Wetenschappelijke artikelen HSCT voor MS

by Bram

Dit is een lijst van de wetenschappelijke artikelen over HSCT voor MS waarvan wij op de hoogte zijn.
Bijgewerkt op 14-4-2020

  • [DOI] A. Mariottini, E. D. Matteis, and P. A. Muraro, “Haematopoietic Stem Cell Transplantation for Multiple Sclerosis: Current Status,” Biodrugs, p. 1–19, 2020.
    [Bibtex]
    @article{10.1007/s40259-020-00414-1,
    author = {Mariottini, Alice and Matteis, Eleonora De and Muraro, Paolo A.},
    title = {{Haematopoietic Stem Cell Transplantation for Multiple Sclerosis: Current Status}},
    issn = {1173-8804},
    doi = {10.1007/s40259-020-00414-1},
    abstract = {{Autologous haematopoietic stem cell transplantation (AHSCT) is a treatment option for aggressive forms of multiple sclerosis (MS) that has been derived from haematological indications and repurposed for treatment of refractory autoimmune diseases. In the present review, a search for clinical studies on AHSCT was performed on the PubMed website and ClinicalTrials.gov databases. Papers were selected according to the following criteria: text written in English language, publication date between 2014 and August 2019, and reports including more than five patients. Prospective randomised and uncontrolled trials and retrospective case series were reviewed to examine the safety and efficacy of the procedure. Treatment protocols, pathological data and economic aspects of AHSCT were also succinctly covered. Growing evidence suggests that long-term suppression of inflammatory activity with stabilization or improvement of disability can be achieved in a high proportion of properly selected patients. More sophisticated outcome measures recently adopted, including effect on brain atrophy and disease biomarkers, are giving further insight into the effectiveness of transplant. The risks of the procedure have decreased to levels that can be considered acceptable for treatment of individuals with aggressive forms of MS. Careful selection of patients with an expected good benefit/risk profile, which is maximal when AHSCT is performed in early phases of the disease, and the expertise of transplant centres are critical to the success of treatment. Higher efficacy of AHSCT than with conventional treatments has recently been demonstrated by one randomised trial and further evidence is awaited from ongoing and planned trials comparing AHSCT with the most effective disease-modifying therapeutic agents.}},
    pages = {1--19},
    journal = {BioDrugs},
    year = {2020}
    }
  • [DOI] S. A. S. Kvistad, A. K. Lehmann, L. H. Trovik, E. K. Kristoffersen, L. Bø, K. Myhr, and Ø. Torkildsen, “Safety and efficacy of autologous hematopoietic stem cell transplantation for multiple sclerosis in Norway.,” Multiple sclerosis (houndmills, basingstoke, england), p. 1352458519893926, 2019.
    [Bibtex]
    @article{10.1177/1352458519893926,
    author = {Kvistad, Silje Agnethe Stokke and Lehmann, Anne Kristine and Trovik, Linn Hereide and Kristoffersen, Einar Klæbo and Bø, Lars and Myhr, Kjell-Morten and Torkildsen, Øivind},
    title = {{Safety and efficacy of autologous hematopoietic stem cell transplantation for multiple sclerosis in Norway.}},
    issn = {1352-4585},
    doi = {10.1177/1352458519893926},
    pmid = {31833798},
    abstract = {{Hematopoietic stem cell treatment (HSCT) is a promising treatment option for multiple sclerosis (MS), but detailed safety and efficacy measures are still scarce.}},
    pages = {1352458519893926},
    journal = {Multiple sclerosis (Houndmills, Basingstoke, England)},
    year = {2019}
    }
  • [DOI] J. J. Moore, J. C. Massey, C. D. Ford, M. L. Khoo, J. J. Zaunders, K. Hendrawan, Y. Barnett, M. H. Barnett, K. A. Kyle, R. Zivadinov, K. C. Ma, S. T. Milliken, I. J. Sutton, and D. D. F. Ma, “Prospective phase II clinical trial of autologous haematopoietic stem cell transplant for treatment refractory multiple sclerosis,” Journal of neurology, neurosurgery & psychiatry, vol. 90, iss. 5, p. 514–521, 2019.
    [Bibtex]
    @article{10.1136/jnnp-2018-319446,
    author = {Moore, John J and Massey, Jennifer C and Ford, Carole D and Khoo, Melissa L and Zaunders, John J and Hendrawan, Kevin and Barnett, Yael and Barnett, Michael H and Kyle, Kain A and Zivadinov, Robert and Ma, Kris C and Milliken, Sam T and Sutton, Ian J and Ma, David D F},
    title = {{Prospective phase II clinical trial of autologous haematopoietic stem cell transplant for treatment refractory multiple sclerosis}},
    issn = {0022-3050},
    doi = {10.1136/jnnp-2018-319446},
    pmid = {30538138},
    abstract = {{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. 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. 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. 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 CD56hi 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. 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. ACTRN12613000339752.}},
    pages = {514--521},
    number = {5},
    volume = {90},
    journal = {Journal of Neurology, Neurosurgery \& Psychiatry},
    year = {2019}
    }
  • [DOI] G. J. Ruiz-Argüelles, A. Ruiz-Arguelles, G. B. Gomez-Cruz, J. M. Olivares-Gazca, J. C. Olivares-Gazca, A. Leon-Peña, M. F. Vallejo-Villalobos, and G. J. Ruiz-Delgado, “Inefficacy of Rituximab Post-Autologous Hematopoietic Stem Cell Transplant to Prevent Relapses in Persons with Multiple Sclerosis,” Biology of blood and marrow transplantation, vol. 25, iss. 3, p. S319, 2019.
    [Bibtex]
    @article{10.1016/j.bbmt.2018.12.515,
    author = {Ruiz-Argüelles, Guillermo Jose and Ruiz-Arguelles, Alejandro and Gomez-Cruz, Gisela Berenice and Olivares-Gazca, Jesús Mauricio and Olivares-Gazca, Juan Carlos and Leon-Peña, Andrés and Vallejo-Villalobos, Maria Fernanda and Ruiz-Delgado, Guillermo J},
    title = {{Inefficacy of Rituximab Post-Autologous Hematopoietic Stem Cell Transplant to Prevent Relapses in Persons with Multiple Sclerosis}},
    issn = {1083-8791},
    doi = {10.1016/j.bbmt.2018.12.515},
    abstract = {{Background In an effort to reset the immune system, individuals with multiple sclerosis (MS) have undergone autologous hematopoietic stem cell transplant; this approach has produced promising results in terms of feasibility, efficacy and safety, however, the role of post-transplant adjuvant therapeutic agents needs to be further clarified. Methods Consecutive patients autografted using the “Mexican method” (ClinicalTrials.gov NCT02674217) to graft persons with MS were prospectively accrued in the study. All autografts were carried out on an outpatient basis, using cyclophosphamide (Cy) and filgrastim as mobilization regimen, the cumulative dose of Cy being 200 mg/kg, delivered on two separate blocks, nine days apart. After granulocyte recovery, all individuals received a rituximab infusion (375 mg/m2) and at discharge, patients were recommended to continue a follow-up period with additional rituximab infusions (100 mg) every two months for 1 year. Results Eighty two subjects were prospectively enrolled between June 2015 and November 2016. Twenty nine were male (35\%). Median age was 45 y (range, 28-66 y). Nineteensubjects (23\%) had primary progressive MS, 37 (45\%) relapsing remitting MS and 26 (32\%) secondary progressive MS. Median EDSS score was 5.5 (range, 0 - 7). After recovering hematopoiesis and receiving the initial dose of rituximab, 41 patients were administered rituximab in their residence countries every two months during one year, whilst 41 did not. There were not significant differences in clinical and demographic data among both groups. In order to analyze data comparatively, the EDSS values prior to and 12 mo. after the HSCT were compared in the groupswith and without additional rituximab; the median change in the EDSS score in the rituximab group was 0 (CI -3.5 to 4), and in the no rituximab group was also 0 (CI -1.5 to 3); accordingly, the change in the EDSS score between patients receiving or not rituximab was not statistically significant (P = 0.93, 95\% CI -0.5 to 0.5). We found no short-term difference in MS-relapse free survival (RFS). Conclusion The 12-month period therapy with rituximab in patients with MS who underwent autologous transplant was not effective to prevent relapses nor to cause reduction in the EDSS score.}},
    pages = {S319},
    number = {3},
    volume = {25},
    journal = {Biology of Blood and Marrow Transplantation},
    year = {2019}
    }
  • [DOI] H. Jessop, D. Farge, R. Saccardi, T. Alexander, M. Rovira, B. Sharrack, R. Greco, N. Wulffraat, J. Moore, M. Kazmi, M. Badoglio, G. Adams, B. Verhoeven, J. Murray, and J. A. Snowden, “General information for patients and carers considering haematopoietic stem cell transplantation (HSCT) for severe autoimmune diseases (ADs): A position statement from the EBMT Autoimmune Diseases Working Party (ADWP), the EBMT Nurses Group, the EBMT Patient, Family and Donor Committee and the Joint Accreditation Committee of ISCT and EBMT (JACIE),” Bone marrow transplantation, vol. 54, iss. 7, p. 933–942, 2019.
    [Bibtex]
    @article{10.1038/s41409-019-0430-7,
    author = {Jessop, Helen and Farge, Dominique and Saccardi, Riccardo and Alexander, Tobias and Rovira, Montserrat and Sharrack, Basil and Greco, Raffaella and Wulffraat, Nico and Moore, John and Kazmi, Majid and Badoglio, Manuela and Adams, Gillian and Verhoeven, Bregje and Murray, John and Snowden, John A.},
    title = {{General information for patients and carers considering haematopoietic stem cell transplantation (HSCT) for severe autoimmune diseases (ADs): A position statement from the EBMT Autoimmune Diseases Working Party (ADWP), the EBMT Nurses Group, the EBMT Patient, Family and Donor Committee and the Joint Accreditation Committee of ISCT and EBMT (JACIE)}},
    issn = {0268-3369},
    doi = {10.1038/s41409-019-0430-7},
    pmid = {30705338},
    abstract = {{Over the last 20 years, haematopoietic stem cell transplantation (HSCT) has been used to treat patients with severe autoimmune and inflammatory diseases whose response to standard treatment options has been limited, resulting in a poor long-term prognosis in terms of survival or disability. The vast majority of patients have received autologous HSCT where an increasing evidence-base supports its use in a wide range of autoimmune diseases, particularly relapsing remitting MS, systemic sclerosis and Crohn’s disease. Compared with standard treatments for autoimmune diseases, HSCT is associated with greater short-term risks, including a risk of treatment-related mortality and long-term complications. There is a need for a careful appraisal of potential benefits and risks by disease and transplant specialists working closely together with patients and carers to determine individual suitability for HSCT. HSCT should be conducted in accredited transplant centres with robust arrangements for long-term follow-up with both disease and transplant specialists. The aim of this open-access position statement is to provide plainly worded guidance for patients and non-specialist clinicians considering HSCT for an autoimmune disease, especially when treatment abroad is being considered. Recent technical publications in the field have been referenced to support the statement and provide more detail for clinicians advising patients.}},
    pages = {933--942},
    number = {7},
    volume = {54},
    journal = {Bone Marrow Transplantation},
    year = {2019}
    }
  • [DOI] R. K. Burt, R. Balabanov, J. Burman, B. Sharrack, J. A. Snowden, M. C. Oliveira, J. Fagius, J. Rose, F. Nelson, A. A. Barreira, K. Carlson, X. Han, D. Moraes, A. Morgan, K. Quigley, K. Yaung, R. Buckley, C. Alldredge, A. Clendenan, M. A. Calvario, J. Henry, B. Jovanovic, and I. B. Helenowski, “Effect of Nonmyeloablative Hematopoietic Stem Cell Transplantation vs Continued Disease-Modifying Therapy on Disease Progression in Patients With Relapsing-Remitting Multiple Sclerosis,” Jama, vol. 321, iss. 2, p. 165, 2019.
    [Bibtex]
    @article{10.1001/jama.2018.18743,
    author = {Burt, Richard K and Balabanov, Roumen and Burman, Joachim and Sharrack, Basil and Snowden, John A and Oliveira, Maria Carolina and Fagius, Jan and Rose, John and Nelson, Flavia and Barreira, Amilton Antunes and Carlson, Kristina and Han, Xiaoqiang and Moraes, Daniela and Morgan, Amy and Quigley, Kathleen and Yaung, Kimberly and Buckley, Regan and Alldredge, Carri and Clendenan, Allison and Calvario, Michelle A and Henry, Jacquelyn and Jovanovic, Borko and Helenowski, Irene B},
    title = {{Effect of Nonmyeloablative Hematopoietic Stem Cell Transplantation vs Continued Disease-Modifying Therapy on Disease Progression in Patients With Relapsing-Remitting Multiple Sclerosis}},
    issn = {0098-7484},
    doi = {10.1001/jama.2018.18743},
    pmid = {30644983},
    pages = {165},
    number = {2},
    volume = {321},
    journal = {JAMA},
    year = {2019}
    }
  • [DOI] R. P. Gale, G. B. Gómez‐Cruz, J. C. Olivares‐Gazca, A. A. León‐Peña, D. Gómez‐Almaguer, A. Gómez‐De‐León, E. E. González‐López, A. Ruiz‐Argüelles, E. Soto‐Vega, M. J. Muñoz‐Pérez, G. J. Ruiz‐Delgado, and G. J. Ruiz‐Argüelles, “Determine safety of outpatient chemotherapy and autotransplants using refrigerated, non‐frozen grafts in persons with multiple sclerosis,” Clinical transplantation, vol. 33, iss. 6, p. e13567, 2019.
