Dit is een lijst van de wetenschappelijke artikelen over HSCT voor MS waarvan wij op de hoogte zijn.
Bijgewerkt op 8-4-2021
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G. J. Ruiz-Arguelles, J. C. Olivares-Gazca, I. Murrieta-Álvarez, J. M. Olivares-Gazca, A. Leon-Peña, Y. Cantero-Fortiz, E. E. G. López, A. Ruiz-Argüelles, A. G. D. Leon, D. Gomez-Almaguer, L. F. Sánchez-Valledor, Y. I. García-Navarrete, A. Cruz-Mora, and G. J. Ruiz-Delgado, “Self-Reported Changes in the Expanded Disability Status Scale (EDSS) Score in Persons with Multiple Sclerosis after Autologous Stem Cell Transplants: Experience with the “Mexican Method”,” Blood, vol. 134, iss. Supplement_1, p. 2020–2020, 2019.
[Bibtex]@article{10.1182/blood-2019-123797, year = {2019}, title = {{Self-Reported Changes in the Expanded Disability Status Scale (EDSS) Score in Persons with Multiple Sclerosis after Autologous Stem Cell Transplants: Experience with the "Mexican Method"}}, author = {Ruiz-Arguelles, Guillermo J and Olivares-Gazca, Juan Carlos and Murrieta-Álvarez, Iván and Olivares-Gazca, Jesús Mauricio and Leon-Peña, Andres and Cantero-Fortiz, Yahveth and López, Elías Eugenio Gonzalez and Ruiz-Argüelles, Alejandro and Leon, Andres Gomez De and Gomez-Almaguer, David and Sánchez-Valledor, Luisa Fernanda and García-Navarrete, Yarely Itzayana and Cruz-Mora, Antonio and Ruiz-Delgado, Guillermo J}, journal = {Blood}, issn = {0006-4971}, doi = {10.1182/blood-2019-123797}, abstract = {{Background Persons with multiple sclerosis (MS) are sometimes treated with high-dose immune suppressive or cytotoxic drugs and an autotransplant. Use of autotransplants may be substantially more common as many cases are not reported. Therapy-related mortality (TRM) has decreased to <2\% because of less intensive pretransplant regimens and better subject selection. Trials have reported a greater proportion of subjects with no evidence of active disease in subjects receiving high-dose therapy and an autotransplant compared with controls. Recent autotransplants use less intensive pretransplant therapy with seemingly similar efficacy and fewer adverse events. Whether the autograft is needed for bone marrow recovery and/or efficacy is uncertain but unlikely to be tested in randomized trials. We previously reported autotransplants for several haematologic neoplasms can be done in an outpatient setting using refrigerated blood cells. We now report data from 739 subjects with MS receiving autotransplants in an outpatient setting using refrigerated blood cells. Methods After June 2015, 739 consecutive patients with MS were autografted in a single center using non-frozen peripheral blood stem cells, on an outpatient basis and conditioning with cyclophosphamide and rituximab. The protocol was registered in ClinicalTrials.gov identifier NCT02674217. Eligibility criteria included all the following: Karnofsky performance score >70\%, extended Disability Status Scale (EDSS ≤8 in the 2 w pretransplant), CNS magnetic resonance image (MRI) ≤3 mo pretransplant, no prior bone marrow toxic drugs, normal heart, liver, lung and kidney function, ≥6 mo since exposure to immune suppressive drugs. Results 495 females and 244 males were included; median age was 47 years. 310 patients presented with relapsing remitting MS (RRMS), 273 with secondary progressive (SPMS) and 156 with primary progressive (PPMS). All procedures were started on an outpatient basis and only 31 persons needed to be admitted to the hospital during the procedure. In order to obtain at least 1x106/Kg viable CD34 cells, one to three apheresis were performed (median 1). Total number of viable CD34+ cells infused ranged between 1 and 37.83 x106 / Kg (median 5.62). Patients recovered above 0.5 x109/L absolute granulocytes on day 8 (median, range 2-13), whereas platelet recovery above 20 x109/L on day 4 (median, range 0-10). Seven individuals required red blood cells and eight needed platelet transfusions. There was one transplant related death and the 30-month overall survival of the patients is 99.9\%. Patients with RRMS or PPMS had a significant drop in the EDSS before and 15-mo after the transplant, whereas patients with SPMS remained stable (A). The response rate (either drop or stabilization of the EDSS score) at 12 months was 78\% for RRMS, 81\% for PPMS and 73\% for SPMS (B), whereas the relapse-free survival was 84\% for all patients (92\% for PPMS, 83\% for RRMS and 81\% for SPMS). Conclusions Changes in the EDSS score consonant with neurological improvement were observed in persons with all types of MS after HSCT employing the "Mexican method". Figure 1 Disclosures Gomez-Almaguer: Amgen: Consultancy, Speakers Bureau; Janssen: Consultancy, Speakers Bureau; Teva: Consultancy, Speakers Bureau; Takeda: Consultancy, Speakers Bureau; Celgene: Consultancy, Speakers Bureau.}}, pages = {2020--2020}, number = {Supplement\_1}, volume = {134} } - I. Muller, C. Moran, B. Lecumberri, B. Decallonne, N. Robertson, J. Jones, and C. M. Dayan, “2019 European Thyroid Association Guidelines on the Management of Thyroid Dysfunction following Immune Reconstitution Therapy,” European thyroid journal, vol. 8, iss. 4, p. 173–185, 2019.
