Publications by authors named "Grizel Anstee"

3 Publications

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Low-Dose Antithymocyte Globulin for Graft-versus-Host-Disease Prophylaxis in Matched Unrelated Allogeneic Hematopoietic Stem Cell Transplantation.

Biol Blood Marrow Transplant 2017 Dec 15;23(12):2096-2101. Epub 2017 Aug 15.

Division of Hematology, Department of Medicine, University of Ottawa, Ottawa, Ontario, Canada; Ottawa Hospital Research Institute, Department of Medicine, Ottawa, Ontario, Canada; The Ottawa Hospital Bone Marrow Transplant Programme, University of Ottawa, Ottawa, Ontario, Canada. Electronic address:

Graft-versus-host disease (GVHD) is a leading cause of morbidity and mortality in allogeneic hematopoietic stem cell transplantation (alloHCT). Prophylactic in vivo T cell depletion with antithymocyte globulin (ATG) has been associated with decreased GVHD rates in many alloHCT settings. Despite decades of clinical study, optimal ATG dosing has not been established. Understanding that higher rates of GVHD are observed with matched unrelated donor (MUD) versus matched related donor (MRD) alloHCT, at our institution MUD alloHCT recipients have historically had low-dose Thymoglobulin (total dose, 2.5 mg/kg; Genzyme-Sanofi, Cambridge, MA) added to our standard MRD GVHD prophylaxis regimen. In this retrospective cohort study we assessed post-HCT the effectiveness of our uniquely low-dose ATG strategy by comparing ATG exposed (MUD) and unexposed (MRD) alloHCT recipients for GVHD and other clinical HCT outcomes. This retrospective single-center study included all HCT patients transplanted for any malignant indication at The Ottawa Hospital from 2009 to 2014. MUD patients received rabbit ATG (Thymoglobulin) at a total dose of 2.5 mg/kg given over 2 days (.5 mg/kg on day -2; 2.0 mg/kg on day -1 before stem cell infusion) in addition to standard GVHD prophylaxis. Primary outcomes assessed were incidence of acute and chronic GVHD, defined as new-onset GVHD requiring systemic immunosuppressive therapy at less or more than 100 days, respectively. Secondary outcomes included disease relapse and survival. There were 110 and 77 patients in the ATG exposed (MUD) and unexposed (MRD) cohorts, respectively. At baseline there were no significant differences in median age at transplant, sex, disease indication or risk index, graft source, conditioning regimen, or intensity between cohorts. A higher proportion of 7/8 mismatched donor transplants (13% versus 3%, P = .02) and a higher median CD34 dose (7.9 versus 4.9 × 10 cells; P < .01) was observed in the ATG exposed cohort. No differences were noted in platelet engraftment. ATG exposed patients had significantly shorter time to neutrophil engraftment than the unexposed cohort (16 versus 19 days, respectively; P < .01). ATG exposed patients had significantly lower rates of GVHD than ATG unexposed patients (57% versus 79%; P = .01), with differences predominantly in rates of chronic GVHD (18% versus 44%, P < .01). At median follow-up of 28 (range, 3 to 69) and 25 (range, 2 to 73) months for survivors in ATG exposed and unexposed cohorts, respectively, no significant differences in overall survival (median overall survival not met for either cohort), relapse incidence (26% versus 29%, P = .73), or relapse-free survival (RFS) (not met in ATG exposed and 26 months in ATG unexposed, P = .22) were observed between groups. The ATG exposed cohort had significantly higher GVHD-free RFS (GRFS) with a 2-year GRFS of 23% versus 3% (P = .003). There were no significant differences between cohorts in proportion of patientswith post-HCT infectious episodes or intensive care unit admissions. Here we report significantly lower rates of chronic GVHD and significant improvement in GRFS in an ATG exposed MUD alloHCT cohort compared with an ATG unexposed MRD cohort. These findings were observed without differences in relapse, survival, infectious complications, or intensive care unit admissions. Our findings highlight the association of unconventionally low-dose ATG with improved GVHD outcomes and suggest a need for prospective study of ATG use in lower doses.
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http://dx.doi.org/10.1016/j.bbmt.2017.08.007DOI Listing
December 2017

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

Lancet 2016 Aug 9;388(10044):576-85. Epub 2016 Jun 9.