    [Bibtex]
    @article{10.1111/ctr.13567,
    author = {Gale, Robert Peter and Gómez‐Cruz, Gisela Berenice and Olivares‐Gazca, Juan Carlos and León‐Peña, Andrés A. and Gómez‐Almaguer, David and Gómez‐De‐León, Andrés and González‐López, Elías Eugenio and Ruiz‐Argüelles, Alejandro and Soto‐Vega, Elena and Muñoz‐Pérez, María José and Ruiz‐Delgado, Guillermo José and Ruiz‐Argüelles, Guillermo José},
    title = {{Determine safety of outpatient chemotherapy and autotransplants using refrigerated, non‐frozen grafts in persons with multiple sclerosis}},
    issn = {0902-0063},
    doi = {10.1111/ctr.13567},
    pmid = {31004516},
    abstract = {{Persons with multiple sclerosis are increasingly treated with intermediate‐ or high‐dose chemotherapy and a hematopoietic cell autotransplant. This is often done in an inpatient setting using frozen blood cell grafts. Determine if chemotherapy and a hematopoietic cell autotransplant can be safely done in an outpatient setting using refrigerated, non‐frozen grafts. We developed an autotransplant protocol actionable in an outpatient setting using a refrigerated, non‐frozen blood graft collected after giving cyclophosphamide, 50 mg/kg/d × 2 days and filgrastim, 10 μg/kg/d. A second identical course was given 9 days later followed by infusion of blood cells stored at 4°C for 1‐4 days. The co‐primary outcomes were rates of granulocyte and platelet recovery and therapy‐related mortality. We treated 426 consecutive subjects. Median age was 47 years (range, 21‐68 years). A total of 145 (34\%) were male. Median graft refrigeration time was 1 day (range, 1‐4 days). Median interval to granulocytes >0.5 × 10E + 9/L was 8 days (range, 2‐12) and to platelets >20 × 10E + 9/L, 8 days (range, 1‐12). Only 15 subjects (4\%) were hospitalized, predominately for iatrogenic pneumothorax (N = 5) and neutropenic fever (N = 4). There was only 1 early death from infection. Intermediate‐dose chemotherapy and a hematopoietic cell autotransplant can be safely done in an outpatient setting using, refrigerated, non‐frozen grafts.}},
    pages = {e13567},
    number = {6},
    volume = {33},
    journal = {Clinical Transplantation},
    year = {2019}
    }
  • [DOI] J. A. Cohen, L. E. Baldassari, H. L. Atkins, J. D. Bowen, C. Bredeson, P. A. Carpenter, J. R. Corboy, M. S. Freedman, L. M. Griffith, R. Lowsky, N. S. Majhail, P. A. Muraro, R. A. Nash, M. C. Pasquini, S. Sarantopoulos, B. N. Savani, J. Storek, K. M. Sullivan, and G. E. Georges, “AUTOLOGOUS HEMATOPOIETIC CELL TRANSPLANTATION FOR TREATMENT-REFRACTORY RELAPSING MULTIPLE SCLEROSIS: POSITION STATEMENT FROM THE AMERICAN SOCIETY FOR BLOOD AND MARROW TRANSPLANTATION.,” Biology of blood and marrow transplantation : journal of the american society for blood and marrow transplantation, vol. 25, iss. 5, p. 845–854, 2019.
    [Bibtex]
    @article{10.1016/j.bbmt.2019.02.014,
    author = {Cohen, Jeffrey A and Baldassari, Laura E and Atkins, Harold L and Bowen, James D and Bredeson, Christopher and Carpenter, Paul A and Corboy, John R and Freedman, Mark S and Griffith, Linda M and Lowsky, Robert and Majhail, Navneet S and Muraro, Paolo A and Nash, Richard A and Pasquini, Marcelo C and Sarantopoulos, Stefanie and Savani, Bipin N and Storek, Jan and Sullivan, Keith M and Georges, George E},
    title = {{AUTOLOGOUS HEMATOPOIETIC CELL TRANSPLANTATION FOR TREATMENT-REFRACTORY RELAPSING MULTIPLE SCLEROSIS: POSITION STATEMENT FROM THE AMERICAN SOCIETY FOR BLOOD AND MARROW TRANSPLANTATION.}},
    issn = {1083-8791},
    doi = {10.1016/j.bbmt.2019.02.014},
    pmid = {30794930},
    abstract = {{Multiple sclerosis (MS) is a chronic, disabling, immune-mediated, central nervous system demyelinating and degenerative disease. Approved disease modifying therapies may be incompletely effective in some patients with highly active relapsing disease and high risk of disability. Immunoablative or myeloablative therapy followed by autologous hematopoietic cell transplantation (AHCT) has been investigated in retrospective studies, clinical trials, and meta-analyses/systematic reviews as an approach to address this unmet clinical need. On behalf of the American Society for Blood and Bone Marrow Transplantation (ASBMT), a panel of experts in AHCT and MS convened to review available evidence and make recommendations on MS as an indication for AHCT. Review of recent literature identified eight retrospective studies, eight clinical trials, and three meta-analyses/systematic reviews. In aggregate, these studies indicate that AHCT is an efficacious and safe treatment for active relapsing forms of MS to prevent clinical relapses, MRI lesion activity, and disability worsening, and to reverse disability, without unexpected adverse events. Based on the available evidence, the ASBMT recommends that treatment-refractory relapsing MS with high risk of future disability be considered a "standard of care, clinical evidence available" indication for AHCT. Collaboration of neurologists with expertise in treating MS and transplant physicians with experience performing AHCT for autoimmune disease is crucial for appropriate patient selection and optimizing transplant procedures to improve patient outcomes. Transplant centers in the United States and Canada are strongly encouraged to report baseline and outcomes data on patients receiving AHCT for multiple sclerosis to the Center for International Blood and Marrow Transplant Research.}},
    pages = {845--854},
    number = {5},
    volume = {25},
    journal = {Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation},
    year = {2019}
    }
  • [DOI] B. Sharrack, R. Saccardi, T. Alexander, M. Badoglio, J. Burman, D. Farge, R. Greco, H. Jessop, M. Kazmi, K. Kirgizov, M. Labopin, G. Mancardi, R. Martin, J. Moore, P. A. Muraro, M. Rovira, M. P. Sormani, and J. A. Snowden, “Autologous haematopoietic stem cell transplantation and other cellular therapy in multiple sclerosis and immune-mediated neurological diseases: updated guidelines and recommendations from the EBMT Autoimmune Diseases Working Party (ADWP) and the Joint Accreditation Committee of EBMT and ISCT (JACIE),” Bone marrow transplantation, p. 1–24, 2019.
    [Bibtex]
    @article{10.1038/s41409-019-0684-0,
    author = {Sharrack, Basil and Saccardi, Riccardo and Alexander, Tobias and Badoglio, Manuela and Burman, Joachim and Farge, Dominique and Greco, Raffaella and Jessop, Helen and Kazmi, Majid and Kirgizov, Kirill and Labopin, Myriam and Mancardi, Gianluigi and Martin, Roland and Moore, John and Muraro, Paolo A. and Rovira, Montserrat and Sormani, Maria Pia and Snowden, John A.},
    title = {{Autologous haematopoietic stem cell transplantation and other cellular therapy in multiple sclerosis and immune-mediated neurological diseases: updated guidelines and recommendations from the EBMT Autoimmune Diseases Working Party (ADWP) and the Joint Accreditation Committee of EBMT and ISCT (JACIE)}},
    issn = {0268-3369},
    doi = {10.1038/s41409-019-0684-0},
    pmid = {31558790},
    abstract = {{These updated EBMT guidelines review the clinical evidence, registry activity and mechanisms of action of haematopoietic stem cell transplantation (HSCT) in multiple sclerosis (MS) and other immune-mediated neurological diseases and provide recommendations for patient selection, transplant technique, follow-up and future development. The major focus is on autologous HSCT (aHSCT), used in MS for over two decades and currently the fastest growing indication for this treatment in Europe, with increasing evidence to support its use in highly active relapsing remitting MS failing to respond to disease modifying therapies. aHSCT may have a potential role in the treatment of the progressive forms of MS with a significant inflammatory component and other immune-mediated neurological diseases, including chronic inflammatory demyelinating polyneuropathy, neuromyelitis optica, myasthenia gravis and stiff person syndrome. Allogeneic HSCT should only be considered where potential risks are justified. Compared with other immunomodulatory treatments, HSCT is associated with greater short-term risks and requires close interspeciality collaboration between transplant physicians and neurologists with a special interest in these neurological conditions before, during and after treatment in accredited HSCT centres. Other experimental cell therapies are developmental for these diseases and patients should only be treated on clinical trials.}},
    pages = {1--24},
    journal = {Bone Marrow Transplantation},
    year = {2019}
    }
  • [DOI] J. C. Massey, I. J. Sutton, D. D. F. Ma, and J. J. Moore, “Regenerating Immunotolerance in Multiple Sclerosis with Autologous Hematopoietic Stem Cell Transplant,” Frontiers in immunology, vol. 9, p. 410, 2018.
    [Bibtex]
    @article{10.3389/fimmu.2018.00410,
    author = {Massey, Jennifer C. and Sutton, Ian J. and Ma, David D. F. and Moore, John J.},
    title = {{Regenerating Immunotolerance in Multiple Sclerosis with Autologous Hematopoietic Stem Cell Transplant}},
    doi = {10.3389/fimmu.2018.00410},
    pmid = {29593711},
    abstract = {{Multiple sclerosis (MS) is an inflammatory disorder of the central nervous system where evidence implicates an aberrant adaptive immune response in the accrual of neurological disability. The inflammatory phase of the disease responds to immunomodulation to varying degrees of efficacy; however, no therapy has been proven to arrest progression of disability. Recently, more intensive therapies, including immunoablation with autologous hematopoietic stem cell transplantation (AHSCT), have been offered as a treatment option to retard inflammatory disease, prior to patients becoming irreversibly disabled. Empirical clinical observations support the notion that the immune reconstitution (IR) that occurs following AHSCT is associated with a sustained therapeutic benefit; however, neither the pathogenesis of MS nor the mechanism by which AHSCT results in a therapeutic benefit has been clearly delineated. Although the antigenic target of the aberrant immune response in MS is not defined, accumulated data suggest that IR following AHSCT results in an immunotolerant state through deletion of pathogenic clones by a combination of direct ablation and induction of a lymphopenic state driving replicative senescence and clonal attrition. Restoration of immunoregulation is evidenced by changes in regulatory T cell populations following AHSCT and normalization of genetic signatures of immune homeostasis. Furthermore, some evidence exists that AHSCT may induce a rebooting of thymic function and regeneration of a diversified naïve T cell repertoire equipped to appropriately modulate the immune system in response to future antigenic challenge. In this review, we discuss the immunological mechanisms of IR therapies, focusing on AHSCT, as a means of recalibrating the dysfunctional immune response observed in MS.}},
    pages = {410},
    volume = {9},
    journal = {Frontiers in Immunology},
    year = {2018}
    }
  • [DOI] P. J. Darlington, B. Stopnicki, T. Touil, J. Doucet, L. Fawaz, M. E. Roberts, M. Boivin, N. Arbour, M. S. Freedman, H. L. Atkins, and A. Bar-Or, “Natural Killer Cells Regulate Th17 Cells After Autologous Hematopoietic Stem Cell Transplantation for Relapsing Remitting Multiple Sclerosis,” Frontiers in immunology, vol. 9, p. 834, 2018.
    [Bibtex]
    @article{10.3389/fimmu.2018.00834,
    author = {Darlington, Peter J. and Stopnicki, Brandon and Touil, Tarik and Doucet, Jean-Sebastien and Fawaz, Lama and Roberts, Morgan E. and Boivin, Marie-Noëlle and Arbour, Nathalie and Freedman, Mark S. and Atkins, Harold L. and Bar-Or, Amit},
    title = {{Natural Killer Cells Regulate Th17 Cells After Autologous Hematopoietic Stem Cell Transplantation for Relapsing Remitting Multiple Sclerosis}},
    doi = {10.3389/fimmu.2018.00834},
    pmid = {29867923},
    abstract = {{In autoimmunity, the balance of different helper T (Th) cell subsets can influence the tissue damage caused by autoreactive T cells. Pro-inflammatory Th1 and Th17 T cells are implicated as mediators of several human autoimmune conditions such as multiple sclerosis (MS). Autologous hematopoietic stem cell transplantation (aHSCT) has been tested in phase 2 clinical trials for MS patients with aggressive disease. Abrogation of new clinical relapses and brain lesions can be seen after ablative aHSCT, accompanied by significant reductions in Th17, but not Th1, cell populations and activity. The cause of this selective decrease in Th17 cell responses following ablative aHSCT is not completely understood. We identified an increase in the kinetics of natural killer (NK) cell reconstitution, relative to CD4+ T cells, in MS patients post-aHSCT, resulting in an increased NK cell:CD4+ T cell ratio that correlated with the degree of decrease in Th17 responses. Ex vivo removal of NK cells from post-aHSCT peripheral blood mononuclear cells resulted in higher Th17 cell responses, indicating that NK cells can regulate Th17 activity. NK cells were also found to be cytotoxic to memory Th17 cells, and this toxicity is mediated through NKG2D-dependent necrosis. Surprisingly, NK cells induced memory T cells to secrete more IL-17A. This was preceded by an early rise in T cell expression of RORC and IL17A mRNA, and could be blocked with neutralizing antibodies against CD58, a costimulatory receptor expressed on NK cells. Thus, NK cells provide initial co-stimulation that supports the induction of a Th17 response, followed by NKG2D-dependent cytotoxicity that limits these cells. Together these data suggest that rapid reconstitution of NK cells following aHSCT contribute to the suppression of the re-emergence of Th17 cells. This highlights the importance of NK cells in shaping the reconstituting immune system following aHSCT in MS patients.}},
    pages = {834},
    volume = {9},
    journal = {Frontiers in Immunology},
    year = {2018}
    }
  • [DOI] A. J. Thompson, S. E. Baranzini, J. Geurts, B. Hemmer, and O. Ciccarelli, “Multiple sclerosis,” The lancet, vol. 391, iss. Mult Scler 23 2017, p. 1622–1636, 2018.
    [Bibtex]
    @article{10.1016/s0140-6736(18)30481-1,
    author = {Thompson, Alan J and Baranzini, Sergio E and Geurts, Jeroen and Hemmer, Bernhard and Ciccarelli, Olga},
    title = {{Multiple sclerosis}},
    issn = {0140-6736},
    doi = {10.1016/s0140-6736(18)30481-1},
    pmid = {29576504},
    abstract = {{Multiple sclerosis continues to be a challenging and disabling condition but there is now greater understanding of the underlying genetic and environmental factors that drive the condition, including low vitamin D levels, cigarette smoking, and obesity. Early and accurate diagnosis is crucial and is supported by diagnostic criteria, incorporating imaging and spinal fluid abnormalities for those presenting with a clinically isolated syndrome. Importantly, there is an extensive therapeutic armamentarium, both oral and by infusion, for those with the relapsing remitting form of the disease. Careful consideration is required when choosing the correct treatment, balancing the side-effect profile with efficacy and escalating as clinically appropriate. This move towards more personalised medicine is supported by a clinical guideline published in 2018. Finally, a comprehensive management programme is strongly recommended for all patients with multiple sclerosis, enhancing health-related quality of life through advocating wellness, addressing aggravating factors, and managing comorbidities. The greatest remaining challenge for multiple sclerosis is the development of treatments incorporating neuroprotection and remyelination to treat and ultimately prevent the disabling, progressive forms of the condition.}},
    pages = {1622--1636},
    number = {Mult Scler 23 2017},
    volume = {391},
    journal = {The Lancet},
    year = {2018}
    }
  • [DOI] C. A. Rush, H. L. Atkins, and M. S. Freedman, “Autologous Hematopoietic Stem Cell Transplantation in the Treatment of Multiple Sclerosis,” Cold spring harbor perspectives in medicine, vol. 9, iss. 3, p. a029082, 2018.