[Bibtex]@article{10.1159/000500881, year = {2019}, title = {{2019 European Thyroid Association Guidelines on the Management of Thyroid Dysfunction following Immune Reconstitution Therapy}}, author = {Muller, Ilaria and Moran, Carla and Lecumberri, Beatriz and Decallonne, Brigitte and Robertson, Neil and Jones, Joanne and Dayan, Colin M.}, journal = {European Thyroid Journal}, issn = {2235-0640}, doi = {10.1159/000500881}, pmid = {31602359}, abstract = {{Thyroid dysfunction (TD) frequently occurs as an autoimmune complication of immune reconstitution therapy (IRT), especially in individuals with multiple sclerosis treated with alemtuzumab, a pan-lymphocyte depleting drug with subsequent recovery of immune cell numbers. Less frequently, TD is triggered by highly active antiretroviral therapy (HAART) in patients infected with human immunodeficiency virus (HIV), or patients undergoing bone-marrow/hematopoietic-stem-cell transplantation (BMT/HSCT). In both alemtuzumab-induced TD and HIV/HAART patients, the commonest disorder is Graves’ disease (GD), followed by hypothyroidism and thyroiditis; Graves’ orbitopathy is observed in some GD patients. On the contrary, GD is rare post-BMT/HSCT, where hypothyroidism predominates probably as a consequence of the associated radiation damage. In alemtuzumab-induced TD, the autoantibodies against the thyrotropin receptor (TRAb) play a major role, and 2 main aspects distinguish this condition from the spontaneous form: (1) up to 20\% of GD cases exhibit a fluctuating course, with alternating phases of hyper- and hypothyroidism, due to the coexistence of TRAb with stimulating and blocking function; (2) TRAb are also positive in about 70\% of hypothyroid patients, with blocking TRAb responsible for nearly half of the cases. The present guidelines will provide up-to-date recommendations and suggestions dedicated to all phases of IRT-induced TD: (1) screening before IRT (recommendations 1–3); (2) monitoring during/after IRT (recommendations 4–7); (3) management of TD post-IRT (recommendations 8–17). The clinical management of IRT-induced TD, and in particular GD, can be challenging. In these guidelines, we propose a summary algorithm which has particular utility for nonspecialist physicians and which is tailored toward management of alemtuzumab-induced TD. However, we recommend prompt referral to specialist endocrinology services following diagnosis of any IRT-induced TD diagnosis, and in particular for pregnant women and those considering pregnancy.}}, pages = {173--185}, number = {4}, volume = {8} } - R. Saccardi, M. Badoglio, J. Burman, G. Helbig, M. A. Kazmi, G. Mancardi, S. Mielke, J. Moore, P. Muraro, J. Sanz, B. Sharrack, M. Smilowski, M. P. Sormani, and J. A. Snowden, “BEAM Vs Cyclophosphamide-Based Conditioning Regimen in Aggressive Multiple Sclerosis: A Retrospective Analysis of European Blood and Marrow Transplantation Society,” Blood, vol. 134, iss. Supplement_1, p. 3313–3313, 2019.
[Bibtex]@article{10.1182/blood-2019-125233, year = {2019}, title = {{BEAM Vs Cyclophosphamide-Based Conditioning Regimen in Aggressive Multiple Sclerosis: A Retrospective Analysis of European Blood and Marrow Transplantation Society}}, author = {Saccardi, Riccardo and Badoglio, Manuela and Burman, Joachim and Helbig, Grzegorz and Kazmi, Majid A and Mancardi, Giovanni and Mielke, Stephan and Moore, John and Muraro, Paolo and Sanz, Jaime and Sharrack, Basil and Smilowski, Marek and Sormani, Maria Pia and Snowden, John A}, journal = {Blood}, issn = {0006-4971}, doi = {10.1182/blood-2019-125233}, abstract = {{Background Multiple Sclerosis (MS) is a chronic, immuno-mediated disease of Central Nervous System (CNS), mostly affecting young adults and frequently resulting in a progressive, irreversible disability despite the administration of approved Disease Modifying Treatments (DMTs). Autologous HSCT was shown to induce a high rate of sustained, treatment-free remissions in cases of aggressive MS, seldom associated to a partial reversal of disability. Toxicity of Conditioning Regimen is still a major concern. We retrospectively analyzed the outcome of 926 MS patients reported to the EBMT Registry who underwent autologous HSCT following the two most frequent CRs for this indication in the last 20 years. Patients and Methods Patient data were extracted from both the EBMT database and a disease-specific database developed by the EBMT Autoimmune Diseases Working Party (ADWP). Patients were selected for having received either BEAM + ATG (BEAM) or HD-Cyclophosphamide + ATG (CYC) as conditioning regimen. Hematological toxicity was assessed through Neutrophil (PMN) engraftment and 100-days (early) mortality (eTRM). MS forms at HSCT were reported as Relapsing-Remitting (RR), Secondary Progressive (SP), Primary Progressive (PP) and Progressive-Relapsing (PR). The impact of variables related to both patients (age, gender, year of HSCT, EDSS at HSCT) and disease characteristics (MS form, interval diagnosis-HSCT) at HSCT in the two groups were also evaluated. Results The utilization of conditioning regimens along the observed time period (1998-2018) was variable, with an increase of the HSCT activity in general after 2010 (230 vs 697 procedures) and a prevalence of BEAM before 2010 (205 BEAM vs 25 CYC) and of CYC thereafter (205 BEAM vs 492 CYC, p=0.001). Also, RR forms of MS prevailed over Progressive forms after 2010 (p=0.001) which is reflected in the different distribution across the two regimens, with RR significantly more frequently treated with CYC-based regimen (p<0.001). Gender distribution and age at HSCT was similar in the two groups (p=ns), whilst the interval between diagnosis and HSCT was longer in BEAM group than CYC (8.47 years ± 5.9 vs 7.57 ±5.5, mean ± SD, p=0.012). PMN engraftment in BEAM/ATG- and CYC/ATG-treated patients occurred at +11.0 (8-42) and +10.9 (8-95) days, respectively (median and range, p=ns). Overall eTRM was low (1.4\%), but slightly higher in BEAM over CYC (8/402, 2\% vs 5/517, 1\%, p=ns). Discussion Although autologous HSCT is increasingly used as a treatment in highly active MS, toxicity remains a principal concern in the neurological community despite a marked decrease of TRM over time. The intensity of conditioning regimens has varied in the literature, but the best toxicity/efficacy ratio remains unclear. The non-myeloablative regimen CYC-ATG has become the most common conditioning regimen despite a lack of comparative data with more intense regimens. In our large retrospective analysis of the two most frequent conditioning regimens in the EBMT Registry, there was no significant difference in major toxicity indicators despite differences in chronological period and patients characteristics in the two groups. Comparative analysis of neurological efficacy is currently ongoing and will inform the toxicity/efficacy ratio and clinical choice of conditioning regimen in autologous HSCT in MS. Disclosures Mielke: Bellicum: Consultancy, Honoraria, Other: Travel (via institution); Jazz Pharma: Honoraria, Other: Travel support, Speakers Bureau; IACH: Other: Travel support; Kiadis Pharma: Consultancy, Honoraria, Other: Travel support (via institution), Speakers Bureau; Miltenyi: Consultancy, Honoraria, Other: Travel and speakers fee (via institution), Speakers Bureau; DGHO: Other: Travel support; GILEAD: Consultancy, Honoraria, Other: travel (via institution), Speakers Bureau; Celgene: Honoraria, Other: Travel support (via institution), Speakers Bureau; ISCT: Other: Travel support; EBMT/EHA: Other: Travel support.}}, pages = {3313--3313}, number = {Supplement\_1}, volume = {134} } - G. J. Ruiz-Arguelles, J. C. Olivares-Gazca, J. M. Olivares-Gazca, A. Leon-Peña, I. Murrieta-Álvarez, Y. Cantero-Fortiz, Y. I. García-Navarrete, A. Cruz-Mora, L. F. Sánchez-Valledor, A. Ruiz-Arguelles, D. Gómez-Almaguer, A. Gómez-De-León, E. González-López, and G. J. Ruiz-Delgado, "Self-Reported Changes in the Expanded Disability Status Scale (EDSS) Score in Persons with Multiple Sclerosis after Autologous Stem Cell Transplants: Experience with the “Mexican Method”," Biology of blood and marrow transplantation, vol. 26, iss. 3, p. S20–S21, 2020.
