Autologous Haematopoietic Stem Cell Transplantation in Multiple Sclerosis: a Review of Current Literature and Future Directions for Transplant Haematologists and Oncologists.
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SUBMITTER: Das J
PROVIDER: S-EPMC6510794 | biostudies-literature | 2019 Apr
REPOSITORIES: biostudies-literature
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Project description:Total body irradiation (TBI) has been a pivotal component of the conditioning regimen for allogeneic myeloablative haematopoietic stem cell transplantation (HSCT) in very-high-risk acute lymphoblastic leukaemia (ALL) for decades, especially in children and young adults. The myeloablative conditioning regimen has two aims: (1) to eradicate leukaemic cells, and (2) to prevent rejection of the graft through suppression of the recipient's immune system. Radiotherapy has the advantage of achieving an adequate dose effect in sanctuary sites and in areas with poor blood supply. However, radiotherapy is subject to radiobiological trade-offs between ALL cell destruction, immune and haematopoietic stem cell survival, and various adverse effects in normal tissue. To diminish toxicity, a shift from single-fraction to fractionated TBI has taken place. However, HSCT and TBI are still associated with multiple late sequelae, leaving room for improvement. This review discusses the past developments of TBI and considerations for dose, fractionation and dose-rate, as well as issues regarding TBI setup performance, limitations and possibilities for improvement. TBI is typically delivered using conventional irradiation techniques and centres have locally developed heterogeneous treatment methods and ways to achieve reduced doses in several organs. There are, however, limitations in options to shield organs at risk without compromising the anti-leukaemic and immunosuppressive effects of conventional TBI. Technological improvements in radiotherapy planning and delivery with highly conformal TBI or total marrow irradiation (TMI), and total marrow and lymphoid irradiation (TMLI) have opened the way to investigate the potential reduction of radiotherapy-related toxicities without jeopardising efficacy. The demonstration of the superiority of TBI compared with chemotherapy-only conditioning regimens for event-free and overall survival in the randomised For Omitting Radiation Under Majority age (FORUM) trial in children with high-risk ALL makes exploration of the optimal use of TBI delivery mandatory. Standardisation and comprehensive reporting of conventional TBI techniques as well as cooperation between radiotherapy centres may help to increase the ratio between treatment outcomes and toxicity, and future studies must determine potential added benefit of innovative conformal techniques to ultimately improve quality of life for paediatric ALL patients receiving TBI-conditioned HSCT.
| S-EPMC8678472 | biostudies-literature
Project description:Background and purposeEffectiveness of autologous haematopoietic stem cell transplantation (AHSCT) in relapsing-remitting multiple sclerosis (MS) is well known, but in secondary-progressive (SP)-MS it is still controversial. Therefore, AHSCT activity was evaluated in SP-MS using low-dose immunosuppression with cyclophosphamide (Cy) as a comparative treatment.MethodsIn this retrospective monocentric 1:2 matched study, SP-MS patients were treated with intermediate-intensity AHSCT (cases) or intravenous pulses of Cy (controls) at a single academic centre in Florence. Controls were selected according to baseline characteristics adopting cardinality matching after trimming on the estimated propensity score. Kaplan-Meier and Cox analyses were used to estimate survival free from relapses (R-FS), survival free from disability progression (P-FS), and no evidence of disease activity 2 (NEDA-2).ResultsA total of 93 SP-MS patients were included: 31 AHSCT, 62 Cy. Mean follow-up was 99 months in the AHSCT group and 91 months in the Cy group. R-FS was higher in AHSCT compared to Cy patients: at Year 5, 100% versus 52%, respectively (p < 0.0001). P-FS did not differ between the groups (at Year 5: 70% in AHSCT and 81% in Cy, p = 0.572), nor did NEDA-2 (p = 0.379). A sensitivity analysis including only the 31 "best-matched" controls confirmed these results. Three neoplasms (2 Cy, 1 AHSCT) and two fatalities (2 Cy) occurred.ConclusionsThis study provides Class III evidence, in SP-MS, on the superior effectiveness of AHSCT compared to Cy on relapse activity, without differences on disability accrual. Although the suppression of relapses was observed in the AHSCT group only, AHSCT did not show advantages over Cy on disability, suggesting that in SP-MS disability progression becomes based more on noninflammatory neurodegeneration than on inflammation.