    [Bibtex]
    @article{10.1101/cshperspect.a029082,
    author = {Rush, Carolina A. and Atkins, Harold L. and Freedman, Mark S.},
    title = {{Autologous Hematopoietic Stem Cell Transplantation in the Treatment of Multiple Sclerosis}},
    issn = {2157-1422},
    doi = {10.1101/cshperspect.a029082},
    pmid = {29610145},
    abstract = {{Multiple sclerosis (MS) is an autoimmune disorder that typically affects young people during their most productive years, causing irreversible damage and accumulation of disability. Treatments over time have had modest effects at completely controlling or suppressing disease activity, but are generally aimed at controlling early dominating inflammation that, over time, accumulates damage and leads to progressive disability. Some unfortunate patients are destined to deteriorate despite even newer and more effective agents because of the inability of these drugs to fully curb the inflammatory component of the disease. These patients require something more that might be capable of halting the disease process. Using high-intensity myeloablative chemotherapeutic agents, it is now possible to completely remove the peripheral immune system and replace it anew from autologous bone marrow–derived hematopoietic stem cells, purged of disease-causing MS cells. This procedure, referred to as hematopoietic stem cell transplantation (HSCT), produces a new immune system that appears tolerant and no longer attacks the central nervous system (CNS).}},
    pages = {a029082},
    number = {3},
    volume = {9},
    journal = {Cold Spring Harbor Perspectives in Medicine},
    year = {2018}
    }
  • [DOI] G. Laureys, B. Willekens, L. Vanopdenbosch, O. Deryck, D. Selleslag, M. D’Haeseleer, A. D. Becker, B. Dubois, D. Dierickx, G. Perrotta, V. D. Wilde, V. van Pesch, N. Straetmans, D. Dive, Y. Beguin, B. V. Wijmeersch, K. Theunissen, T. Kerre, and A. V. de Velde, “A Belgian consensus protocol for autologous hematopoietic stem cell transplantation in multiple sclerosis,” Acta neurologica belgica, vol. 118, iss. 2, p. 161–168, 2018.
    [Bibtex]
    @article{10.1007/s13760-018-0905-0,
    author = {Laureys, Guy and Willekens, Barbara and Vanopdenbosch, Ludo and Deryck, Olivier and Selleslag, Dominik and D’Haeseleer, Miguel and Becker, Ann De and Dubois, Bénédicte and Dierickx, Daan and Perrotta, Gaetano and Wilde, Virginie De and Pesch, Vincent van and Straetmans, Nicole and Dive, Dominique and Beguin, Yves and Wijmeersch, Bart Van and Theunissen, Koen and Kerre, Tessa and Velde, Ann Van de},
    title = {{A Belgian consensus protocol for autologous hematopoietic stem cell transplantation in multiple sclerosis}},
    issn = {0300-9009},
    doi = {10.1007/s13760-018-0905-0},
    pmid = {29536270},
    abstract = {{Multiple sclerosis is considered to be an immune mediated inflammatory disorder of the central nervous system. It mainly affects young, socioeconomic active patients. Although our armamentarium for this disease has significantly evolved in recent years some patients remain refractory to conventional therapies. In these cases, autologous hematopoietic stem cell transplantation can be considered as a therapeutic option. Decreasing morbidity, mortality, and increasing patient awareness have led to rising inquiry by our patients about this treatment option. With the aim of a standardized protocol and data registration, a Belgian working party on stem cell therapy in multiple sclerosis was established. In this paper, we report the consensus protocol of this working party on autologous hematopoietic stem cell transplantation in multiple sclerosis.}},
    pages = {161--168},
    number = {2},
    volume = {118},
    journal = {Acta Neurologica Belgica},
    local-url = {file://localhost/Users/bplatel/Documents/Papers%20Library/Laureys-2018-Acta%20Neurol%20Belg.pdf},
    year = {2018}
    }
  • [DOI] P. A. Muraro, M. Pasquini, H. L. Atkins, J. D. Bowen, D. Farge, A. Fassas, M. S. Freedman, G. E. Georges, F. Gualandi, N. Hamerschlak, E. Havrdova, V. K. Kimiskidis, T. Kozak, G. L. Mancardi, L. Massacesi, D. A. Moraes, R. A. Nash, S. Pavletic, J. Ouyang, M. Rovira, A. Saiz, B. Simoes, M. Trněný, L. Zhu, M. Badoglio, X. Zhong, M. P. Sormani, and R. Saccardi, “Long-term Outcomes After Autologous Hematopoietic Stem Cell Transplantation for Multiple Sclerosis,” Jama neurology, vol. 74, iss. 4, p. 459, 2017.
    [Bibtex]
    @article{10.1001/jamaneurol.2016.5867,
    author = {Muraro, Paolo A. and Pasquini, Marcelo and Atkins, Harold L. and Bowen, James D. and Farge, Dominique and Fassas, Athanasios and Freedman, Mark S. and Georges, George E. and Gualandi, Francesca and Hamerschlak, Nelson and Havrdova, Eva and Kimiskidis, Vassilios K. and Kozak, Tomas and Mancardi, Giovanni L. and Massacesi, Luca and Moraes, Daniela A. and Nash, Richard A. and Pavletic, Steven and Ouyang, Jian and Rovira, Montserrat and Saiz, Albert and Simoes, Belinda and Trněný, Marek and Zhu, Lin and Badoglio, Manuela and Zhong, Xiaobo and Sormani, Maria Pia and Saccardi, Riccardo},
    title = {{Long-term Outcomes After Autologous Hematopoietic Stem Cell Transplantation for Multiple Sclerosis}},
    issn = {2168-6149},
    doi = {10.1001/jamaneurol.2016.5867},
    pmid = {28241268},
    abstract = {{Importance Autologous hematopoietic stem cell transplantation (AHSCT) may be effective in aggressive forms of multiple sclerosis (MS) that fail to respond to standard therapies. Objective To evaluate the long-term outcomes in patients who underwent AHSCT for the treatment of MS in a large multicenter cohort. Design, Setting, and Participants Data were obtained in a multicenter, observational, retrospective cohort study. Eligibility criteria were receipt of AHSCT for the treatment of MS between January 1995 and December 2006 and the availability of a prespecified minimum data set comprising the disease subtype at baseline; the Expanded Disability Status Scale (EDSS) score at baseline; information on the administered conditioning regimen and graft manipulation; and at least 1 follow-up visit or report after transplant. The last patient visit was on July 1, 2012. To avoid bias, all eligible patients were included in the analysis regardless of their duration of follow-up. Data analysis was conducted from September 1, 2014 to April 27, 2015. Exposures Demographic, disease-related, and treatment-related exposures were considered variables of interest, including age, disease subtype, baseline EDSS score, number of previous disease-modifying treatments, and intensity of the conditioning regimen. Main Outcomes and Measures The primary outcomes were MS progression-free survival and overall survival. The probabilities of progression-free survival and overall survival were calculated using Kaplan-Meier survival curves and multivariable Cox proportional hazards regression analysis models. Results Valid data were obtained from 25 centers in 13 countries for 281 evaluable patients, with median follow-up of 6.6 years (range, 0.2-16 years). Seventy-eight percent (218 of 281) of patients had progressive forms of MS. The median EDSS score before mobilization of peripheral blood stem cells was 6.5 (range, 1.5-9). Eight deaths (2.8\%; 95\% CI, 1.0\%-4.9\%) were reported within 100 days of transplant and were considered transplant-related mortality. The 5-year probability of progression-free survival as assessed by the EDSS score was 46\% (95\% CI, 42\%-54\%), and overall survival was 93\% (95\% CI, 89\%-96\%) at 5 years. Factors associated with neurological progression after transplant were older age (hazard ratio [HR], 1.03; 95\% CI, 1.00-1.05), progressive vs relapsing form of MS (HR, 2.33; 95\% CI, 1.27-4.28), and more than 2 previous disease-modifying therapies (HR, 1.65; 95\% CI, 1.10-2.47). Higher baseline EDSS score was associated with worse overall survival (HR, 2.03; 95\% CI, 1.40-2.95). Conclusions and Relevance In this observational study of patients with MS treated with AHSCT, almost half of them remained free from neurological progression for 5 years after transplant. Younger age, relapsing form of MS, fewer prior immunotherapies, and lower baseline EDSS score were factors associated with better outcomes. The results support the rationale for further randomized clinical trials of AHSCT for the treatment of MS.}},
    pages = {459},
    number = {4},
    volume = {74},
    journal = {JAMA Neurology},
    year = {2017}
    }
  • [DOI] G. Mancardi, M. P. Sormani, P. A. Muraro, G. Boffa, and R. Saccardi, “Intense immunosuppression followed by autologous haematopoietic stem cell transplantation as a therapeutic strategy in aggressive forms of multiple sclerosis,” Multiple sclerosis journal, vol. 24, iss. 3, p. 245–255, 2017.
    [Bibtex]
    @article{10.1177/1352458517742532,
    author = {Mancardi, Gianluigi and Sormani, Maria Pia and Muraro, Paolo A and Boffa, Giacomo and Saccardi, Riccardo},
    title = {{Intense immunosuppression followed by autologous haematopoietic stem cell transplantation as a therapeutic strategy in aggressive forms of multiple sclerosis}},
    issn = {1352-4585},
    doi = {10.1177/1352458517742532},
    pmid = {29125439},
    abstract = {{In the majority of relapsing multiple sclerosis patients, the disease can be quite easily controlled by already available, approved therapies. There are, however, some aggressive cases who continue to have clinical and magnetic resonance imaging (MRI) activity in spite of the treatment. These are the cases who may now receive benefit from intense immunosuppression followed by autologous haematopoietic stem cell transplantation (aHSCT). In this review, we describe the method and the rationale of aHSCT, the more recently published studies that demonstrate its efficacy in selected multiple sclerosis cases, the problems related to safety and the transplant-related mortality risk of the procedure. A description of the ideal patient who can take advantage of aHSCT is outlined and, finally, the ongoing studies which are near to completion or are close to starting are briefly reported.}},
    pages = {245--255},
    number = {3},
    volume = {24},
    journal = {Multiple Sclerosis Journal},
    year = {2017}
    }
  • [DOI] M. Harris, M. Cossburn, and R. Gregory, “Immunoablation and aHSCT for aggressive multiple sclerosis,” The lancet, vol. 389, iss. 10072, p. 907–908, 2017.
    [Bibtex]
    @article{10.1016/s0140-6736(17)30605-0,
    author = {Harris, Matthew and Cossburn, Mark and Gregory, Ralph},
    title = {{Immunoablation and aHSCT for aggressive multiple sclerosis}},
    issn = {0140-6736},
    doi = {10.1016/s0140-6736(17)30605-0},
    pmid = {28271841},
    pages = {907--908},
    number = {10072},
    volume = {389},
    journal = {The Lancet},
    year = {2017}
    }
  • [DOI] R. A. Nash, G. J. Hutton, M. K. Racke, U. Popat, S. M. Devine, K. C. Steinmiller, L. M. Griffith, P. A. Muraro, H. Openshaw, P. H. Sayre, O. Stuve, D. L. Arnold, M. H. Wener, G. E. Georges, A. Wundes, G. H. Kraft, and J. D. Bowen, “High-dose immunosuppressive therapy and autologous HCT for relapsing-remitting MS,” Neurology, vol. 88, iss. 9, p. 842–852, 2017.
    [Bibtex]
    @article{10.1212/wnl.0000000000003660,
    author = {Nash, Richard A. and Hutton, George J. and Racke, Michael K. and Popat, Uday and Devine, Steven M. and Steinmiller, Kaitlyn C. and Griffith, Linda M. and Muraro, Paolo A. and Openshaw, Harry and Sayre, Peter H. and Stuve, Olaf and Arnold, Douglas L. and Wener, Mark H. and Georges, George E. and Wundes, Annette and Kraft, George H. and Bowen, James D.},
    title = {{High-dose immunosuppressive therapy and autologous HCT for relapsing-remitting MS}},
    issn = {0028-3878},
    doi = {10.1212/wnl.0000000000003660},
    pmid = {28148635},
    abstract = {{Objective: To evaluate the safety, efficacy, and durability of multiple sclerosis (MS) disease stabilization after high-dose immunosuppressive therapy (HDIT) and autologous hematopoietic cell transplantation (HCT). Methods: High-Dose Immunosuppression and Autologous Transplantation for Multiple Sclerosis (HALT-MS) is a phase II clinical trial of HDIT\/HCT for patients with relapsing-remitting (RR) MS who experienced relapses with disability progression (Expanded Disability Status Scale \[EDSS\] 3.0–5.5) while on MS disease-modifying therapy. The primary endpoint was event-free survival (EFS), defined as survival without death or disease activity from any one of: disability progression, relapse, or new lesions on MRI. Participants were evaluated through 5 years posttransplant. Toxicities were reported using the National Cancer Institute Common Terminology Criteria for Adverse Events (AE). Results: Twenty-five participants were evaluated for transplant and 24 participants underwent HDIT\/HCT. Median follow-up was 62 months (range 12–72). EFS was 69.2\% (90\% confidence interval \[CI\] 50.2–82.1). Progression-free survival, clinical relapse-free survival, and MRI activity-free survival were 91.3\% (90\% CI 74.7\%–97.2\%), 86.9\% (90\% CI 69.5\%–94.7\%), and 86.3\% (90\% CI 68.1\%–94.5\%), respectively. AE due to HDIT\/HCT were consistent with expected toxicities and there were no significant late neurologic adverse effects noted. Improvements were noted in neurologic disability with a median change in EDSS of −0.5 (interquartile range −1.5 to 0.0; p = 0.001) among participants who survived and completed the study. Conclusion: HDIT\/HCT without maintenance therapy was effective for inducing long-term sustained remissions of active RRMS at 5 years. ClinicalTrials.gov identifier: NCT00288626. Classification of evidence: This study provides Class IV evidence that participants with RRMS experienced sustained remissions with toxicities as expected from HDIT\/HCT.}},
    pages = {842--852},
    number = {9},
    volume = {88},
    journal = {Neurology},
    year = {2017}
    }
  • [DOI] J. F. Swart, E. M. Delemarre, F. van Wijk, J. Boelens, J. Kuball, J. M. van Laar, and N. M. Wulffraat, “Haematopoietic stem cell transplantation for autoimmune diseases,” Nature reviews rheumatology, vol. 13, iss. 4, p. 244–256, 2017.