[Bibtex]@article{10.1016/j.bbmt.2019.12.086, year = {2020}, title = {{Self-Reported Changes in the Expanded Disability Status Scale (EDSS) Score in Persons with Multiple Sclerosis after Autologous Stem Cell Transplants: Experience with the “Mexican Method”}}, author = {Ruiz-Arguelles, Guillermo J. and Olivares-Gazca, Juan Carlos and Olivares-Gazca, Jesús Mauricio and Leon-Peña, Andrés and Murrieta-Álvarez, Iván and Cantero-Fortiz, Yahveth and García-Navarrete, Yarely Itzayana and Cruz-Mora, Antonio and Sánchez-Valledor, Luisa Fernanda and Ruiz-Arguelles, Alejandro and Gómez-Almaguer, David and Gómez-De-León, Andrés and González-López, Elías and Ruiz-Delgado, Guillermo J.}, journal = {Biology of Blood and Marrow Transplantation}, issn = {1083-8791}, doi = {10.1016/j.bbmt.2019.12.086}, abstract = {{Background Persons with multiple sclerosis (MS) are sometimes treated with high-dose immune suppressive or cytotoxic drugs and an autotransplant. Therapy-related mortality (TRM) has decreased to <2\% because of less intensive pretransplant regimens and better subject selection. Trials have reported a greater proportion of subjects with no evidence of active disease in subjects receiving high-dose therapy and an autotransplant compared with controls. Recent autotransplants use less intensive pretransplant therapy with seemingly similar efficacy and fewer adverse events. We previously reported autotransplants for several haematologic neoplasms can be done in an outpatient setting using refrigerated blood cells. We now report data from 739 subjects with MS receiving autotransplants in an outpatient setting using refrigerated blood cells. Methods 739 consecutive patients with MS were autografted in a single center using non-frozen peripheral blood stem cells, on an outpatient basis and conditioning with cyclophosphamide and rituximab (Figure 1). The protocol was registered in ClinicalTrials.gov identifier NCT02674217. Eligibility criteria included all the following: Karnofsky performance score >70\%, extended Disability Status Scale (EDSS ≤8 in the 2 w pretransplant), CNS magnetic resonance image (MRI) ≤3 mo pretransplant, no prior bone marrow toxic drugs, normal heart, liver, lung and kidney function, ≥6 mo since exposure to immune suppressive drugs. Results 495 females and 244 males were included; median age was 47 years. 310 patients presented with relapsing remitting MS (RRMS), 273 with secondary progressive (SPMS) and 156 with primary progressive (PPMS). All procedures were started on an outpatient basis and only 31 persons needed to be admitted to the hospital during the procedure. In order to obtain at least 1 × 106/Kg viable CD34 cells, one to three apheresis were performed. Total number of viable CD34+ cells infused ranged between 1 and 37.83 × 106/Kg. Patients recovered above 0.5 × 109/L absolute granulocytes on day 8 whereas platelet recovery above 20 × 109/L on day 4. Seven individuals required red blood cells and eight needed platelet transfusions. There were two transplant related deaths and the 30-month overall survival of the patients is 99.7\%. All patients had a significant drop in the EDSS 12 and 18-mo after the transplant. The response rate (either drop or stabilization of the EDSS score) were at 12 and 18 months respectively: 85 and 88\% for RRMS; 75 and 84\% for PPMS and 79 and 85\% for SPMS (Figure 2). Conclusions Changes in the EDSS score consonant with neurological improvement were observed in persons with all types of MS after HSCT employing the “Mexican method”.}}, pages = {S20--S21}, number = {3}, volume = {26} } - S. Ng and K. M. Sullivan, "Application of stem cell transplantation in autoimmune diseases," Current opinion in hematology, vol. 26, iss. 6, p. 392–398, 2019.
[Bibtex]@article{10.1097/moh.0000000000000531, year = {2019}, title = {{Application of stem cell transplantation in autoimmune diseases}}, author = {Ng, Sue-Ann and Sullivan, Keith M}, journal = {Current Opinion in Hematology}, issn = {1065-6251}, doi = {10.1097/moh.0000000000000531}, pmid = {31490316}, abstract = {{Autologous hematopoietic stem cell transplantation (HSCT) is a promising therapeutic modality for severe autoimmune diseases. In this review, we will outline the immunological mechanisms and the clinical evidence and experiences for therapeutic HSCT in autoimmune diseases, with particular focus on systemic sclerosis and multiple sclerosis.}}, pages = {392--398}, number = {6}, volume = {26} } - C. M. Research, "Fecal Microbiota Transplantation After Autologous HSCT in Patients With Multiple Sclerosis," Case medical research, 2019.
[Bibtex]@article{10.31525/ct1-nct04203017, year = {2019}, title = {{Fecal Microbiota Transplantation After Autologous HSCT in Patients With Multiple Sclerosis}}, author = {Research, Case Medical}, journal = {Case Medical Research}, issn = {2643-4652}, doi = {10.31525/ct1-nct04203017} } - G. O. Gillard, J. L. Proctor, M. L. Brooks, T. L. Lamothe, S. L. Hyzy, S. M. McDonough, N. Clark, R. Palchaudhuri, A. Bhat, G. N. Sarma, P. R. Bhattarai, P. Sawant, B. R. Pearse, C. F. McDonagh, A. E. Boitano, and M. P. Cooke, "A Novel Targeted Approach to Achieve Immune System Reset: CD45-Targeted Antibody Drug Conjugates Enable Autologous HSCT and Ameliorate Disease in Preclinical Autoimmune Disease Models," Biology of blood and marrow transplantation, vol. 26, iss. 3, p. S307–S308, 2020.
