous hematopoietic stem cell transplantation (ASCT). Traditionally, tunneled silastic catheters have been inserted in these patients. However, changes in resource allocation, resulting in reduced surgery and surgeon time and decreasing toxicity associated with ASCT, have caused changes in venous access needs and options. This led the advanced practice nurse in the transplant program to evaluate other central access devices, which resulted in the introduction of peripherally inserted central catheters (PICCs) for this patient population. This study reports the results of a retrospective analysis comparing efficacy and complication profiles between 50 patients with the traditional Hickman catheter and 70 patients with PICCs.

Autologous Stem Cell Transplantation for Stiff Person Syndrome: Two Cases From the Ottawa Blood and Marrow Transplant Program

IMPORTANCE Stiff person syndrome (SPS) is a rare neurological disease causing significant functional disability for patients and presenting a therapeutic challenge for clinicians. Autologous hematopoietic stem cell transplantation (auto-HSCT) has been used successfully to remit autoimmune-mediated neurological diseases. We report 2 cases of severe SPS treated with auto-HSCT, a novel therapy for this disease. OBSERVATIONS Two anti-glutamic acid decarboxylase antibody-positive patients with SPS had an autologous hematopoietic stem cell graft collected and stored. Subsequently, the patients underwent auto-HSCT. Both patients achieved clinical remission with sustained, marked improvement in symptoms and a return to premorbid functioning, now more than 2.5 and 4.5 years after the procedure. CONCLUSIONS AND RELEVANCE Stiff person syndrome represents a novel indication for auto-HSCT. The resolution of clinical manifestations of SPS despite the persistence of anti-glutamic acid decarboxylase antibodies following auto-HSCT suggests that the antibody does not play a direct role in pathogenesis of SPS.

Long-term graft function following autologous hematopoietic cell transplantation and the impact of preemptive plerixafor in predicted poor mobilizers

It is generally accepted that peripheral blood autologous hematopoietic cell transplantation (AHCT) requires a minimum of 2× 10 CD34+ cells/kg for successful engraftment in the early post-transplant period. The American Society for Blood and Marrow Transplant (ASBMT) recommends a target dose of 3–5× 10 CD34+ cells/kg. Prior studies have shown that infusion of fewer CD34+ cells results in poor hematopoietic function at 6 and 12 months ; however, whether there is an optimal CD34+ dose needed to sustain long-term graft function has not been established. This study sought to establish the minimum number of CD34+ cells/kg required for, and to identify factors that may be predictive of, long-term hematopoietic function. A secondary objective was to assess the long-term outcomes of AHCT following preemptive use of plerixafor. A retrospective review of all autologous collections between January 2004 and September 2013 at The Ottawa Hospital was performed. All patients included in the study had consented to having their data collected. Patients were excluded if they did not proceed to AHCT, were not followed locally, or if the AHCT was for a nonhematological indication. The study was approved by the institution’s Research Ethics Board. Blood counts were collected at 6, 12, 24, 36, 48, and 60 months (with a 30-day margin of error if >6 months post-transplant) after the date of AHCT and until either relapse or January 2016 (the study end date). Poor long-term hematopoietic function was defined as an absolute neutrophil count (ANC) <1× 10/L, hemoglobin <100 g/L, or platelets <100× 10/L. After May 2009, plerixafor became available through a special access program. Though there was variation between physician practices, the general institutional practice was to use plerixafor preemptively for patients with a pre-collection CD34+ count of <2× 10 cells/kg, i.e., predicted poor mobilizers (PPMs). The precollection CD34+ count was determined by dividing the number of CD34+ cells/μL by the patient’s weight to predict the number of CD34+ cells obtained with 10-L apheresis. To study the impact of preemptive plerixafor, clinical outcomes of PPMs who received plerixafor were compared to those of PPMs prior to plerixafor availability. The collection procedure was performed as previously described. Data on post-transplant transfusion requirements, culture-positive infections, and infections requiring hospital admission were collected. Logistic regression was used to analyze the factors associated with poor long-term graft function. Chi-square tests were used to analyze the number of patients with poor long-term graft function at 1, 2, 3, 4, and 5 years based on infused CD34+ cell dose and to assess the differences in clinical outcomes between PPM and plerixafor-mobilized patients. The median CD34+ dose, CD34+ cell yield, and peripheral blood counts of these

Effect of Donor Age and Donor Relatedness on Time to Allogeneic Hematopoietic Cell Transplantation in Acute Leukemia

Relapse after allogeneic hematopoietic cell transplantation (HCT) for acute leukemia can be reduced when pursued early after first complete remission. The impact of donor age and donor relatedness on the time from diagnosis to transplant in patients with acute leukemia was examined to clarify the design of future prospective studies that can address optimal donor choice. Files of 100 consecutive patients undergoing transplantation for leukemia were reviewed. Recipients of related donors (RDs) and unrelated donors (UDs) were not significantly different in terms of recipient gender, age, underlying diagnosis, disease risk index, graft source, or donor HLA match. UDs were significantly younger than RDs (median age, 29 versus 51, P < .001). Multivariate linear regression revealed that when controlling for age of donor and recipient, the time from diagnosis to transplant was 35% longer with UDs compared with RDs (P = .018). No significant correlation was observed between donor and recipient age on length of time to transplant (P = .134 and P = .850, respectively), when controlling for other variables. The steps in UD procurement that contribute most to the longer time to transplant relate to activating the donor workup and scheduling the donor workup before cell collection. Understanding sources of delay in the transplant process will help transplant centers and UD registries reduce the time to transplant for patients with acute leukemia and will provide necessary insight for the design of prospective controlled studies that can address optimal donor choice.