    [Bibtex]
    @article{10.1038/nrrheum.2017.7,
    author = {Swart, Joost F. and Delemarre, Eveline M. and Wijk, Femke van and Boelens, Jaap-Jan and Kuball, Jürgen and Laar, Jacob M. van and Wulffraat, Nico M.},
    title = {{Haematopoietic stem cell transplantation for autoimmune diseases}},
    issn = {1759-4790},
    doi = {10.1038/nrrheum.2017.7},
    pmid = {28228650},
    abstract = {{Haematopoietic stem cell transplantation (HSCT) requires a careful selection of patients according to autoimmune disease, and a consideration of therapeutic alternatives, risks and benefits, and the expertise of the transplantation teamThe need for graft manipulation before HSCT is uncertainIndividualized conditioning regimens might provide increased long-term remission rates, and stem cell rescue could minimize the duration of neutropenia and improve the containment of virusesHSCT resets the immune system by renewing the CD4+ T cell compartment, especially within the Treg cell population, and by restoring T cell receptor diversity and functionIn patients with systemic sclerosis, HSCT results in increased mortality within the first year but a considerable long-term, event-free survival benefit afterwards Haematopoietic stem cell transplantation (HSCT) requires a careful selection of patients according to autoimmune disease, and a consideration of therapeutic alternatives, risks and benefits, and the expertise of the transplantation team The need for graft manipulation before HSCT is uncertain Individualized conditioning regimens might provide increased long-term remission rates, and stem cell rescue could minimize the duration of neutropenia and improve the containment of viruses HSCT resets the immune system by renewing the CD4+ T cell compartment, especially within the Treg cell population, and by restoring T cell receptor diversity and function In patients with systemic sclerosis, HSCT results in increased mortality within the first year but a considerable long-term, event-free survival benefit afterwards In this Review, the authors discuss the therapeutic application of haematopoietic stem cell transplantation in different autoimmune diseases, describing the immunological mechanisms and the risks and benefits of this procedure. Autologous haematopoietic stem cell transplantation (HSCT) is the only treatment that is able to induce long-term, drug-free and symptom-free remission in several refractory autoimmune rheumatic diseases. Over 3,000 HSCT procedures for rheumatic and nonrheumatic severe autoimmune diseases have been performed worldwide. Specific conditioning regimens are currently used to eradicate the autoreactive immunological memory of patients. Although in vivo immune cell depletion with antithymocyte globulin or anti-CD52 is the norm for many regimens, ex vivo selection of CD34+ stem cells from the graft is controversial. Following the extensive immune depletion associated with serotherapy and chemotherapy, HSCT effectively resets the immune system by renewing the CD4+ T cell compartment, especially the regulatory T cell population. The risk of transplant-related mortality (TRM) within the first 100 days should be weighed against the risk of disease-related mortality, and the careful selection and screening of patients before transplantation is essential. Systemic sclerosis is the first autoimmune disease for which HSCT has been shown, in a randomized, controlled trial, to be associated with increased TRM in the first year but a significant long-term, event-free survival benefit afterwards. In this Review, we discuss the immunological mechanisms of HSCT in various autoimmune diseases and current HSCT regimens. After carefully taking into consideration the risks and benefits of HSCT and alternative therapies, we also discuss the efficacy, complications and proposed indications of this procedure.}},
    pages = {244--256},
    number = {4},
    volume = {13},
    journal = {Nature Reviews Rheumatology},
    year = {2017}
    }
  • [DOI] N. J. Scolding, M. Pasquini, S. C. Reingold, J. A. Cohen, I. C. C. T. M. on for Sclerosis:, H. Atkins, B. Banwell, A. Bar-Or, B. Bebo, J. Bowen, R. Burt, P. Calabresi, J. Cohen, G. Comi, P. Connick, A. Cross, G. Cutter, T. Derfuss, C. Ffrench-Constant, M. Freedman, J. Galipeau, M. Goldman, S. Goldman, A. Goodman, A. Green, L. Griffith, H. Hartung, B. Hemmer, I. Hyun, E. Iacobaeus, M. Inglese, B. Jubelt, D. Karussis, P. Küry, D. Landsman, C. Laule, R. Liblau, G. Mancardi, R. A. Marrie, A. Miller, R. Miller, D. Miller, E. Mowry, P. Muraro, R. Nash, D. Ontaneda, M. Pasquini, D. Pelletier, L. Peruzzotti-Jametti, S. Pluchino, M. Racke, S. Reingold, C. Rice, O. Ringdén, A. Rovira, R. Saccardi, S. Sadiq, S. Sarantopoulos, S. Savitz, N. Scolding, P. S. Sorensen, M. P. Sormani, O. Stuve, P. Tesar, A. Thompson, M. Trojano, A. Uccelli, B. Uitdehaag, U. Utz, S. Vukusic, E. Waubant, and A. Wilkins, “Cell-based therapeutic strategies for multiple sclerosis,” Brain, vol. 140, iss. 11, p. 2776–2796, 2017.
    [Bibtex]
    @article{10.1093/brain/awx154,
    author = {Scolding, Neil J and Pasquini, Marcelo and Reingold, Stephen C and Cohen, Jeffrey A and Sclerosis:, International Conference on Cell-Based Therapies for Multiple and Atkins, Harold and Banwell, Brenda and Bar-Or, Amit and Bebo, Bruce and Bowen, James and Burt, Richard and Calabresi, Peter and Cohen, Jeffrey and Comi, Giancarlo and Connick, Peter and Cross, Anne and Cutter, Gary and Derfuss, Tobias and Ffrench-Constant, Charles and Freedman, Mark and Galipeau, Jacques and Goldman, Myla and Goldman, Steven and Goodman, Andrew and Green, Ari and Griffith, Linda and Hartung, Hans-Peter and Hemmer, Bernhard and Hyun, Insoo and Iacobaeus, Ellen and Inglese, Matilde and Jubelt, Burk and Karussis, Dimitrios and Küry, Patrick and Landsman, Douglas and Laule, Cornelia and Liblau, Roland and Mancardi, Giovanni and Marrie, Ruth Ann and Miller, Aaron and Miller, Robert and Miller, David and Mowry, Ellen and Muraro, Paolo and Nash, Richard and Ontaneda, Daniel and Pasquini, Marcelo and Pelletier, Daniel and Peruzzotti-Jametti, Luca and Pluchino, Stefano and Racke, Michael and Reingold, Stephen and Rice, Claire and Ringdén, Olle and Rovira, Alex and Saccardi, Riccardo and Sadiq, Saud and Sarantopoulos, Stefanie and Savitz, Sean and Scolding, Neil and Sorensen, Per Soelberg and Sormani, Maria Pia and Stuve, Olaf and Tesar, Paul and Thompson, Alan and Trojano, Maria and Uccelli, Antonio and Uitdehaag, Bernard and Utz, Ursula and Vukusic, Sandra and Waubant, Emmanuelle and Wilkins, Alastair},
    title = {{Cell-based therapeutic strategies for multiple sclerosis}},
    issn = {0006-8950},
    doi = {10.1093/brain/awx154},
    pmid = {29053779},
    pages = {2776--2796},
    number = {11},
    volume = {140},
    journal = {Brain},
    year = {2017}
    }
  • [DOI] B. Casanova, I. Jarque, F. Gascón, J. C. Hernández-Boluda, F. Pérez-Miralles, J. de la Rubia, C. Alcalá, J. Sanz, J. Mallada, A. Cervelló, A. Navarré, M. Carcelén-Gadea, I. Boscá, S. Gil-Perotin, C. Solano, M. A. Sanz, and F. Coret, “Autologous hematopoietic stem cell transplantation in relapsing-remitting multiple sclerosis: comparison with secondary progressive multiple sclerosis,” Neurological sciences, vol. 38, iss. 7, p. 1213–1221, 2017.
    [Bibtex]
    @article{10.1007/s10072-017-2933-6,
    author = {Casanova, Bonaventura and Jarque, Isidro and Gascón, Francisco and Hernández-Boluda, Juan Carlos and Pérez-Miralles, Francisco and Rubia, Javier de la and Alcalá, Carmen and Sanz, Jaime and Mallada, Javier and Cervelló, Angeles and Navarré, Arantxa and Carcelén-Gadea, María and Boscá, Isabel and Gil-Perotin, Sara and Solano, Carlos and Sanz, Miguel Angel and Coret, Francisco},
    title = {{Autologous hematopoietic stem cell transplantation in relapsing-remitting multiple sclerosis: comparison with secondary progressive multiple sclerosis}},
    issn = {1590-1874},
    doi = {10.1007/s10072-017-2933-6},
    pmid = {28396953},
    abstract = {{The main objective of our work is to describe the long-term results of myeloablative autologous hematopoietic stem cell transplant (AHSCT) in multiple sclerosis patients. Patients that failed to conventional therapies for multiple sclerosis (MS) underwent an approved protocol for AHSCT, which consisted of peripheral blood stem cell mobilization with cyclophosphamide and granulocyte colony-stimulating factor (G-CSF), followed by a conditioning regimen of BCNU, Etoposide, Ara-C, Melphalan IV, plus Rabbit Thymoglobulin. Thirty-eight MS patients have been transplanted since 1999. Thirty-one patients have been followed for more than 2 years (mean 8.4 years). There were 22 relapsing-remitting multiple sclerosis (RRMS) patients and 9 secondary progressive multiple sclerosis (SPMS) patients. No death related to AHSCT. A total of 10 patients (32.3\%) had at least one relapse during post-AHSCT evolution, 6 patients in the RRMS group (27.2\%) and 4 in the SPMS group (44.4\%). After AHSCT, 7 patients (22.6\%) experienced progression of disability, all within SP form. By contrast, no patients with RRMS experienced worsening of disability after a median follow-up of 5.4 years, 60\% of them showed a sustained reduction in disability (SRD), defined as the improvement of 1.0 point in the expanded disability status scale (EDSS) sustains for 6 months (0.5 in cases of EDSS ≥ 5.5). The only clinical variable that predicted a poor response to AHSCT was a high EDSS in the year before transplant. AHSCT using the BEAM-ATG scheme is safe and efficacious to control the aggressive forms of RRMS.}},
    pages = {1213--1221},
    number = {7},
    volume = {38},
    journal = {Neurological Sciences},
    year = {2017}
    }
  • [DOI] M. P. Sormani, P. A. Muraro, I. Schiavetti, A. Signori, A. Laroni, R. Saccardi, and G. L. Mancardi, “Autologous hematopoietic stem cell transplantation in multiple sclerosis,” Neurology, vol. 88, iss. 22, p. 2115–2122, 2017.
    [Bibtex]
    @article{10.1212/wnl.0000000000003987,
    author = {Sormani, Maria Pia and Muraro, Paolo A and Schiavetti, Irene and Signori, Alessio and Laroni, Alice and Saccardi, Riccardo and Mancardi, Gian Luigi},
    title = {{Autologous hematopoietic stem cell transplantation in multiple sclerosis}},
    issn = {0028-3878},
    doi = {10.1212/wnl.0000000000003987},
    pmid = {28455383},
    abstract = {{To summarize the evidence on immunoablative therapy followed by autologous hematopoietic stem cell transplantation (aHSCT) to manage severe and treatment-refractory multiple sclerosis (MS).}},
    pages = {2115--2122},
    number = {22},
    volume = {88},
    journal = {Neurology},
    year = {2017}
    }
  • [DOI] P. A. Muraro, R. Martin, G. L. Mancardi, R. Nicholas, M. P. Sormani, and R. Saccardi, “Autologous haematopoietic stem cell transplantation for treatment of multiple sclerosis,” Nature reviews neurology, vol. 13, iss. 7, p. 391–405, 2017.
    [Bibtex]
    @article{10.1038/nrneurol.2017.81,
    author = {Muraro, Paolo A. and Martin, Roland and Mancardi, Giovanni Luigi and Nicholas, Richard and Sormani, Maria Pia and Saccardi, Riccardo},
    title = {{Autologous haematopoietic stem cell transplantation for treatment of multiple sclerosis}},
    issn = {1759-4758},
    doi = {10.1038/nrneurol.2017.81},
    pmid = {28621766},
    abstract = {{Ablative therapy and autologous haematopoietic stem cell transplantation (AHSCT) is an increasingly studied and used strategy for the treatment of multiple sclerosis (MS)AHSCT confers benefits for patients with MS by achieving radical suppression of inflammatory MS activityQualitative changes in the reconstituted immune system and durable remissions without additional immune intervention support the notion that AHSCT regenerates the immune system (a process known as immune resetting)Complete suppression of MS disease activity for 4–5 years has been documented in 70–80\% of patients with relapsing–remitting MS who have undergone AHSCT; neurological improvements have also been demonstratedOptimal candidates for AHSCT are young, ambulatory and have inflammatory-active relapsing–remitting MS (RRMS); current appropriate indications for AHSCT include aggressive and highly active treatment-refractory RRMSClinical trials to compare AHSCT with approved drugs in RRMS and determine its benefits in inflammatory-active progressive MS are warranted, but progress is hindered by a lack of investment and funding Ablative therapy and autologous haematopoietic stem cell transplantation (AHSCT) is an increasingly studied and used strategy for the treatment of multiple sclerosis (MS) AHSCT confers benefits for patients with MS by achieving radical suppression of inflammatory MS activity Qualitative changes in the reconstituted immune system and durable remissions without additional immune intervention support the notion that AHSCT regenerates the immune system (a process known as immune resetting) Complete suppression of MS disease activity for 4–5 years has been documented in 70–80\% of patients with relapsing–remitting MS who have undergone AHSCT; neurological improvements have also been demonstrated Optimal candidates for AHSCT are young, ambulatory and have inflammatory-active relapsing–remitting MS (RRMS); current appropriate indications for AHSCT include aggressive and highly active treatment-refractory RRMS Clinical trials to compare AHSCT with approved drugs in RRMS and determine its benefits in inflammatory-active progressive MS are warranted, but progress is hindered by a lack of investment and funding Autologous haematopoietic stem cell transplantation has produced striking results in patients with aggressive multiple sclerosis in small trials. In this Review, Muraro et al. provide an overview of the procedure, detail evidence for its high efficacy in multiple sclerosis, and provide recommendations for its clinical use and future trials. Autologous haematopoietic stem cell transplantation (AHSCT) is a multistep procedure that enables destruction of the immune system and its reconstitution from haematopoietic stem cells. Originally developed for the treatment of haematological malignancies, the procedure has been adapted for the treatment of severe immune-mediated disorders. Results from ∼20 years of research make a compelling case for selective use of AHSCT in patients with highly active multiple sclerosis (MS), and for controlled trials. Immunological studies support the notion that AHSCT causes qualitative immune resetting, and have provided insight into the mechanisms that might underlie the powerful treatment effects that last well beyond recovery of immune cell numbers. Indeed, studies have demonstrated that AHSCT can entirely suppress MS disease activity for 4–5 years in 70–80\% of patients, a rate that is higher than those achieved with any other therapies for MS. Treatment-related mortality, which was 3.6\% in studies before 2005, has decreased to 0.3\% in studies since 2005. Current evidence indicates that the patients who are most likely to benefit from and tolerate AHSCT are young, ambulatory and have inflammatory MS activity. Clinical trials are required to rigorously test the efficacy, safety and cost-effectiveness of AHSCT against highly active MS drugs.}},
    pages = {391--405},
    number = {7},
    volume = {13},
    journal = {Nature Reviews Neurology},
    year = {2017}
    }
  • [DOI] L. C. M. Arruda, E. Clave, H. Moins-Teisserenc, C. Douay, D. Farge, and A. Toubert, “Resetting the immune response after autologous hematopoietic stem cell transplantation for autoimmune diseases,” Current research in translational medicine, vol. 64, iss. 2, p. 107–113, 2016.