[Bibtex]@article{10.1016/j.bbmt.2019.12.407, year = {2020}, title = {{A Novel Targeted Approach to Achieve Immune System Reset: CD45-Targeted Antibody Drug Conjugates Enable Autologous HSCT and Ameliorate Disease in Preclinical Autoimmune Disease Models}}, author = {Gillard, Geoffrey O. and Proctor, Jennifer L. and Brooks, Melissa L. and Lamothe, Tahirih L. and Hyzy, Sharon L. and McDonough, Sean M. and Clark, Nicholas and Palchaudhuri, Rahul and Bhat, Anjali and Sarma, Ganapathy N. and Bhattarai, Prashant Raj and Sawant, Pranoti and Pearse, Bradley R. and McDonagh, Charlotte F. and Boitano, Anthony E. and Cooke, Michael P.}, journal = {Biology of Blood and Marrow Transplantation}, issn = {1083-8791}, doi = {10.1016/j.bbmt.2019.12.407}, abstract = {{Resetting the immune system through autologous hematopoietic stem cell transplant (autoHSCT) is a highly effective treatment in patients with autoimmune diseases (AID). AutoHSCT achieved long-term remission in patients with relapsed refractory and secondary progressive multiple sclerosis (Muraro 2017), superior to their previous standard of care (Burt 2019). AutoHSCT in scleroderma patients achieved superior outcomes in two randomized studies (Tyndall 2014, Sullivan 2018). These impressive results are achieved by both eradication of autoreactive immune effector cells and re-establishment of a self-tolerant immune system, i.e., immune system reset. However, only a fraction of eligible patients undergo autoHSCT, in part due to toxicity associated with current conditioning regimens that remove the disease-causing cells. To enable more patients to benefit from immune reset without debilitating chemotherapy, we generated novel anti-human CD45 ADCs that cross react with NHP and evaluated these for the ability to deplete hematopoietic cells in vitro and in vivo (Fig.1). In vitro the CD45-ADC efficiently killed human CD34+ progenitors and peripheral CD3+ T cells from both healthy donors and MS patients. In vivo in humanized NSG mice, single doses of the CD45-ADCs were well-tolerated and led to depletion of human hematopoietic cells in BM (Fig. 1A) and periphery. In NHPs, single doses of CD45-ADCs were well tolerated and depleted BM HSCs and peripheral lymphocytes (Fig.1B). CD45-ADC treatment of hNSGs with sclerodermatous xenoGVHD resulted in resolution of symptoms (Fig. 1C). To model the complete immune reset approach in mouse models of AID, we generated a tool anti-mouse CD45 ADC. A single-dose enabled full myeloablation (>99\% depletion of LT-HSCs) and complete donor chimerism with congenic HSCT (>90\% chimerism at 16 weeks). In an adoptive transfer model of type I diabetes, treatment with a single dose of CD45-ADC and congenic HSCT led to disease prevention. In a murine model of MS EAE, a single dose of the CD45-ADC followed by congenic HSCT enabled full donor chimerism; treatment prior to disease onset significantly delayed disease onset and reduced disease severity; treatment after disease onset also halted progression of symptoms. These data demonstrate that CD45-ADC conditioning followed by congenic HSCT is sufficient for full myeloablation and immune reset. Experiments are ongoing, and evaluation of this ADC in murine models of diabetes and arthritis will be presented. These results indicate that targeted immune depletion with a single dose of CD45-ADC may be sufficient to enable auto-HSCT and immune reset in multiple AID indications. Targeted conditioning with CD45-ADC may enable more patients to benefit from immune reset through removal of pathogenic cells and autoHSCT without the morbidity and mortality associated with current chemotherapeutic conditioning.}}, pages = {S307--S308}, number = {3}, volume = {26} } - T. Alexander, R. Greco, and J. A. Snowden, "Hematopoietic Stem Cell Transplantation for Autoimmune Disease," Annual review of medicine, vol. 72, iss. 1, p. 1–14, 2020.
[Bibtex]@article{10.1146/annurev-med-070119-115617, year = {2020}, title = {{Hematopoietic Stem Cell Transplantation for Autoimmune Disease}}, author = {Alexander, Tobias and Greco, Raffaella and Snowden, John A.}, journal = {Annual Review of Medicine}, issn = {0066-4219}, doi = {10.1146/annurev-med-070119-115617}, pmid = {33106103}, abstract = {{The introduction of targeted biologic therapies has changed the treatment landscape for autoimmune diseases (ADs) substantially, but although these therapies provide more specificity, they require continuous administration, rarely restore organ function or reverse disability, and are not curative. Over the last 25 years, hematopoietic stem cell transplantation (HSCT) has been increasingly used to treat patients in whom the risk:benefit ratio of HSCT is acceptable. In contrast to chronic suppression of immune function, this intensive one-off procedure aims to provide treatment-free remissions by the reinduction of self-tolerance. The European Society of Blood and Marrow Transplantation (EBMT) Autoimmune Diseases Working Party (ADWP) has been central to development of this approach, with over 3,300 HSCT registrations for ADs. Recent data have improved the evidence base to support autologous HSCT in multiple sclerosis, systemic sclerosis, and Crohn's disease, along with a wide range of rarer disease indications, and autologous HSCT has become an integral part of treatment algorithms in various ADs. Expected final online publication date for the Annual Review of Medicine, Volume 72 is January 27, 2021. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.}}, pages = {1--14}, number = {1}, volume = {72} } - I. Murrieta-Álvarez, Y. Cantero-Fortiz, A. A. León-Peña, J. C. Olivares-Gazca, J. M. Priesca-Marín, G. J. Ruiz-Delgado, A. Gómez-De-León, E. E. Gonzalez-Lopez, J. C. Jaime-Pérez, D. Gómez-Almaguer, and G. J. Ruiz-Argüelles, "The 1,000th Transplant for Multiple Sclerosis and Other Autoimmune Disorders at the HSCT-México Program: A Myriad of Experiences and Knowledge," Frontiers in neurology, vol. 12, p. 647425, 2021.