Ottawa Hospital Research Institute, Ottawa, ON, Canada; Department of Medicine, University of Ottawa, Ottawa, ON, Canada; The Ottawa Hospital MS Clinic, Ottawa, ON, Canada.

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 disease's aggressive nature.

Funding: Multiple Sclerosis Scientific Research Foundation.
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http://dx.doi.org/10.1016/S0140-6736(16)30169-6DOI Listing
August 2016

Myasthenia Gravis Treated With Autologous Hematopoietic Stem Cell Transplantation.

JAMA Neurol 2016 06;73(6):652-8

Division of Hematology, University of Ottawa, Ottawa, Ontario, Canada2The Ottawa Hospital Research Institute, Ottawa, Ontario, Canada3The Bone Marrow Transplant Programme, University of Ottawa, The Ottawa Hospital, Ottawa, Ontario, Canada.

Importance: Some patients with myasthenia gravis (MG) do not respond to conventional treatment and have severe or life-threatening symptoms. Alternate and emerging therapies have not yet proved consistently or durably effective. Autologous hematopoietic stem cell transplant (HSCT) has been effective in treating other severe autoimmune neurologic conditions and may have similar application in MG.

Objective: To report 7 cases of severe MG treated with autologous HSCT in which consistent, durable, symptom-free, and treatment-free remission was achieved.

Design, Setting, And Participants: This retrospective cohort study reports outcomes at The Ottawa Hospital, a large, Canadian, tertiary care referral center with expertise in neurology and HSCT, from January 1, 2001, through December 31, 2014, with a median follow-up of 40 months (range, 29-149 months). Data collection and analysis were performed from February 1 through August 31, 2015. All patients with MG treated with autologous HSCT at The Ottawa Hospital were included. All had persistent severe or life-threatening MG-related symptoms despite continued use of intensive immunosuppressive therapies.

Interventions: Autologous hematopoietic stem cell grafts were mobilized with cyclophosphamide and granulocyte colony-stimulating factor, collected by peripheral blood leukapheresis, and purified away from contaminating lymphocytes using CD34 immunomagnetic selection. Patients were treated with intensive conditioning chemotherapy regimens to destroy the autoreactive immune system followed by graft reinfusion for blood and immune reconstitution.

Main Outcomes And Measures: The primary outcome was MG disease activity after autologous HSCT measured by frequency of emergency department visits and hospitalizations and Myasthenia Gravis Foundation of America (MGFA) clinical classification, MGFA therapy status, and MGFA postintervention status. Safety outcomes included all severe autologous HSCT-related complications.

Results: Seven patients underwent autologous HSCT, 6 for MG and 1 for follicular lymphoma with coincident active MG. Mean (SD) ages at MG diagnosis and at autologous HSCT were 37 (11) and 44 (10) years, respectively. Five patients (71%) had concurrent autoimmune or lymphoproliferative illnesses related to immune dysregulation. All patients had distinct clinical and electromyographic evidence of MG (MGFA clinical classification IIIb-V). All patients achieved durable MGFA complete stable remission with no residual MG symptoms and freedom from any ongoing MG therapy (MGFA postintervention status of complete stable remission). Three patients (43%) experienced transient viral reactivations, and 1 (14%) developed a secondary autoimmune disease after autologous HSCT, all of which resolved or stabilized with treatment. There were no treatment- or MG-related deaths.

Conclusions And Relevance: Autologous HSCT results in long-term symptom- and treatment-free remission in patients with severe MG. The application of autologous HSCT for this and other autoimmune neurologic conditions warrants prospective study.
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http://dx.doi.org/10.1001/jamaneurol.2016.0113DOI Listing
June 2016
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