    [Bibtex]
    @article{10.1016/j.retram.2016.03.004,
    author = {Arruda, L.C.M. and Clave, E. and Moins-Teisserenc, H. and Douay, C. and Farge, D. and Toubert, A.},
    title = {{Resetting the immune response after autologous hematopoietic stem cell transplantation for autoimmune diseases}},
    issn = {2452-3186},
    doi = {10.1016/j.retram.2016.03.004},
    pmid = {27316394},
    abstract = {{Autologous hematopoietic stem cell transplantation (AHSCT) is currently investigated as treatment for severe and refractory autoimmune diseases, such as multiple sclerosis (MS), systemic sclerosis (SSc), Crohn's disease (CD) and systemic lupus erythematosus. Randomized clinical trials in MS, SSc and CD have shown the efficacy of AHSCT to promote control of disease activity and progression, when compared to conventional treatment. The use of high dose immunosuppressive conditioning is essential to eliminate the autoimmune repertoire, and the re-infusion of autologous hematopoietic stem cells avoids long-term leucopenia by reconstitution of both immune and hematological systems. Recent studies showed that AHSCT is able to deplete the autoimmune compartment and further promote the formation of a new auto-tolerant immune repertoire, reducing the inflammatory milieu and leading to long-term clinical remission without any complementary post-graft treatment. Deep knowledge about the mechanisms of action related to AHSCT-induced remission is required for the management of possible post-AHSCT relapse and improvement of clinical protocols. This paper will review the mechanisms enrolled in the immune response resetting promoted by AHSCT in patients with autoimmune diseases.}},
    pages = {107--113},
    number = {2},
    volume = {64},
    journal = {Current Research in Translational Medicine},
    year = {2016}
    }
  • [DOI] B. M. Segal and O. Stüve, “Primary progressive multiple sclerosis—why we are failing,” The lancet, vol. 387, iss. 10023, p. 1032–1034, 2016.
    [Bibtex]
    @article{10.1016/s0140-6736(16)00158-6,
    author = {Segal, Benjamin M and Stüve, Olaf},
    title = {{Primary progressive multiple sclerosis—why we are failing}},
    issn = {0140-6736},
    doi = {10.1016/s0140-6736(16)00158-6},
    pmid = {26827076},
    pages = {1032--1034},
    number = {10023},
    volume = {387},
    journal = {The Lancet},
    year = {2016}
    }
  • [DOI] M. P. Sormani, P. A. Muraro, R. Saccardi, and G. Mancardi, “NEDA status in highly active MS can be more easily obtained with autologous hematopoietic stem cell transplantation than other drugs,” Multiple sclerosis journal, vol. 23, iss. 2, p. 201–204, 2016.
    [Bibtex]
    @article{10.1177/1352458516645670,
    author = {Sormani, Maria Pia and Muraro, Paolo A and Saccardi, Riccardo and Mancardi, Gianluigi},
    title = {{NEDA status in highly active MS can be more easily obtained with autologous hematopoietic stem cell transplantation than other drugs}},
    issn = {1352-4585},
    doi = {10.1177/1352458516645670},
    pmid = {27207454},
    abstract = {{The no evidence of disease activity (NEDA) composite measure has emerged as one attractive new target of therapies in relapsing–remitting multiple sclerosis (RRMS), consisting of the following features: (1) no relapses, (2) no disability progression, and (3) no magnetic resonance imaging (MRI) activity (new or enlarging T2 lesions or Gd-enhancing lesions). Achievement of NEDA status in patients receiving a disease-modifying therapy (DMT) seems to be an ambitious but ideal goal for therapies in RRMS. Recently, published post hoc analyses of clinical trials reported percentages of RRMS patients maintaining the NEDA status after 2 years of therapy ranging between 13\% and 46\%. Long-term assessment of NEDA patients in real-life settings showed very low probability to be NEDA in the long run. Against this scenario, immunoablative therapy followed by autologous hematopoietic stem cell transplantation (aHSCT) demonstrated the potential to maintain a much higher proportion of NEDA patients at 2 years (ranging from 78\% to 83\%) and also at 5 years (ranging from 60\% to 68\%). This is even more relevant when considering that MS patients who underwent aHSCT are much more active than patients usually enrolled in clinical trials. The emerging evidence of the efficacy of this therapeutic approach in early aggressive and treatment-resistant RRMS calls for the organization of a randomized comparative trial to fully evaluate the risk–benefit profile of aHSCT in patients with highly active MS not responding to DMTs.}},
    pages = {201--204},
    number = {2},
    volume = {23},
    journal = {Multiple Sclerosis Journal},
    year = {2016}
    }
  • [DOI] H. L. Atkins, M. Bowman, D. Allan, G. Anstee, D. L. Arnold, A. Bar-Or, I. Bence-Bruckler, P. Birch, C. Bredeson, J. Chen, D. Fergusson, M. Halpenny, L. Hamelin, L. Huebsch, B. Hutton, P. Laneuville, Y. Lapierre, H. Lee, L. Martin, S. McDiarmid, P. O’Connor, T. Ramsay, M. Sabloff, L. Walker, and M. S. Freedman, “Immunoablation and autologous haemopoietic stem-cell transplantation for aggressive multiple sclerosis: a multicentre single-group phase 2 trial,” The lancet, vol. 388, iss. 10044, p. 576–585, 2016.
    [Bibtex]
    @article{10.1016/s0140-6736(16)30169-6,
    author = {Atkins, Harold L and Bowman, Marjorie and Allan, David and Anstee, Grizel and Arnold, Douglas L and Bar-Or, Amit and Bence-Bruckler, Isabelle and Birch, Paul and Bredeson, Christopher and Chen, Jacqueline and Fergusson, Dean and Halpenny, Mike and Hamelin, Linda and Huebsch, Lothar and Hutton, Brian and Laneuville, Pierre and Lapierre, Yves and Lee, Hyunwoo and Martin, Lisa and McDiarmid, Sheryl and O'Connor, Paul and Ramsay, Timothy and Sabloff, Mitchell and Walker, Lisa and Freedman, Mark S},
    title = {{Immunoablation and autologous haemopoietic stem-cell transplantation for aggressive multiple sclerosis: a multicentre single-group phase 2 trial}},
    issn = {0140-6736},
    doi = {10.1016/s0140-6736(16)30169-6},
    pmid = {27291994},
    abstract = {{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.}},
    pages = {576--585},
    number = {10044},
    volume = {388},
    journal = {The Lancet},
    year = {2016}
    }
  • [DOI] M. M. Bakhuraysah, C. Siatskas, and S. Petratos, “Hematopoietic stem cell transplantation for multiple sclerosis: is it a clinical reality?,” Stem cell research & therapy, vol. 7, iss. 1, p. 12, 2016.
    [Bibtex]
    @article{10.1186/s13287-015-0272-1,
    author = {Bakhuraysah, Maha M. and Siatskas, Christopher and Petratos, Steven},
    title = {{Hematopoietic stem cell transplantation for multiple sclerosis: is it a clinical reality?}},
    doi = {10.1186/s13287-015-0272-1},
    pmid = {26772391},
    abstract = {{Hematopoietic stem cell transplantation (HSCT) is a treatment paradigm that has long been utilized for cancers of the blood and bone marrow but has gained some traction as a treatment paradigm for multiple sclerosis (MS). Success in the treatment of patients with this approach has been reported primarily when strict inclusion criteria are imposed that have eventuated a more precise understanding of MS pathophysiology, thereby governing trial design. Moreover, enhancing the yield and purity of hematopoietic stem cells during isolation along with the utility of appropriate conditioning agents has provided a clearer foundation for clinical translation studies. To support this approach, preclinical data derived from animal models of MS, experimental autoimmune encephalomyelitis, have provided clear identification of multipotent stem cells that can reconstitute the immune system to override the autoimmune attack of the central nervous system. In this review, we will discuss the rationale of HSCT to treat MS by providing the benefits and complications of the clinically relevant protocols, the varying graft types, and conditioning regimens. However, we emphasize that future trials based on HSCT should be focused on specific therapeutic strategies to target and limit ongoing neurodegeneration and demyelination in progressive MS, in the hope that such treatment may serve a greater catchment of patient cohorts with potentially enhanced efficiency and lower toxicity. Despite these future ambitions, a proposed international multicenter, randomized clinical trial of HSCT should be governed by the best standard care of treatment, whereby MS patients are selected upon strict clinical course criteria and long-term follow-up studies of patients from international registries are imposed to advocate HSCT as a therapeutic option in the management of MS.}},
    pages = {12},
    number = {1},
    volume = {7},
    journal = {Stem Cell Research \& Therapy},
    year = {2016}
    }
  • [DOI] H. Lee, S. Narayanan, R. A. Brown, J. T. Chen, H. L. Atkins, M. S. Freedman, and D. L. Arnold, “Brain atrophy after bone marrow transplantation for treatment of multiple sclerosis,” Multiple sclerosis journal, vol. 23, iss. 3, p. 420–431, 2016.
    [Bibtex]
    @article{10.1177/1352458516650992,
    author = {Lee, Hyunwoo and Narayanan, Sridar and Brown, Robert A and Chen, Jacqueline T and Atkins, Harold L and Freedman, Mark S and Arnold, Douglas L},
    title = {{Brain atrophy after bone marrow transplantation for treatment of multiple sclerosis}},
    issn = {1352-4585},
    doi = {10.1177/1352458516650992},
    pmid = {27246142},
    abstract = {{A cohort of patients with poor-prognosis multiple sclerosis (MS) underwent chemotherapy-based immune ablation followed by immune reconstitution with an autologous hematopoietic stem cell transplant (IA/aHSCT). This eliminated new focal inflammatory activity, but resulted in early acceleration of brain atrophy. We modeled the time course of whole-brain volume in 19 patients to identify the baseline predictors of atrophy and to estimate the average rate of atrophy after IA/aHSCT. Percentage whole-brain volume changes were calculated between the baseline and follow-up magnetic resonance imaging (MRI; mean duration: 5 years). A mixed-effects model was applied using two predictors: total busulfan dose and baseline volume of T1-weighted white-matter lesions. Treatment was followed by accelerated whole-brain volume loss averaging 3.3\%. Both the busulfan dose and the baseline lesion volume were significant predictors. The atrophy slowed progressively over approximately 2.5 years. There was no evidence that resolution of edema contributed to volume loss. The mean rate of long-term atrophy was −0.23\% per year, consistent with the rate expected from normal aging. Following IA/aHSCT, MS patients showed accelerated whole-brain atrophy that was likely associated with treatment-related toxicity and degeneration of “committed” tissues. Atrophy eventually slowed to that expected from normal aging, suggesting that stopping inflammatory activity in MS can reduce secondary degeneration and atrophy.}},
    pages = {420--431},
    number = {3},
    volume = {23},
    journal = {Multiple Sclerosis Journal},
    year = {2016}
    }
  • [DOI] D. Currò and G. Mancardi, “Autologous hematopoietic stem cell transplantation in multiple sclerosis: 20 years of experience,” Neurological sciences, vol. 37, iss. 6, p. 857–865, 2016.
    [Bibtex]
    @article{10.1007/s10072-016-2564-3,
    author = {Currò, Daniela and Mancardi, Gianluigi},
    title = {{Autologous hematopoietic stem cell transplantation in multiple sclerosis: 20 years of experience}},
    issn = {1590-1874},
    doi = {10.1007/s10072-016-2564-3},
    pmid = {27071689},
    abstract = {{Intense immunosuppression followed by autologous hematopoietic stem cell transplantation (AHSCT) has been widely used in the last 20 years for the treatment of aggressive forms of autoimmune disorders, especially multiple sclerosis (MS). All clinical studies, although small and uncontrolled, demonstrate a great efficacy of this procedure in halting inflammation and disease activity, even in those patients affected by “malignant forms” of MS. The long-term follow-up has also revealed the possible maintenance of positive results in the course of time, and this evidence is supported by immunological data that suggest the possibility of a resetting of the immune system after AHSCT. The safety of AHSCT has improved in the last years, but the transplant related mortality is still nowadays of about 1-2 \%, pointing out that a careful selection of patients to submit to AHSCT is mandatory. The long clinical experience allowed to identify the ideal candidate: a young patient, with a short disease duration, with recurring and disabling relapses and the presence of inflammatory activity on brain magnetic resonance scans, unresponsive to approved therapies. A large, randomized clinical study comparing AHSCT with the best approved therapies is still necessary to confirm the role of transplantation in MS treatment.}},
    pages = {857--865},
    number = {6},
    volume = {37},
    journal = {Neurological Sciences},
    year = {2016}
    }
  • [DOI] D. Obradović, L. Tukić, S. Radovinović-Tasić, B. Petrović, M. Elez, G. Ostojić, and B. Balint, “Autologous hematopoietic stem cell transplantation in combination with immunoablative protocol in secondary progressive multiple sclerosis: A 10-year follow-up of the first transplanted patient,” Vojnosanitetski pregled, vol. 73, iss. 5, p. 504–508, 2016.
    [Bibtex]
    @article{10.2298/vsp150304045o,
    author = {Obradović, Dragana and Tukić, Ljiljana and Radovinović-Tasić, Sanja and Petrović, Boris and Elez, Marija and Ostojić, Gordana and Balint, Bela},
    title = {{Autologous hematopoietic stem cell transplantation in combination with immunoablative protocol in secondary progressive multiple sclerosis: A 10-year follow-up of the first transplanted patient}},
    issn = {0042-8450},
    doi = {10.2298/vsp150304045o},
    pmid = {27430119},
    abstract = {{Introduction. Multiple sclerosis (MS) is an immunemediated disease of the central nervous system that affects young individuals and leads to severe disability. High dose immunoablation followed by autologous hemopoietic stem cell transplantation (AHSCT) has been considered in the last 15 years as potentialy effective therapeutic approach for agressive MS. The most recent long-time follow-up results suggest that AHSCT is not only effective for highly aggressive MS, but for relapsing-remitting MS as well, providing long-term remission, or maybe even cure. We presented a 10- year follow-up of the first MS patient being treated by immunoablation therapy and AHSCT. Case report. A 27-year-old male experienced the first symptoms - intermitent numbness and paresthesia of arms and legs of what was treated for two years by psychiatrist as anxiety disorder. After he developed severe paraparesis he was admitted to the Neurology Clinic and diagnosed with MS. Our patient developed aggressive MS with frequent relapses, rapid disability progression and transition to secondary progressive form 6 years after MS onset [the Expanded Disability Status Scale (EDSS) 7.0 Ambulation Index (AI) 7]. AHSCT was performed, cyclophosphamide was used for hemopoietic stem cell mobilization and the BEAM protocol was used as conditionig regimen. No major adverse events followed the AHSCT. Neurological impairment improved, EDSS 6.5, AI 6 and during a 10-year followup remained unchanged. Brain MRI follow-up showed the absence of gadolinium enhancing lesions and a mild progression of brain atrophy. Conclusion. The patient with rapidly evolving, aggressive, noninflammatory MS initialy improved and remained stable, without disability progression for 10 years, after AHSCT. This kind of treatment should be considered in aggressive MS, or in disease modifying treatment nonresponsive MS patients, since appropriately timed AHSCT treatment may not only prevent disability progression but reduce the achieved level of disability, as well.}},
    pages = {504--508},
    number = {5},
    volume = {73},
    journal = {Vojnosanitetski pregled},
    year = {2016}
    }
  • [DOI] L. Szczechowski, M. Śmiłowski, G. Helbig, M. Krawczyk-Kuliś, and S. Kyrcz-Krzemień, “Autologous hematopoietic stem cell transplantation (AHSCT) for aggressive multiple sclerosis – whom, when and how,” International journal of neuroscience, vol. 126, iss. 10, p. 1–5, 2016.