[Bibtex]@article{10.3389/fneur.2021.647425, year = {2021}, keywords = {hsct}, title = {{The 1,000th Transplant for Multiple Sclerosis and Other Autoimmune Disorders at the HSCT-México Program: A Myriad of Experiences and Knowledge}}, author = {Murrieta-Álvarez, Iván and Cantero-Fortiz, Yahveth and León-Peña, Andrés A. and Olivares-Gazca, Juan C. and Priesca-Marín, José Manuel and Ruiz-Delgado, Guillermo J. and Gómez-De-León, Andrés and Gonzalez-Lopez, Elías Eugenio and Jaime-Pérez, José Carlos and Gómez-Almaguer, David and Ruiz-Argüelles, Guillermo J.}, journal = {Frontiers in Neurology}, issn = {1664-2295}, doi = {10.3389/fneur.2021.647425}, pmid = {33692748}, abstract = {{After gaining experience conducting both auto and allografts in persons with hematological diseases in the HSCT programs in Puebla and Monterrey, México, this study outlines subsequent program autografting patients with autoimmune conditions. The first transplant in multiple sclerosis was conducted in Puebla on July 5, 2006. From 2015 we increased activity autografting persons with autoimmune conditions in the two campuses of the HSCT-México program: Puebla and Monterrey. By December 6, 2020, patient number 1,000 in the program was autografted. In our experience, a significant reduction in the expanded disability status scale score was achieved in all of the three phenotypes of the disease (from a median of 5.1 to 4.5 points), whereas the response rate (defined as a decrease of at least 0.5 of EDSS score regardless of baseline EDSS, or unchanged EDSS) was 83, 78, and 73\% after 12 months in the relapsing-remitting, primary-progressive and secondary-progressive forms of multiple sclerosis, respectively. In addition to analyzing the viability, safety, and efficacy of our method, this study contributes new knowledge to the field of both stem cell transplantation and multiple sclerosis.}}, pages = {647425}, volume = {12}, local-url = {file://localhost/Users/bramplatel/Downloads/fneur-12-647425.pdf} } - A. E. Miller, T. Chitnis, B. A. Cohen, K. Costello, N. L. Sicotte, R. Stacom, and N. M. A. C. N. M. S. of the Society, "Autologous Hematopoietic Stem Cell Transplant in Multiple Sclerosis," Jama neurology, vol. 78, iss. 2, 2021.
[Bibtex]@article{10.1001/jamaneurol.2020.4025, year = {2021}, title = {{Autologous Hematopoietic Stem Cell Transplant in Multiple Sclerosis}}, author = {Miller, Aaron E and Chitnis, Tanuja and Cohen, Bruce A and Costello, Kathleen and Sicotte, Nancy L and Stacom, Rachael and Society, National Medical Advisory Committee of the National Multiple Sclerosis}, journal = {JAMA Neurology}, issn = {2168-6149}, doi = {10.1001/jamaneurol.2020.4025}, pmid = {33104165}, abstract = {{Autologous hematopoietic stem cell transplant (AHSCT) for multiple sclerosis has gained increasing interest in recent years. Despite the availability of many US Food and Drug Administration–approved disease-modifying therapies, some patients do not respond adequately and others may have very early aggressive disease that prompts consideration of alternative, highly effective, long-lasting therapy. The National Medical Advisory Committee of the National Multiple Sclerosis Society has reviewed recent literature on AHSCT for the purpose of making recommendations about its use based on current knowledge, as well as pointing out areas of controversy and issues requiring further research. Studies on AHSCT have repeatedly demonstrated high efficacy and a durable outcome in people with relapsing multiple sclerosis. Recent studies have shown considerable improvement in the safety of the procedure, with much lower mortality rates than were reported earlier. Consensus is emerging about the characteristics of the best candidates for the procedure. Questions remain about the ideal protocol, particularly about the best conditioning regimen to be used to kill immune cells. Larger randomized clinical trials are needed to address the question of whether AHSCT has advantages over the most efficacious disease-modifying agents currently available. One such trial (Best Available Therapy Versus Autologous Hematopoietic Stem Cell Transplant for Multiple Sclerosis [BEAT-MS) is currently in progress. The National Multiple Sclerosis Society believes that AHSCT may be a useful treatment option for people with relapsing multiple sclerosis who demonstrate substantial breakthrough disease activity (ie, new inflammatory central nervous system lesions and/or clinical relapses) despite treatment with high-efficacy disease-modifying therapy or have contraindications to high-efficacy disease-modifying therapies. The best candidates are likely people younger than 50 years with shorter durations of disease (<10 years). The procedure should only be performed at centers with substantial experience and expertise. Ideally, recipients of the procedure should be entered into a single database, and further research is needed to establish ideal cell mobilization and immune-conditioning regimens.}}, number = {2}, volume = {78}, keywords = {} } - R. K. Burt, P. Tappenden, X. Han, K. Quigley, I. Arnautovic, B. Sharrack, J. A. Snowden, and D. Hartung, "Health economics and patient outcomes of hematopoietic stem cell transplantation versus disease-modifying therapies for relapsing remitting multiple sclerosis in the United States of America," Multiple sclerosis and related disorders, vol. 45, p. 102404, 2020.
[Bibtex]@article{10.1016/j.msard.2020.102404, year = {2020}, title = {{Health economics and patient outcomes of hematopoietic stem cell transplantation versus disease-modifying therapies for relapsing remitting multiple sclerosis in the United States of America}}, author = {Burt, Richard K and Tappenden, Paul and Han, Xiaoqiang and Quigley, Kathleen and Arnautovic, Indira and Sharrack, Basil and Snowden, John A and Hartung, Daniel}, journal = {Multiple Sclerosis and Related Disorders}, issn = {2211-0348}, doi = {10.1016/j.msard.2020.102404}, abstract = {{ Objective : To estimate differences in treatment costs and health outcomes between non-myeloablative hematopoietic stem cell transplantation (HSCT) and disease-modifying therapies (DMTs) for the treatment of relapsing-remitting multiple sclerosis (RRMS). Methods : We collected data on costs and reimbursements for patients who underwent HSCT for RRMS at Northwestern Memorial Hospital in Chicago (USA) between January 2017 and January 2019. The costs of HSCT were compared against those for DMTs in the United States, obtained from the literature. We also conducted a literature review to interpret the cost comparisons in terms of disease control and patients’ wellbeing defined as no evidence of disease activity (NEDA), neurologic disability by the Expanded Disability Status Scale (EDSS), and quality of life by the short form SF-36, respectively. Results : Outside of the data, herein, no other studies on cost of HSCT for RRMS were found in the literature. HSCT mean total costs, based on our own hospital, were \$85,184 (range (\$70,635 to \$120,260). Mean revenue collected was \$95,268 (range \$16,544 to \$173,204). In comparison, according to the literature, 2019 DMT costs in the USA ranged between \$80,000 to \$100,000 per year per patient. Compared to DMTs, studies of HSCT reported greater improvement in no evidence of disease activity, disability, and quality of life. Limitations : Costs of HSCT would be expected to vary by conditioning regimen utilized, patient selection, center experience, and regional variation. No cost data on other HSCT regimens or on the three most recently licensed DMTs, alemtuzumab, ocrelizumab, and cladribine, are available. Randomized trials for cost comparisons are missing and variations in HSCT designs, populations, and methodology preclude more precise cost estimates. Conclusion : Costs of non-myeloablative HSCT after which DMTs are indefinitely discontinued, are approximately the same cost as those for one year of prescription DMTs. Since DMTs assessed in this analysis are given on an ongoing basis, whilst HSCT is not, HSCT is expected to produce long-term cost-savings. When considered alongside the available clinical evidence, which suggests that HSCT may generate more health gains than DMTs, HSCT is likely to represent a cost-effective use of resources. Model-based health economic analyses are required to substantiate this conclusion.}}, pages = {102404}, volume = {45}, keywords = {} } - A. Bertolotto, S. Martire, L. Mirabile, M. Capobianco, M. D. Gobbi, and D. Cilloni, "Autologous Hematopoietic Stem Cell Transplantation (AHSCT): Standard of Care for Relapsing–Remitting Multiple Sclerosis Patients," Neurology and therapy, 2020.