| S-EPMC9306891 | biostudies-literature
Project description:Bronchiolitis obliterans syndrome (BOS) may develop after either lung or haematopoietic stem cell transplantation (HSCT), with similarities in histopathological features and clinical manifestations. However, there are differences in the contributory factors and clinical trajectories between the two conditions. BOS after HSCT occurs due to systemic graft-versus-host disease (GVHD), whereas BOS after lung transplantation is limited to the lung allograft. BOS diagnosis after HSCT is more challenging, as the lung function decline may occur due to extrapulmonary GVHD, causing sclerosis or inflammation in the fascia or muscles of the respiratory girdle. Treatment is generally empirical with no established effective therapies. This review provides rare insights and commonalities of both conditions, which are not well elaborated elsewhere in contemporary literature, and highlights the importance of cross disciplinary learning from experts in other transplant modalities. Treatment algorithms for each condition are presented, based on the published literature and consensus clinical opinion. Immunosuppression should be optimised, and other conditions or contributory factors treated where possible. When initial treatment fails, the ultimate therapeutic option is lung transplantation (or re-transplantation in the case of BOS after lung transplantation) in carefully selected candidates. Novel therapies under investigation include aerosolised liposomal cyclosporine, Janus kinase inhibitors, antifibrotic therapies and (in patients with BOS after lung transplantation) B-cell-directed therapies. Effective novel treatments that have a tangible impact on survival and thereby avoid the need for lung transplantation or re-transplantation are urgently required.
| S-EPMC9309343 | biostudies-literature
Project description:Autologous haematopoietic stem cell transplantation (aHSCT) is gaining traction as a valuable treatment option for patients affected by severe multiple sclerosis (MS), particularly the relapsing-remitting form. We describe the current literature in terms of clinical trials, observational and retrospective studies, as well as immune reconstitution following transplantation, with a focus on the conditioning regimens used for transplantation. The evidence base predominantly consists of non-randomised, uncontrolled clinical trials or data from retrospective or observational cohorts, i.e. very few randomised or controlled trials. Most often, intermediate-intensity conditioning regimens are used, with promising results from both myeloablative and lymphoablative strategies, as well as from regimens that are low and high intensity. Efficacy of transplantation, which is likely secondary to immune reconstitution and restored immune tolerance, is, therefore, not clearly dependent on the intensity of the conditioning regimen. However, the conditioning regimen may well influence the immune response to transplantation. Heterogeneity of conditioning regimens among studies hinders synthesis of the articles assessing post-aHSCT immune system changes. Factors associated with better outcomes were lower Kurtzke Expanded Disability Status Scale, relapsing-remitting MS, younger age, and shorter disease duration at baseline, which supports the guidance for patient selection proposed by the European Society for Blood and Marrow Transplantation. Interestingly, promising outcomes were described for patients with secondary progressive MS by some studies, which may be worth taking into account when considering treatment options for patients with active, progressive disease. Of note, a significant proportion of patients develop autoimmune disease following transplantation, with alemtuzumab-containing regimens associated with the highest incidence.