    [Bibtex]
    @article{10.3109/00207454.2015.1121388,
    author = {Szczechowski, Lech and Śmiłowski, Marek and Helbig, Grzegorz and Krawczyk-Kuliś, Małgorzata and Kyrcz-Krzemień, Sławomira},
    title = {{Autologous hematopoietic stem cell transplantation (AHSCT) for aggressive multiple sclerosis – whom, when and how}},
    issn = {0020-7454},
    doi = {10.3109/00207454.2015.1121388},
    pmid = {26577419},
    abstract = {{Multiple sclerosis (MS) is an autoimmune disease of the central nervous system that leads to an inflammatory process resulting in demyelination and axonal degeneration. The most common form of MS is the relapsing-remitting MS (RRMS) characterized by the presence of numerous relapses. After few years of disease course, 90\% of those patients eventually develop a secondary progressive form. About 10\% of patients may suffer from a slowly progressive MS form – the primary progressive. The current treatment of RRMS includes immunomodulatory and immunosuppressive agents, which are effective, but usually in earlier and more benign forms. The immunomodulatory treatment has limited efficacy in aggressive forms of RRMS, and relapses occur despite treatment continuation. AHSCT should be considered as a therapeutic approach for patients with aggressive relapsing-remitting and aggressive progressive MS who failed conventional therapy. The mechanism of action of AHSCT for MS results from resetting the aberrant patient's immune system and eliminating the autoreactive T-lymphocytes. AHSCT can serve as an effective and safe procedure only when strict neurological eligibility criteria are adhered. The procedure should be performed in highly specialized hematological centers. The aim of our paper is to summarize the current eligibility criteria for AHSCT in MS patients as well as to present data on efficacy and safety of this approach.}},
    pages = {1--5},
    number = {10},
    volume = {126},
    journal = {International Journal of Neuroscience},
    year = {2016}
    }
  • [DOI] J. L. Shevchenko, A. N. Kuznetsov, T. I. Ionova, V. Y. Melnichenko, D. A. Fedorenko, K. A. Kurbatova, G. I. Gorodokin, and A. A. Novik, “Long-term outcomes of autologous hematopoietic stem cell transplantation with reduced-intensity conditioning in multiple sclerosis: physician’s and patient’s perspectives,” Annals of hematology, vol. 94, iss. 7, p. 1149–1157, 2015.
    [Bibtex]
    @article{10.1007/s00277-015-2337-8,
    author = {Shevchenko, Jury L. and Kuznetsov, Alexey N. and Ionova, Tatyana I. and Melnichenko, Vladimir Y. and Fedorenko, Denis A. and Kurbatova, Kira A. and Gorodokin, Gary I. and Novik, Andrei A.},
    title = {{Long-term outcomes of autologous hematopoietic stem cell transplantation with reduced-intensity conditioning in multiple sclerosis: physician’s and patient’s perspectives}},
    issn = {0939-5555},
    doi = {10.1007/s00277-015-2337-8},
    pmid = {25711670},
    abstract = {{High-dose immunosuppressive therapy (HDIT) with autologous hematopoietic stem cell transplantation (AHSCT) is a promising approach to treatment of multiple sclerosis (MS) patients. In this paper, we present the long-term outcomes of a prospective single-center study with the analysis of the safety and efficacy of HDIT + AHSCT with reduced-intensity BEAM-like conditioning regimen in 99 MS patients: mean age—35 years old; male/female—39/60; median Expanded Disability Status Scale (EDSS) = 3.5; 43 relapsing/remitting MS, 56 progressive MS. No transplant-related deaths were observed. The mobilization and transplantation procedures were well tolerated. At 6 months post-transplant, neurological improvement or stabilization was observed in all the patients except one. Cumulative incidence of disease progression was 16.7 \% at 8 years after HDIT + AHSCT. Estimated event-free survival at median follow-up of 48.9 months was 80 \%: 83.3 \% in relapsing/remitting MS vs 75.5 \% in progressive MS. Sixty-four patients who did not progress during the first 3 years post-transplant and were monitored for more than 3 years were included in long-term outcome analysis. At the median long-term follow-up of 62 months, 47 \% of patients improved by at least 0.5 points on the EDSS scale as compared to baseline and exhibited improvement during the entire period of follow-up; 45 \% of patients were stable. No active, new, or enlarging lesions on magnetic resonance imaging were registered in patients without disease progression. AHSCT was accompanied by a significant improvement in patient’s quality of life. Due to the fact that patient selection was quite different to the other studies and that the information about disease activity prior in the disease course and its treatment was inhomogeneous, comparison with the results in the literature should be done with caution. Thus, the risk/benefit ratio of HDIT + AHSCT with reduced-intensity BEAM-like conditioning regimen in our population of MS patients is very favorable. The consistency of our long-term clinical and quality of life results, together with the persistence of improvement, is in favor of the efficacy and safety of this treatment approach in MS patients.}},
    pages = {1149--1157},
    number = {7},
    volume = {94},
    journal = {Annals of Hematology},
    year = {2015}
    }
  • [DOI] R. K. Burt, R. Balabanov, X. Han, B. Sharrack, A. Morgan, K. Quigley, K. Yaung, I. B. Helenowski, B. Jovanovic, D. Spahovic, I. Arnautovic, D. C. Lee, B. C. Benefield, S. Futterer, M. C. Oliveira, and J. Burman, “Association of Nonmyeloablative Hematopoietic Stem Cell Transplantation With Neurological Disability in Patients With Relapsing-Remitting Multiple Sclerosis,” Jama, vol. 313, iss. 3, p. 275–284, 2015.
    [Bibtex]
    @article{10.1001/jama.2014.17986,
    author = {Burt, Richard K. and Balabanov, Roumen and Han, Xiaoqiang and Sharrack, Basil and Morgan, Amy and Quigley, Kathleeen and Yaung, Kim and Helenowski, Irene B. and Jovanovic, Borko and Spahovic, Dzemila and Arnautovic, Indira and Lee, Daniel C. and Benefield, Brandon C. and Futterer, Stephen and Oliveira, Maria Carolina and Burman, Joachim},
    title = {{Association of Nonmyeloablative Hematopoietic Stem Cell Transplantation With Neurological Disability in Patients With Relapsing-Remitting Multiple Sclerosis}},
    issn = {0098-7484},
    doi = {10.1001/jama.2014.17986},
    pmid = {25602998},
    abstract = {{Importance No current therapy for relapsing-remitting multiple sclerosis (MS) results in significant reversal of disability.Objective To determine the association of nonmyeloablative hematopoietic stem cell transplantation with neurological disability and other clinical outcomes in patients with MS.Design, Setting, and Participants Case series of patients with relapsing-remitting MS (n = 123) or secondary-progressive MS (n = 28) (mean age, 36 years; range, 18-60 years; 85 women) treated at a single US institution between 2003 and 2014 and followed up for 5 years. Final follow-up was completed in June 2014.Interventions Treatment with cyclophosphamide and alemtuzumab (22 patients) or cyclophosphamide and thymoglobulin (129 patients) followed by infusion of unmanipulated peripheral blood stem cells.Main Outcomes and Measures Primary end point was reversal or progression of disability measured by change in the Expanded Disability Status Scale (EDSS) score of 1.0 or greater (score range, 0-10). Secondary outcomes included changes in the Neurologic Rating Scale (NRS) score of 10 or greater (score range, 0-100), Multiple Sclerosis Functional Composite (MSFC) score, quality-of-life Short Form 36 questionnaire scores, and T2 lesion volume on brain magnetic resonance imaging scan.Results Outcome analysis was available for 145 patients with a median follow-up of 2 years and a mean of 2.5 years. Scores from the EDSS improved significantly from a pretransplant median of 4.0 to 3.0 (interquartile range [IQR], 1.5 to 4.0; n = 82) at 2 years and to 2.5 (IQR, 1.9 to 4.5; n = 36) at 4 years (P < .001 at each assessment). There was significant improvement in disability (decrease in EDSS score of ≥1.0) in 41 patients (50\%; 95\% CI, 39\% to 61\%) at 2 years and in 23 patients (64\%; 95\% CI, 46\% to 79\%) at 4 years. Four-year relapse-free survival was 80\% and progression-free survival was 87\%. The NRS scores improved significantly from a pretransplant median of 74 to 88.0 (IQR, 77.3 to 93.0; n = 78) at 2 years and to 87.5 (IQR, 75.0 to 93.8; n = 34) at 4 years (P < .001 at each assessment). The median MSFC scores were 0.38 (IQR, −0.01 to 0.64) at 2 years (P < .001) and 0.45 (0.04 to 0.60) at 4 years (P = .02). Total quality-of-life scores improved from a mean of 46 (95\% CI, 43 to 49) pretransplant to 64 (95\% CI, 61 to 68) at a median follow-up of 2 years posttransplant (n = 132) (P < .001). There was a decrease in T2 lesion volume from a pretransplant median of 8.57 cm3 (IQR, 2.78 to 22.08 cm3) to 5.74 cm3 (IQR, 1.88 to 14.45 cm3) (P < .001) at the last posttransplant assessment (mean follow-up, 27 months; n = 128).Conclusions and Relevance Among patients with relapsing-remitting MS, nonmyeloablative hematopoietic stem cell transplantation was associated with improvement in neurological disability and other clinical outcomes. These preliminary findings from this uncontrolled study require confirmation in randomized trials.}},
    pages = {275--284},
    number = {3},
    volume = {313},
    journal = {JAMA},
    year = {2015}
    }
  • [DOI] S. Rogne, "Unethical for neurologists.pdf," Tidsskrift for den norske lægeforening : tidsskrift for praktisk medicin, ny række, vol. 134, iss. 20, p. 1931–2, 2014.
    [Bibtex]
    @article{10.4045/tidsskr.14.1027,
    author = {Rogne, Sigbjørn},
    title = {{Unethical for neurologists.pdf}},
    issn = {0029-2001},
    doi = {10.4045/tidsskr.14.1027},
    pmid = {25350436},
    pages = {1931--2},
    number = {20},
    volume = {134},
    journal = {Tidsskrift for den Norske lægeforening : tidsskrift for praktisk medicin, ny række},
    year = {2014}
    }
  • [DOI] S. E. Lutz, J. Lengfeld, and D. Agalliu, "Stem cell-based therapies for multiple sclerosis: recent advances in animal models and human clinical trials," Regenerative medicine, vol. 9, iss. 2, p. 129–132, 2014.
    [Bibtex]
    @article{10.2217/rme.14.1,
    author = {Lutz, Sarah E and Lengfeld, Justin and Agalliu, Dritan},
    title = {{Stem cell-based therapies for multiple sclerosis: recent advances in animal models and human clinical trials}},
    issn = {1746-0751},
    doi = {10.2217/rme.14.1},
    pmid = {24750052},
    pages = {129--132},
    number = {2},
    volume = {9},
    journal = {Regenerative Medicine},
    year = {2014}
    }
  • [DOI] D. Curro’, L. Vuolo, F. Gualandi, A. Bacigalupo, L. Roccatagliata, E. Capello, A. Uccelli, R. Saccardi, M. P. Sormani, and G. Mancardi, "Low intensity lympho-ablative regimen followed by autologous hematopoietic stem cell transplantation in severe forms of multiple sclerosis: A MRI-based clinical study," Multiple sclerosis journal, vol. 21, iss. 11, p. 1423–1430, 2014.
    [Bibtex]
    @article{10.1177/1352458514564484,
    author = {Curro’, Daniela and Vuolo, Luisa and Gualandi, Francesca and Bacigalupo, Andrea and Roccatagliata, Luca and Capello, Elisabetta and Uccelli, Antonio and Saccardi, Riccardo and Sormani, Maria Pia and Mancardi, Gianluigi},
    title = {{Low intensity lympho-ablative regimen followed by autologous hematopoietic stem cell transplantation in severe forms of multiple sclerosis: A MRI-based clinical study}},
    issn = {1352-4585},
    doi = {10.1177/1352458514564484},
    pmid = {25583838},
    abstract = {{Autologous hematopoietic stem cell transplantation (AHSCT) has been successfully used to treat aggressive forms of multiple sclerosis (MS) that are unresponsive to approved therapies. In the last years, in view of the risk of mortality related to the procedure, the utilization of low-intensity conditioning regimens has been considered. To report magnetic resonance imaging (MRI) and clinical data in a small cohort of patients treated with a low-intensity lympho-ablative regimen, followed by AHSCT. Seven patients affected by relapsing–remitting MS (RRMS) underwent AHSCT, with cyclophosphamide 120 mg/kg in 2 days as the conditioning regimen; and were then followed with serial MRI evaluations until 36 months, with clinical evaluations until 60 months. The mean number of gadolinium (Gd)-enhancing lesions significantly decreased after treatment, but a complete suppression of inflammatory activity was not obtained. No deaths occurred, but every patient developed adverse events, although not severe. After 5 years of follow-up, two patients remained stable, one patient markedly improved and four patients had a mild progression of the disease. Only one patient experienced a relapse after treatment. A low-intensity conditioning regimen with AHSCT has a profound effect on MRI inflammation and relapses, but is not able to completely abrogate MRI activity and disease progression of aggressive RRMS.}},
    pages = {1423--1430},
    number = {11},
    volume = {21},
    journal = {Multiple Sclerosis Journal},
    year = {2014}
    }
  • [DOI] H. L. Atkins and M. S. Freedman, "Hematopoietic Stem Cell Therapy for Multiple Sclerosis: Top 10 Lessons Learned," Neurotherapeutics, vol. 10, iss. 1, p. 68–76, 2013.