[Bibtex]@article{10.1007/s40120-020-00200-9, year = {2020}, keywords = {ms,rrms,hsct}, title = {{Autologous Hematopoietic Stem Cell Transplantation (AHSCT): Standard of Care for Relapsing–Remitting Multiple Sclerosis Patients}}, author = {Bertolotto, Antonio and Martire, Serena and Mirabile, Luca and Capobianco, Marco and Gobbi, Marco De and Cilloni, Daniela}, journal = {Neurology and Therapy}, issn = {2193-8253}, doi = {10.1007/s40120-020-00200-9}, abstract = {{Autologous hematopoietic stem cell transplantation (AHSCT) has been used in the treatment of highly active multiple sclerosis (MS) for over two decades. It has been demonstrated to be highly efficacious in relapsing–remitting (RR) MS patients failing to respond to disease-modifying drugs (DMDs). AHSCT guarantees higher rates of no evidence of disease activity (NEDA) than those achieved with any other DMDs, but it is also associated with greater short-term risks which have limited its use. In the 2019 updated EBMT and ASBMT guidelines, which review the clinical evidence of AHSCT in MS, AHSCT indication for highly active RRMS has changed from “clinical option” to “standard of care”. On this basis, AHSCT must be proposed on equal footing with second-line DMDs to patients with highly active RRMS, instead of being considered as a last resort after failure of all available treatments. The decision-making process requires a close collaboration between transplant hematologists and neurologists and a full discussion of risk–benefit of AHSCT and alternative treatments. In this context, we propose a standardized protocol for decision-making and informed consent process.}} } - 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, year = {2019}, title = {{AUTOLOGOUS HEMATOPOIETIC CELL TRANSPLANTATION FOR TREATMENT-REFRACTORY RELAPSING MULTIPLE SCLEROSIS: POSITION STATEMENT FROM THE AMERICAN SOCIETY FOR BLOOD AND MARROW TRANSPLANTATION.}}, 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}, journal = {Biology of blood and marrow transplantation : journal of 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} } - A. Mariottini, E. D. Matteis, and P. A. Muraro, "Haematopoietic Stem Cell Transplantation for Multiple Sclerosis: Current Status," Biodrugs, vol. 34, iss. 3, p. 307–325, 2020.
[Bibtex]@article{10.1007/s40259-020-00414-1, year = {2020}, title = {{Haematopoietic Stem Cell Transplantation for Multiple Sclerosis: Current Status}}, author = {Mariottini, Alice and Matteis, Eleonora De and Muraro, Paolo A.}, journal = {BioDrugs}, issn = {1173-8804}, doi = {10.1007/s40259-020-00414-1}, pmid = {32166703}, 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 = {307--325}, number = {3}, volume = {34}, keywords = {} } - 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. Muraro, M. Rovira, M. P. Sormani, J. Snowden, J. Snowden, R. Saccardi, E. McGrath, F. Bambi, F. Sanchez-Guijo, N. Worel, J. Snowden, T. Alexander, M. Badolglio, M. Abinun, R. Arnold, C. Brierley, J. Burman, C. Castilla-Llorente, N. Cooper, T. Daikeler, N. del Papa, D. Farge, J. Finke, R. Greco, H. Hagglund, J. Henes, F. Hiepe, H. Jessop, D. Kiely, M. Labopin, M. Kazmi, K. Kirgizov, G. Mancardi, Z. Marjanovic, R. Martin, T. Martin, D. Ma, J. Moore, P. Miller, P. Muraro, M. Oliveira, A. Polushin, F. Onida, B. Simoes, M. Puyade, I. Resnick, M. Rovira, R. Saccardi, M. Saif, I. Sakellari, B. Sharrack, E. Snarski, H. U. Scherer, C. Sossa, J. de Vries-Bouwstra, N. Wulffraat, and E. Zaccara, "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, vol. 55, iss. 2, p. 1–24, 2020.
[Bibtex]@article{10.1038/s41409-019-0684-0, year = {2020}, 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)}}, 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 and Rovira, Montserrat and Sormani, Maria Pia and Snowden, John and Snowden, John and Saccardi, Riccardo and McGrath, Eoin and Bambi, Franco and Sanchez-Guijo, Fermín and Worel, Nina and Snowden, John and Alexander, Tobias and Badolglio, Manuela and Abinun, Mario and Arnold, Renate and Brierley, Charlotte and Burman, Joachim and Castilla-Llorente, Cristina and Cooper, Nichola and Daikeler, Thomas and Papa, Nicoletta del and Farge, Dominique and Finke, Jurgen and Greco, Raffaella and Hagglund, Hans and Henes, Joerg and Hiepe, Falk and Jessop, Helen and Kiely, David and Labopin, Myriam and Kazmi, Majid and Kirgizov, Kirill and Mancardi, Gianluigi and Marjanovic, Zora and Martin, Roland and Martin, Thierry and Ma, David and Moore, John and Miller, Paul and Muraro, Paolo and Oliveira, Maria-Carolina and Polushin, Alexey and Onida, Francesco and Simoes, Belinda and Puyade, Mathieu and Resnick, Igor and Rovira, Montserrat and Saccardi, Riccardo and Saif, Muhammad and Sakellari, Ioanna and Sharrack, Basil and Snarski, Emilian and Scherer, Hans Ulrich and Sossa, Claudia and Vries-Bouwstra, Jeska de and Wulffraat, Nico and Zaccara, Eleanora}, journal = {Bone Marrow Transplantation}, 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}, number = {2}, volume = {55}, keywords = {} } - D. Karussis and P. Petrou, "Immune reconstitution therapy (IRT) in multiple sclerosis: the rationale," Immunologic research, vol. 66, iss. 6, p. 642–648, 2018.
[Bibtex]@article{10.1007/s12026-018-9032-5, year = {2018}, title = {{Immune reconstitution therapy (IRT) in multiple sclerosis: the rationale}}, author = {Karussis, Dimitrios and Petrou, Panayiota}, journal = {Immunologic Research}, issn = {0257-277X}, doi = {10.1007/s12026-018-9032-5}, pmid = {30443887}, abstract = {{Immunotherapy of multiple sclerosis (MS) and other neuroimmune diseases is rapidly evolving. For the past 25 years, there has been an accelerating inclusion of new immunomodulating drugs. Based on their molecular construction and their basic mechanism of action, immunotherapeutic agents belong to the following categories: (1) cytotoxic drugs, (2) synthetic immunomodulators, (3) monoclonal antibodies, (4) vaccines (T cell vaccines, antigen vaccines), (5) oral tolerizing agents, (6) modalities that act as indirect immunosuppressants (plasmapheresis, intravenous immunoglobulins [IVIG]), and (7) cellular therapies. MS immunotherapies may also be classified in a different way, into treatments that are given continuously (chronic treatments) and medications that are applied intermittently (IRTs). The principle behind the latter is depletion of the immune system that allows it to rebuild itself. Upon its reconstitution/resetting, the immune system regains the ability to respond to infections and survey the periphery for cancer. An IRT by definition is given at short intermittent courses and not continuously. IRT modalities were shown to induce long-term remission of MS that, in some cases, is close to the definition of a “cure.” There are cohorts of patients having been treated with the IRTs, alemtuzumab, and HSCT, who experience—under these modalities—no evidence of disease activity (NEDA) for over 10 years. Most importantly, IRTs cause radical changes in the lymphocyte repertoire after the reconstitution phase that may explain the long-term beneficial effects of IRT and the possibility of re-induction of self-tolerance to self/myelin antigens. In comparison, a chronic treatment cannot result in cure of the autoimmune reactivity, because it only blocks the immune system, as long as it is given; it cannot therefore radically affect the immunopathogenesis of the disease. The risks of adverse events related to immune suppression (such as opportunistic infections and secondary malignancies) with IRTs are lower and front-loaded, whereas the common side effects of chronic immunomodulation are higher and accumulate with time. In conclusion, IRT provides a novel concept for MS therapy with substantial advantages over chronic immunosuppression. IRT therapies have shown a significantly higher level of efficacy in MS. The “Holy grail” of the treatment of autoimmunity, which is to re-induce the disrupted self-tolerance, seems to be achievable—at least in part—with this approach. Moreover, the benefits of IRT, administered in short pulses, include significantly higher adherence to treatment and lower risks for accumulative side effects that are typically associated with chronic immunosuppression.}}, pages = {642--648}, number = {6}, volume = {66}, keywords = {} } - 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, year = {2010}, title = {{Autologous haematopoietic stem cell transplantation for secondary progressive multiple sclerosis: an exploratory cost-effectiveness analysis}}, 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}, journal = {Bone Marrow Transplantation}, 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}, keywords = {} } - 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, year = {2015}, title = {{Long-term outcomes of autologous hematopoietic stem cell transplantation with reduced-intensity conditioning in multiple sclerosis: physician’s and patient’s perspectives}}, 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.}, journal = {Annals of Hematology}, 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}, keywords = {} } - 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, year = {1978}, title = {{Transplantation of autoimmune potential. III. Immunological hyper-responsiveness and elevated endogenous spleen colony formation in lethally irradiated recipients of NZB bone marrow cells.}}, author = {Morton, J I and Siegel, B V}, journal = {Immunology}, issn = {0019-2805}, pmid = {350760}, pmcid = {PMC1457211}, pages = {863--8}, number = {5}, volume = {34}, keywords = {} } - 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, year = {2014}, title = {{Unethical for neurologists.pdf}}, author = {Rogne, Sigbjørn}, journal = {Tidsskrift for den Norske lægeforening : tidsskrift for praktisk medicin, ny række}, issn = {0029-2001}, doi = {10.4045/tidsskr.14.1027}, pmid = {25350436}, pages = {1931--2}, number = {20}, volume = {134}, keywords = {} } - 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, year = {2014}, title = {{Stem cell-based therapies for multiple sclerosis: recent advances in animal models and human clinical trials}}, author = {Lutz, Sarah E and Lengfeld, Justin and Agalliu, Dritan}, journal = {Regenerative Medicine}, issn = {1746-0751}, doi = {10.2217/rme.14.1}, pmid = {24750052}, pages = {129--132}, number = {2}, volume = {9}, keywords = {} } - 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, year = {2002}, title = {{Stem cell transplantation in multiple sclerosis: multiple choices and multiple challengesy}}, author = {Hintzen, R Q}, journal = {Multiple Sclerosis}, 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}, keywords = {} } - 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, year = {2019}, title = {{Safety and efficacy of autologous hematopoietic stem cell transplantation for multiple sclerosis in Norway.}}, 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}, journal = {Multiple sclerosis (Houndmills, Basingstoke, England)}, 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}, keywords = {} } - 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, year = {2016}, title = {{Resetting the immune response after autologous hematopoietic stem cell transplantation for autoimmune diseases}}, author = {Arruda, L.C.M. and Clave, E. and Moins-Teisserenc, H. and Douay, C. and Farge, D. and Toubert, A.}, journal = {Current Research in Translational Medicine}, 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}, keywords = {} } - 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, year = {2005}, title = {{Thymic output generates a new and diverse TCR repertoire after autologous stem cell transplantation in multiple sclerosis patients}}, 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}, journal = {The Journal of Experimental Medicine}, 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}, keywords = {} } - 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, year = {2018}, title = {{Regenerating Immunotolerance in Multiple Sclerosis with Autologous Hematopoietic Stem Cell Transplant}}, author = {Massey, Jennifer C. and Sutton, Ian J. and Ma, David D. F. and Moore, John J.}, journal = {Frontiers in Immunology}, 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}, keywords = {} } - 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, year = {2006}, title = {{Randomized controlled trials of autologous hematopoietic stem cell transplantation for autoimmune diseases: The evolution from myeloablative to lymphoablative transplant regimens}}, 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.}, journal = {Arthritis \& Rheumatism}, issn = {1529-0131}, doi = {10.1002/art.22256}, pmid = {17133541}, pages = {3750--3760}, number = {12}, volume = {54}, keywords = {} } - 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, year = {2019}, title = {{Prospective phase II clinical trial of autologous haematopoietic stem cell transplant for treatment refractory multiple sclerosis}}, 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}, journal = {Journal of Neurology, Neurosurgery \& Psychiatry}, 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}, keywords = {} } - 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, year = {1993}, 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.