    [Bibtex]
    @article{10.1007/s13311-012-0162-5,
    author = {Atkins, Harold L. and Freedman, Mark S.},
    title = {{Hematopoietic Stem Cell Therapy for Multiple Sclerosis: Top 10 Lessons Learned}},
    issn = {1933-7213},
    doi = {10.1007/s13311-012-0162-5},
    pmid = {23192675},
    abstract = {{Reports from more than 600 hematopoietic stem cell transplants (HSCT) have appeared in the medical literature for the last 1 and one-half decades. The patient’s own stem cells are harvested and stored temporarily while high doses of chemotherapy and biologics are used to destroy the auto-destructive immune system. The immune system is regenerated from the infused autologous hematopoietic stem cells. Increasing clinical experience has refined patient selection criteria and management in the peri-transplant period leading to a reduction in treatment-related complications. HSCT, when used to treat patients with aggressive highly active multiple sclerosis, can reduce or eliminate ongoing clinical relapses, halt further progression, and reduce the burden of disability in some patients, in the absence of chronic treatment with disease-modifying agents. The top 10 lessons learned from the growing experience using HSCT for the treatment of multiple sclerosis are discussed.}},
    pages = {68--76},
    number = {1},
    volume = {10},
    journal = {Neurotherapeutics},
    year = {2013}
    }
  • [DOI] J. A. Snowden, R. Saccardi, M. Allez, S. Ardizzone, R. Arnold, R. Cervera, C. Denton, C. Hawkey, M. Labopin, G. Mancardi, R. Martin, J. J. Moore, J. Passweg, C. Peters, M. Rabusin, M. Rovira, J. M. van Laar, and D. Farge, "Haematopoietic SCT in severe autoimmune diseases: updated guidelines of the European Group for Blood and Marrow Transplantation," Bone marrow transplantation, vol. 47, iss. 6, p. 770–790, 2012.
    [Bibtex]
    @article{10.1038/bmt.2011.185,
    author = {Snowden, J A and Saccardi, R and Allez, M and Ardizzone, S and Arnold, R and Cervera, R and Denton, C and Hawkey, C and Labopin, M and Mancardi, G and Martin, R and Moore, J J and Passweg, J and Peters, C and Rabusin, M and Rovira, M and Laar, J M van and Farge, D},
    title = {{Haematopoietic SCT in severe autoimmune diseases: updated guidelines of the European Group for Blood and Marrow Transplantation}},
    issn = {0268-3369},
    doi = {10.1038/bmt.2011.185},
    pmid = {22002489},
    abstract = {{In 1997, the first consensus guidelines for haematopoietic SCT (HSCT) in autoimmune diseases (ADs) were published, while an international coordinated clinical programme was launched. These guidelines provided broad principles for the field over the following decade and were accompanied by comprehensive data collection in the European Group for Blood and Marrow Transplantation (EBMT) AD Registry. Subsequently, retrospective analyses and prospective phase I/II studies generated evidence to support the feasibility, safety and efficacy of HSCT in several types of severe, treatment-resistant ADs, which became the basis for larger-scale phase II and III studies. In parallel, there has also been an era of immense progress in biological therapy in ADs. The aim of this document is to provide revised and updated guidelines for both the current application and future development of HSCT in ADs in relation to the benefits, risks and health economic considerations of other modern treatments. Patient safety considerations are central to guidance on patient selection and HSCT procedural aspects within appropriately experienced and Joint Accreditation Committee of International Society for Cellular Therapy and EBMT accredited centres. A need for prospective interventional and non-interventional studies, where feasible, along with systematic data reporting, in accordance with EBMT policies and procedures, is emphasized.}},
    pages = {770--790},
    number = {6},
    volume = {47},
    journal = {Bone Marrow Transplantation},
    year = {2012}
    }
  • [DOI] T. Daikeler, A. Tichelli, and J. Passweg, "Complications of autologous hematopoietic stem cell transplantation for patients with autoimmune diseases," Pediatric research, vol. 71, iss. 2-4, p. 439–444, 2012.
    [Bibtex]
    @article{10.1038/pr.2011.57,
    author = {Daikeler, Thomas and Tichelli, André and Passweg, Jakob},
    title = {{Complications of autologous hematopoietic stem cell transplantation for patients with autoimmune diseases}},
    issn = {0031-3998},
    doi = {10.1038/pr.2011.57},
    pmid = {22430379},
    abstract = {{Autologous hematopoietic stem cell transplantation (HSCT) has been used to treat severe and refractory autoimmune diseases (ADs) in children and adults for more than 15 years. The aim of this treatment is to restore tolerance through an intense lymphodepleting conditioning, and many patients have achieved lasting remissions. However, HSCT is associated with significant morbidity and mortality and is therefore not yet standard of care. Pre-existing reduced organ function of patients with ADs may increase the organ toxicity of conditioning. In the early post-HSCT phase, bacterial or fungal infections occur and therapy-associated lymphopenia sets patients at risk for reactivation of endogenous viruses and other opportunistic infections. During re-emerging of lymphopoiesis after HSCT, de novo autoimmunity may develop through loss of central or peripheral control mechanisms. Late effects of autologous HSCT (e.g., on the endocrine system) and a potentially increased frequency of secondary malignancies are of concern. The steadily increasing knowledge about specific complications occurring in patients with ADs after HSCT has led to the adaption of treatment protocols and has already reduced toxicity. Further prospective long-term follow-up studies are needed to identify patients at risk for developing serious complications after HSCT.}},
    pages = {439--444},
    number = {2-4},
    volume = {71},
    journal = {Pediatric Research},
    year = {2012}
    }
  • [DOI] P. Tappenden, R. Saccardi, C. Confavreux, B. Sharrack, P. A. Muraro, G. L. Mancardi, T. Kozak, D. Farge-Bancel, J. Madan, R. Rafia, R. Akehurst, and J. Snowden, "Autologous haematopoietic stem cell transplantation for secondary progressive multiple sclerosis: an exploratory cost-effectiveness analysis," Bone marrow transplantation, vol. 45, iss. 6, p. 1014–1021, 2010.
    [Bibtex]
    @article{10.1038/bmt.2009.305,
    author = {Tappenden, P and Saccardi, R and Confavreux, C and Sharrack, B and Muraro, P A and Mancardi, G L and Kozak, T and Farge-Bancel, D and Madan, J and Rafia, R and Akehurst, R and Snowden, J},
    title = {{Autologous haematopoietic stem cell transplantation for secondary progressive multiple sclerosis: an exploratory cost-effectiveness analysis}},
    issn = {0268-3369},
    doi = {10.1038/bmt.2009.305},
    pmid = {19855441},
    abstract = {{Treatment options for secondary progressive multiple sclerosis (SPMS) are limited. Mitoxantrone is routinely used to stabilize disease progression; however, evolving evidence suggests clinical benefit from intensive treatment with autologous haematopoietic stem cell transplantation (HSCT). Given differences in cost and outcomes, preliminary cost-effectiveness studies are warranted if this approach is to be developed for more widespread application in SPMS. We developed a decision-analytic Markov model to explore the potential cost-effectiveness of autologous HSCT versus mitoxantrone in SPMS, using patient-level data from registry sources. The model evaluates the lifetime costs and health outcomes associated with disability progression and relapse. Sensitivity analyses were undertaken to examine the uncertainty surrounding cost-effectiveness outcomes. In the absence of randomised controlled trial (RCT) evidence, conditions for comparative analysis were not ideal. Under optimistic assumptions, HSCT is estimated to cost below £3000 per quality adjusted life year gained. However, when a strict 6-month sustained progression rule is adopted, HSCT may be less effective and more expensive than mitoxantrone. The model results were sensitive to reducing procedural costs and HSCT-related mortality. We conclude that HSCT could potentially achieve an acceptable level of cost-effectiveness. However, caution should be exercised as large, high-quality RCTs comparing HSCT versus mitoxantrone are necessary to validate these findings.}},
    pages = {1014--1021},
    number = {6},
    volume = {45},
    journal = {Bone Marrow Transplantation},
    year = {2010}
    }
  • [DOI] A. Awad and O. Stüve, "Review: Cyclophosphamide in multiple sclerosis: scientific rationale, history and novel treatment paradigms," Therapeutic advances in neurological disorders, vol. 2, iss. 6, p. 357–368, 2009.
    [Bibtex]
    @article{10.1177/1756285609344375,
    author = {Awad, Amer and Stüve, Olaf},
    title = {{Review: Cyclophosphamide in multiple sclerosis: scientific rationale, history and novel treatment paradigms}},
    issn = {1756-2856},
    doi = {10.1177/1756285609344375},
    pmid = {21180630},
    abstract = {{For patients with relapsing-remitting multiple sclerosis (RRMS), there are currently six approved medications that have been shown to alter the natural course of the disease. The approved medications include three beta interferon formulations, glatiramer acetate, natalizumab and mitoxantrone. Treating aggressive forms of RRMS and progressive disease forms of MS still presents a great challenge to neurologists. Intense immunosuppression has long been thought to be the only feasible therapeutic option. In patients with progressive forms of MS, lymphoid tissues have been detected in the central nervous system (CNS) that may play a critical role in perpetuating local inflammation. Agents that are currently approved for patients with MS have no or very limited bioavailability in the brain and spinal cord. In contrast, cyclophosphamide (CYC), an alkylating agent, penetrates the blood-brain barrier and CNS parenchyma well. However, while CYC has been used in clinical trials and off-label in clinical practice in patients with MS for over three decades, data on its efficacy in very heterogeneous groups of study patients have been conflicting. New myeloablative treatment paradigms with CYC may provide a therapeutic option in patients that do not respond to other agents. In this article we review the scientific rationale that led to the initial clinical trials with CYC. We will also outline the safety, tolerability and efficacy of CYC and provide neurologists with guidelines for its use in patients with MS and other inflammatory disorders of the CNS, including neuromyelitis optica (NMO). Finally, an outlook into relatively novel treatment approaches is provided.}},
    pages = {357--368},
    number = {6},
    volume = {2},
    journal = {Therapeutic Advances in Neurological Disorders},
    year = {2009}
    }
  • [DOI] I. Metz, C. F. Lucchinetti, H. Openshaw, A. Garcia-Merino, H. Lassmann, M. S. Freedman, H. L. Atkins, B. Azzarelli, O. J. Kolar, and W. Brück, "Autologous haematopoietic stem cell transplantation fails to stop demyelination and neurodegeneration in multiple sclerosis," Brain, vol. 130, iss. 5, p. 1254–1262, 2007.
    [Bibtex]
    @article{10.1093/brain/awl370,
    author = {Metz, Imke and Lucchinetti, Claudia F. and Openshaw, Harry and Garcia-Merino, Antonio and Lassmann, Hans and Freedman, Marc S. and Atkins, Harold L. and Azzarelli, Biagio and Kolar, Oldrich J. and Brück, Wolfgang},
    title = {{Autologous haematopoietic stem cell transplantation fails to stop demyelination and neurodegeneration in multiple sclerosis}},
    issn = {0006-8950},
    doi = {10.1093/brain/awl370},
    pmid = {17293360},
    abstract = {{The present study analyses autopsy material from five multiple sclerosis patients who received autologous stem cell transplantation. A total of 53 white matter lesions were investigated using routine and immunohistochemical stainings to characterize the demyelinating activity, inflammatory infiltrates, acutely damaged axons and macrophages/microglial cells. We found evidence for ongoing active demyelination in all of the five patients. The inflammatory infiltrate within the lesions showed only very few T cells and CD8+ cytotoxic T cells dominated the T cell population. B cells and plasma cells were completely absent from the lesions. High numbers of acutely damaged axons were found in active lesion areas. Tissue injury was associated with activated macrophages/microglial cells. The present results indicate that ongoing demyelination and axonal degeneration exist despite pronounced immunosuppression. Our data parallel results from some of the clinical phase I/II studies showing continued clinical disease progression in multiple sclerosis patients with high expanded disability system scores despite autologous stem cell transplantation.}},
    pages = {1254--1262},
    number = {5},
    volume = {130},
    journal = {Brain},
    year = {2007}
    }
  • [DOI] R. K. Burt, A. Marmont, Y. Oyama, S. Slavin, R. Arnold, F. Hiepe, A. Fassas, J. Snowden, F. Schuening, H. Myint, D. D. Patel, D. Collier, H. Heslop, R. Krance, L. Statkute, L. Verda, A. Traynor, T. Kozak, R. Q. Hintzen, J. W. Rose, J. Voltarelli, Y. Loh, M. Territo, B. A. Cohen, R. M. Craig, J. Varga, and W. G. Barr, "Randomized controlled trials of autologous hematopoietic stem cell transplantation for autoimmune diseases: The evolution from myeloablative to lymphoablative transplant regimens," Arthritis & rheumatism, vol. 54, iss. 12, p. 3750–3760, 2006.
    [Bibtex]
    @article{10.1002/art.22256,
    author = {Burt, Richard K. and Marmont, Alberto and Oyama, Yu and Slavin, Shimon and Arnold, Renate and Hiepe, Falk and Fassas, Athanasios and Snowden, John and Schuening, Friedrich and Myint, Han and Patel, Dhavalkumar D. and Collier, David and Heslop, Helen and Krance, Robert and Statkute, Laisvyde and Verda, Larissa and Traynor, Ann and Kozak, Tomas and Hintzen, Rogier Q. and Rose, John W. and Voltarelli, Julio and Loh, Yvonne and Territo, Mary and Cohen, Bruce A. and Craig, Robert M. and Varga, John and Barr, Walter G.},
    title = {{Randomized controlled trials of autologous hematopoietic stem cell transplantation for autoimmune diseases: The evolution from myeloablative to lymphoablative transplant regimens}},
    issn = {1529-0131},
    doi = {10.1002/art.22256},
    pmid = {17133541},
    pages = {3750--3760},
    number = {12},
    volume = {54},
    journal = {Arthritis \& Rheumatism},
    year = {2006}
    }
  • [DOI] P. A. Muraro, D. C. Douek, A. Packer, K. Chung, F. J. Guenaga, R. Cassiani-Ingoni, C. Campbell, S. Memon, J. W. Nagle, F. T. Hakim, R. E. Gress, H. F. McFarland, R. K. Burt, and R. Martin, "Thymic output generates a new and diverse TCR repertoire after autologous stem cell transplantation in multiple sclerosis patients," The journal of experimental medicine, vol. 201, iss. 5, p. 805–816, 2005.