}}, 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}, journal = {Journal of Clinical Investigation}, 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}, keywords = {} } - 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, year = {1997}, title = {{Peripheral blood stem cell transplantation in the treatment of progressive multiple sclerosis: first results of a pilot study}}, author = {Fassas, A and Anagnostopoulos, A and Kazis, A and Kapinas, K and Sakellari, I and Kimiskidis, V and Tsompanakou, A}, journal = {Bone Marrow Transplantation}, 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}, keywords = {} } - 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, year = {1998}, title = {{New Opportunities for the Treatment of Severe Autoimmune Diseases: Bone Marrow Transplantation}}, author = {Bekkum, D.W. van}, journal = {Clinical Immunology and Immunopathology}, issn = {0090-1229}, doi = {10.1006/clin.1998.4563}, pmid = {9756718}, pages = {1--10}, number = {1}, volume = {89}, keywords = {} } - 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, year = {2016}, title = {{NEDA status in highly active MS can be more easily obtained with autologous hematopoietic stem cell transplantation than other drugs}}, author = {Sormani, Maria Pia and Muraro, Paolo A and Saccardi, Riccardo and Mancardi, Gianluigi}, journal = {Multiple Sclerosis Journal}, 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}, keywords = {} } - 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, year = {2016}, title = {{Primary progressive multiple sclerosis—why we are failing}}, author = {Segal, Benjamin M and Stüve, Olaf}, journal = {The Lancet}, issn = {0140-6736}, doi = {10.1016/s0140-6736(16)00158-6}, pmid = {26827076}, pages = {1032--1034}, number = {10023}, volume = {387}, keywords = {} } - 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, year = {2014}, title = {{Low intensity lympho-ablative regimen followed by autologous hematopoietic stem cell transplantation in severe forms of multiple sclerosis: A MRI-based clinical study}}, 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}, journal = {Multiple Sclerosis Journal}, 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}, keywords = {} } - 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, year = {2018}, title = {{Natural Killer Cells Regulate Th17 Cells After Autologous Hematopoietic Stem Cell Transplantation for Relapsing Remitting Multiple Sclerosis}}, 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}, journal = {Frontiers in Immunology}, 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}, keywords = {} } - 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, year = {2017}, title = {{Long-term Outcomes After Autologous Hematopoietic Stem Cell Transplantation for Multiple Sclerosis}}, 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}, journal = {JAMA Neurology}, 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}, keywords = {} } - 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, year = {2017}, title = {{Intense immunosuppression followed by autologous haematopoietic stem cell transplantation as a therapeutic strategy in aggressive forms of multiple sclerosis}}, author = {Mancardi, Gianluigi and Sormani, Maria Pia and Muraro, Paolo A and Boffa, Giacomo and Saccardi, Riccardo}, journal = {Multiple Sclerosis Journal}, 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}, keywords = {} } - 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, year = {2019}, title = {{Inefficacy of Rituximab Post-Autologous Hematopoietic Stem Cell Transplant to Prevent Relapses in Persons with Multiple Sclerosis}}, 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}, journal = {Biology of Blood and Marrow Transplantation}, 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}, keywords = {} } - 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, year = {2017}, title = {{Immunoablation and aHSCT for aggressive multiple sclerosis}}, author = {Harris, Matthew and Cossburn, Mark and Gregory, Ralph}, journal = {The Lancet}, issn = {0140-6736}, doi = {10.1016/s0140-6736(17)30605-0}, pmid = {28271841}, pages = {907--908}, number = {10072}, volume = {389}, keywords = {} } - 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, year = {2017}, title = {{High-dose immunosuppressive therapy and autologous HCT for relapsing-remitting MS}}, 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.}, journal = {Neurology}, 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}, keywords = {} } - 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, year = {2005}, title = {{Hematopoietic Stem Cell Transplantation for Multiple Sclerosis}}, 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}, journal = {Archives of Neurology}, issn = {0003-9942}, doi = {10.1001/archneur.62.6.860}, pmid = {15956156}, pages = {860--864}, number = {6}, volume = {62}, keywords = {} } - 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, year = {2013}, title = {{Hematopoietic Stem Cell Therapy for Multiple Sclerosis: Top 10 Lessons Learned}}, author = {Atkins, Harold L. and Freedman, Mark S.}, journal = {Neurotherapeutics}, 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}, keywords = {} } - 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, year = {2016}, title = {{Immunoablation and autologous haemopoietic stem-cell transplantation for aggressive multiple sclerosis: a multicentre single-group phase 2 trial}}, 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}, journal = {The Lancet}, 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}, keywords = {} } - 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, year = {2019}, 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)}}, 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.}, journal = {Bone Marrow Transplantation}, 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}, keywords = {} } - 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, year = {2019}, title = {{Effect of Nonmyeloablative Hematopoietic Stem Cell Transplantation vs Continued Disease-Modifying Therapy on Disease Progression in Patients With Relapsing-Remitting Multiple Sclerosis}}, 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}, journal = {JAMA}, issn = {0098-7484}, doi = {10.1001/jama.2018.18743}, pmid = {30644983}, pages = {165}, number = {2}, volume = {321}, keywords = {} } - 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, year = {2019}, title = {{Determine safety of outpatient chemotherapy and autotransplants using refrigerated, non‐frozen grafts in persons with multiple sclerosis}}, 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}, journal = {Clinical Transplantation}, 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}, keywords = {} } - 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, year = {2016}, title = {{Hematopoietic stem cell transplantation for multiple sclerosis: is it a clinical reality?}}, author = {Bakhuraysah, Maha M. and Siatskas, Christopher and Petratos, Steven}, journal = {Stem Cell Research \& Therapy}, 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}, keywords = {} } - 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, year = {2017}, title = {{Haematopoietic stem cell transplantation for autoimmune diseases}}, 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.}, journal = {Nature Reviews Rheumatology}, 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}, keywords = {} } - 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, year = {2012}, title = {{Haematopoietic SCT in severe autoimmune diseases: updated guidelines of the European Group for Blood and Marrow Transplantation}}, 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}, journal = {Bone 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}, keywords = {} } - 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, year = {2016}, title = {{Brain atrophy after bone marrow transplantation for treatment of multiple sclerosis}}, 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}, journal = {Multiple Sclerosis Journal}, 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}, keywords = {} }
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