    [Bibtex]
    @article{10.1084/jem.20041679,
    author = {Muraro, Paolo A. and Douek, Daniel C. and Packer, Amy and Chung, Katherine and Guenaga, Francisco J. and Cassiani-Ingoni, Riccardo and Campbell, Catherine and Memon, Sarfraz and Nagle, James W. and Hakim, Frances T. and Gress, Ronald E. and McFarland, Henry F. and Burt, Richard K. and Martin, Roland},
    title = {{Thymic output generates a new and diverse TCR repertoire after autologous stem cell transplantation in multiple sclerosis patients}},
    issn = {0022-1007},
    doi = {10.1084/jem.20041679},
    pmid = {15738052},
    pmcid = {PMC2212822},
    abstract = {{Clinical trials have indicated that autologous hematopoietic stem cell transplantation (HSCT) can persistently suppress inflammatory disease activity in a subset of patients with severe multiple sclerosis (MS), but the mechanism has remained unclear. To understand whether the beneficial effects on the course of disease are mediated by lympho-depletive effects alone or are sustained by a regeneration of the immune repertoire, we examined the long-term immune reconstitution in patients with MS who received HSCT. After numeric recovery of leukocytes, at 2-yr follow-up there was on average a doubling of the frequency of naive CD4+ T cells at the expense of memory T cells. Phenotypic and T cell receptor excision circle (TREC) analysis confirmed a recent thymic origin of the expanded naive T cell subset. Analysis of the T cell receptor repertoire showed the reconstitution of an overall broader clonal diversity and an extensive renewal of clonal specificities compared with pretherapy. These data are the first to demonstrate that long-term suppression of inflammatory activity in MS patients who received HSCT does not depend on persisting lymphopenia and is associated with profound qualitative immunological changes that demonstrate a de novo regeneration of the T cell compartment.}},
    pages = {805--816},
    number = {5},
    volume = {201},
    journal = {The Journal of Experimental Medicine},
    year = {2005}
    }
  • [DOI] R. K. Burt, B. Cohen, J. Rose, F. Petersen, Y. Oyama, D. Stefoski, G. Katsamakis, E. Carrier, T. Kozak, P. A. Muraro, R. Martin, R. Hintzen, S. Slavin, D. Karussis, S. Haggiag, J. C. Voltarelli, G. W. Ellison, B. Jovanovic, U. Popat, J. McGuirk, L. Statkute, L. Verda, J. Haas, and R. Arnold, "Hematopoietic Stem Cell Transplantation for Multiple Sclerosis," Archives of neurology, vol. 62, iss. 6, p. 860–864, 2005.
    [Bibtex]
    @article{10.1001/archneur.62.6.860,
    author = {Burt, Richard K. and Cohen, Bruce and Rose, John and Petersen, Finn and Oyama, Yu and Stefoski, Dusan and Katsamakis, George and Carrier, Ewa and Kozak, Tomas and Muraro, Paolo A. and Martin, Roland and Hintzen, Roger and Slavin, Shimon and Karussis, Dimitrios and Haggiag, Shalom and Voltarelli, Julio C. and Ellison, George W. and Jovanovic, Borko and Popat, Uday and McGuirk, Joseph and Statkute, Laisvyde and Verda, Larissa and Haas, Judith and Arnold, Renate},
    title = {{Hematopoietic Stem Cell Transplantation for Multiple Sclerosis}},
    issn = {0003-9942},
    doi = {10.1001/archneur.62.6.860},
    pmid = {15956156},
    pages = {860--864},
    number = {6},
    volume = {62},
    journal = {Archives of Neurology},
    year = {2005}
    }
  • [DOI] R. Saccardi, G. L. Mancardi, A. Solari, A. Bosi, P. Bruzzi, P. D. Bartolomeo, A. Donelli, M. Filippi, A. Guerrasio, F. Gualandi, G. L. Nasa, A. Murialdo, F. Pagliai, F. Papineschi, B. Scappini, and A. M. Marmont, "Autologous HSCT for severe progressive multiple sclerosis in a multicenter trial: impact on disease activity and quality of life," Blood, vol. 105, iss. 6, p. 2601–2607, 2005.
    [Bibtex]
    @article{10.1182/blood-2004-08-3205,
    author = {Saccardi, Riccardo and Mancardi, Gian Luigi and Solari, Alessandra and Bosi, Alberto and Bruzzi, Paolo and Bartolomeo, Paolo Di and Donelli, Amedea and Filippi, Massimo and Guerrasio, Angelo and Gualandi, Francesca and Nasa, Giorgio La and Murialdo, Alessandra and Pagliai, Francesca and Papineschi, Federico and Scappini, Barbara and Marmont, Alberto M.},
    title = {{Autologous HSCT for severe progressive multiple sclerosis in a multicenter trial: impact on disease activity and quality of life}},
    issn = {0006-4971},
    doi = {10.1182/blood-2004-08-3205},
    pmid = {15546956},
    abstract = {{Hematopoietic stem cell transplantation (HSCT) has been proposed for the treatment of severe multiple sclerosis (MS). In a phase 2 multicenter study we selected 19 non–primary progressive MS patients showing high disease activity on the basis of both brain magnetic resonance imaging (MRI) and sustained clinical deterioration despite conventional treatments. After stem cell mobilization with cyclophosphamide (CY) and filgrastim, patients were conditioned with BCNU (1,3-bis(2-chloroethyl)-1-nitrosourea), cytosine arabinoside, etoposide, and melphalan (BEAM) followed by antithymocyte globulin (ATG). Unmanipulated peripheral blood stem cells (PBSCs) were then infused. No maintenance treatment was administered with a median follow-up of 36 months (range, 12 to 72 months). All patients showed clinical stabilization or improvement; 3 subsequently deteriorated, 1 beyond the baseline. No MRI active lesions were detected after the HSCT except in 1 patient who showed a new lesion at 4.5 years. Infections were limited and restricted to 3 months after HSCT. Health-related quality of life was assessed through the 54-item MS quality of life (MSQOL-54) questionnaire, showing a statistically significant improvement in both composite scores and in most of the individual domains. HSCT is able to induce a prolonged clinical stabilization in severe progressive MS patients, resulting in both sustained treatment-free periods and quality of life improvement.}},
    pages = {2601--2607},
    number = {6},
    volume = {105},
    journal = {Blood},
    year = {2005}
    }
  • [DOI] R. Q. Hintzen, "Stem cell transplantation in multiple sclerosis: multiple choices and multiple challengesy," Multiple sclerosis, vol. 8, iss. 2, p. 155–160, 2002.
    [Bibtex]
    @article{10.1191/1352458502ms789oa,
    author = {Hintzen, R Q},
    title = {{Stem cell transplantation in multiple sclerosis: multiple choices and multiple challengesy}},
    issn = {1352-4585},
    doi = {10.1191/1352458502ms789oa},
    pmid = {11990873},
    abstract = {{Multiple sclerosis (MS) is generally considered as an autoimmune disease of the central nervous system. This concept has led to the idea that profound immunosuppression followed by transplantation of stem cell grafts would stop, or at least slow down, disease activity. Supported by the positive effects of hematopoietic stem cell transplantation (HSCT) on experimental autoimmune encephalomyelitis and by anecdotal reports on the beneficial effect of HSCT on MS patients with concomitant malignant disease, HSCT programs for MS have been initiated worldwide. At this stage, it is impossible to draw general conclusions from the preliminary data reported and therefore overenthusiastic expectations should be tempered. The follow-up periods are too short, the groups are too small, the selected patients and protocols too heterogeneous, and publication bias on positive results cannot be excluded. However, there is ample evidence that HSCT is a technically feasible approach in MS, not more dangerous than in the hemato-oncological diseases. For every step in the HSCT procedure, there are many different options. The time has come for a systematic analysis of the safety and efficacy associated with the different methodologies.}},
    pages = {155--160},
    number = {2},
    volume = {8},
    journal = {Multiple Sclerosis},
    year = {2002}
    }
  • [DOI] D. W. van Bekkum, "New Opportunities for the Treatment of Severe Autoimmune Diseases: Bone Marrow Transplantation," Clinical immunology and immunopathology, vol. 89, iss. 1, p. 1–10, 1998.
    [Bibtex]
    @article{10.1006/clin.1998.4563,
    author = {Bekkum, D.W. van},
    title = {{New Opportunities for the Treatment of Severe Autoimmune Diseases: Bone Marrow Transplantation}},
    issn = {0090-1229},
    doi = {10.1006/clin.1998.4563},
    pmid = {9756718},
    pages = {1--10},
    number = {1},
    volume = {89},
    journal = {Clinical Immunology and Immunopathology},
    year = {1998}
    }
  • [DOI] A. Fassas, A. Anagnostopoulos, A. Kazis, K. Kapinas, I. Sakellari, V. Kimiskidis, and A. Tsompanakou, "Peripheral blood stem cell transplantation in the treatment of progressive multiple sclerosis: first results of a pilot study," Bone marrow transplantation, vol. 20, iss. 8, p. 631–638, 1997.
    [Bibtex]
    @article{10.1038/sj.bmt.1700944,
    author = {Fassas, A and Anagnostopoulos, A and Kazis, A and Kapinas, K and Sakellari, I and Kimiskidis, V and Tsompanakou, A},
    title = {{Peripheral blood stem cell transplantation in the treatment of progressive multiple sclerosis: first results of a pilot study}},
    issn = {0268-3369},
    doi = {10.1038/sj.bmt.1700944},
    pmid = {9383225},
    abstract = {{Several experimental autoimmune diseases (AID), including allergic encephalomyelitis, ie the multiple sclerosis (MS) model, respond to TBI and chemotherapy followed by BMT. Remissions of AID may also occur in patients with concomitant malignancies treated with allogeneic or autologous BMT. These observations have emphasized the possibility of treating AID with high-dose therapy and haematopoietic stem cell transplantation (HSCT). In a phase I/II pilot study, 15 patients with progressive MS were treated with BEAM followed by autologous blood SCT and antithymocyte globulin (ATG). Patients were severely disabled, with median EDSS and SNRS scores of 6 (5–7.5) and 42 (33–62), respectively. Cyclophosphamide (4 g/m2) and G/GM-CSF (5 μ g/kg/day) were used for stem cell mobilization, which caused no neurotoxicity. On days +1 and +2, ATG (2.5–5 mg/kg) was given for in vivo T cell-depletion. Allergy (93\%) and infections (87\%) were the principal toxic complications. Mild, transient, neurotoxicity was observed in six patients in the immediate post-transplant period. The median follow-up time is 6 months (6–18). Durable neurologic improvements have been detected on both the EDSS (7/15) and SNRS (15/15) systems. One patient worsened at 3 months and two have relapsed. Autologous HSCT appears feasible in MS; it does not aggravate disability and seems to offer a clinical benefit. However, these observations need confirmation and long-term outcomes will show if benefits counterbalance toxicity and cost.}},
    pages = {631--638},
    number = {8},
    volume = {20},
    journal = {Bone Marrow Transplantation},
    year = {1997}
    }
  • [DOI] L. McAllister, P. Beatty, and J. Rose, "Allogeneic bone marrow transplant for chronic myelogenous leukemia in a patient with multiple sclerosis," Bone marrow transplantation, vol. 19, iss. 4, p. 395–397, 1997.
    [Bibtex]
    @article{10.1038/sj.bmt.1700666,
    author = {McAllister, LD and Beatty, PG and Rose, J},
    title = {{Allogeneic bone marrow transplant for chronic myelogenous leukemia in a patient with multiple sclerosis}},
    issn = {0268-3369},
    doi = {10.1038/sj.bmt.1700666},
    pmid = {9051253},
    abstract = {{Multiple sclerosis (MS) is a demyelinating disease of the central nervous system in which immune mechanisms appear to be an important component of the pathophysiology. Although the clinical manifestations are variable, a subset of patients develops a progressive clinical course associated with marked neurologic impairment and significant morbidity. BMT has been proposed as a treatment for such patients based on preclinical data as well as clinical observations in other autoimmune diseases. We report clinical and MRI findings in an MS patient, later diagnosed with CML, and treated with an allogeneic BMT.}},
    pages = {395--397},
    number = {4},
    volume = {19},
    journal = {Bone Marrow Transplantation},
    year = {1997}
    }
  • [DOI] D. M. Karussis, U. Vourka-Karussis, D. Lehmann, H. Ovadia, R. Mizrachi-Koll, A. Ben-Nun, O. Abramsky, and S. Slavin, "Prevention and reversal of adoptively transferred, chronic relapsing experimental autoimmune encephalomyelitis with a single high dose cytoreductive treatment followed by syngeneic bone marrow transplantation.," Journal of clinical investigation, vol. 92, iss. 2, p. 765–772, 1993.
    [Bibtex]
    @article{10.1172/jci116648,
    author = {Karussis, D M and Vourka-Karussis, U and Lehmann, D and Ovadia, H and Mizrachi-Koll, R and Ben-Nun, A and Abramsky, O and Slavin, S},
    title = {{Prevention and reversal of adoptively transferred, chronic relapsing experimental autoimmune encephalomyelitis with a single high dose cytoreductive treatment followed by syngeneic bone marrow transplantation.}},
    issn = {0021-9738},
    doi = {10.1172/jci116648},
    pmid = {7688762},
    abstract = {{A chronic relapsing form of experimental autoimmune encephalomyelitis (CR-EAE) was induced in SJL/J mice by adoptive transfer of lymph node cells (LNC) sensitized to guinea pig myelin basic protein (GMBP). We examined the efficacy of high dose immunosuppressive regimens (cyclophosphamide [CY] 300 mg/kg or total body irradiation [TBI] 900 cGy) followed by syngeneic bone marrow transplantation (SBMT) in prevention and treatment of already established CR-EAE. Treatment with TBI and SBMT on day 5 after the induction of CR-EAE, just before the onset of clinical signs, completely inhibited the appearance of the paralytic signs. The same treatment, applied 4 d after the clinical onset of the disease, led to a significant regression of the paralytic signs and to a total inhibition of spontaneous relapses during a follow-up period of 2 mo. Challenge of mice with GMBP+CFA 78 d after the passive induction of CR-EAE induced a relapse of the disease 7 d later in almost all of the untreated mice; in contrast, the same challenge given to TBI+SBMT-treated mice caused a delayed relapse (30 d later) in only a minority (3/7) of the challenged mice. In vitro lymphocytic proliferative responses to GMBP and purified protein derivative were significantly lower in TBI/SBMT-treated mice before and after the GMBP challenge, although these mice were fully immunocompetent, as evidenced by their normal lymphocytic proliferation to concanavalin A (ConA) and the FACS analysis of their lymphocytic subpopulations. A similar beneficial therapeutic effect was observed in mice treated with CY followed by SBMT, after the onset of CR-EAE. Our results could support possible clinical applications of similar therapeutic strategies, involving acute immunosuppression followed by stem cell transplantation and retolerization of the reconstituting immune cells in life-threatening neurological and multisystemic autoimmune diseases.}},
    pages = {765--772},
    number = {2},
    volume = {92},
    journal = {Journal of Clinical Investigation},
    year = {1993}
    }
  • J. I. Morton and B. V. Siegel, "Transplantation of autoimmune potential. III. Immunological hyper-responsiveness and elevated endogenous spleen colony formation in lethally irradiated recipients of NZB bone marrow cells.," Immunology, vol. 34, iss. 5, p. 863–8, 1978.
    [Bibtex]
    @article{undefined,
    author = {Morton, J I and Siegel, B V},
    title = {{Transplantation of autoimmune potential. III. Immunological hyper-responsiveness and elevated endogenous spleen colony formation in lethally irradiated recipients of NZB bone marrow cells.}},
    issn = {0019-2805},
    pmid = {350760},
    pmcid = {PMC1457211},
    pages = {863--8},
    number = {5},
    volume = {34},
    journal = {Immunology},
    year = {1978}
    }

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