| S-EPMC8995166 | biostudies-literature
Project description:Abstract Multiple sclerosis has been established as an inflammatory disease of the central nervous system. Many aspects of the pathophysiology are still unknown and it is presently unclear how different treatments affect the immunopathology of multiple sclerosis. In this study, we explored cytokines discriminating between individuals with multiple sclerosis and healthy controls and then how these cytokines were affected by treatment intervention with autologous haematopoietic stem cell transplantation or intrathecal rituximab. CSF from individuals with multiple sclerosis and healthy controls were analysed with a proximity extension assay to simultaneously determine the level of 92 cytokines and other inflammation-related proteins. In total, CSF from 158 multiple sclerosis patients and 53 healthy controls were analysed. Sixty-four patients with relapsing-remitting multiple sclerosis and 27 with progressive multiple sclerosis took part in a cross-sectional study and underwent lumbar puncture on a single occasion. Forty-five patients with relapsing-remitting multiple sclerosis were treated with autologous haematopoietic stem cell transplantation and underwent lumbar puncture at baseline and then at follow-up visits made at 1-, 2- and 5 years. Twenty-two patients with progressive multiple sclerosis were treated with intrathecal rituximab and followed with lumbar punctures at baseline and then at follow-up visits made at 3-, 6- and 12 months. Of the 92 studied cytokines, 16 were found to be altered in multiple sclerosis and 11 were decreased after treatment with autologous haematopoietic stem cell transplantation. None of the studied cytokines was affected by treatment with intrathecal rituximab for progressive multiple sclerosis. Some proteins were highly associated with each other. Therefore, a cluster analysis was made and then the highest-ranked protein from the four highest-ranked clusters was used for the subsequent analyses. CCL3, IL-12B, CXCL10 and IL-8 discriminated between multiple sclerosis patients and controls, but only IL-12B differed between patients with relapsing-remitting and progressive multiple sclerosis. The CSF concentrations of CCL3, IL-12B and CXCL10 were decreased after autologous haematopoietic stem cell transplantation, whereas IL-8 appeared to be unaffected by this intervention. High concentrations of IL-8 were associated with worse outcome in both treatment groups. Overall, the results suggest a profound effect of autologous haematopoietic stem cell transplantation on the inflammatory milieu of the CSF in multiple sclerosis. Burman et al. measured CSF concentrations of 92 cytokines in patients with multiple sclerosis. CCL3, IL-12B, CXCL10 and IL-8 discriminated best between patients and healthy controls. The CSF concentrations of CCL3, IL-12B and CXCL10 decreased after treatment intervention with autologous haematopoietic stem cell transplantation for relapsing-remitting multiple sclerosis. Graphical Abstract Graphical abstract
| S-EPMC9901571 | biostudies-literature
Project description:ObjectiveTo compare outcomes after treatment with autologous haematopoietic stem cell transplantation (AHSCT) and alemtuzumab (ALZ) in patients with relapsing-remitting multiple sclerosis.MethodsPatients treated with AHSCT (n=69) received a conditioning regimen of cyclophosphamide (200 mg/kg) and rabbit anti-thymocyte globulinerG (6.0 mg/kg). Patients treated with ALZ (n=75) received a dose of 60 mg over 5 days, a repeated dose of 36 mg over 3 days after 1 year and then as needed. Follow-up visits with assessment of the expanded disability status scale score, adverse events and MR investigations were made at least yearly.ResultsThe Kaplan-Meier estimates of the primary outcome measure 'no evidence of disease activity' was 88% for AHSCT and 37% for ALZ at 3 years, p<0.0001. The secondary endpoint of annualised relapse rate was 0.04 for AHSCT and 0.1 for ALZ, p=0.03. At last follow-up, the proportions of patients who improved, were stable or worsened were 57%/41%/1% (AHSCT) and 45%/43%/12% (ALZ), p=0.06 Adverse events grade three or higher were present in 48/69 patients treated with AHSCT and 0/75 treated with ALZ in the first 100 days after treatment initiation. The most common long-term adverse event was thyroid disease with Kaplan-Meier estimates at 3 years of 21% for AHSCT and 46% for ALZ, p=0.005.ConclusionsIn this observational cohort study, treatment with AHSCT was associated with a higher likelihood of maintaining 'no evidence of disease activity'. Adverse events were more frequent with AHSCT in the first 100 days, but thereafter more common in patients treated with ALZ.
| S-EPMC7841472 | biostudies-literature
Project description:Autologous haematopoietic stem cell transplantation (AHSCT) has been proposed as a treatment modality which may arrest the autoimmune disease process and lead to sustained treatment-free remissions. Since the first consensus statement in 1997, approximately 200 autologous bone marrow or haematopoietic stem cell transplantations (HSCTs) have been reported worldwide for systemic lupus erythematosus (SLE). The current state of AHSCT in SLE was reviewed at a recent meeting of the autoimmune working party of the European Group for Blood and Marrow Transplantation. There was general agreement among experts in this field that in patients with severe SLE refractory to conventional immunosuppressive treatments, AHSCT can achieve sustained clinical remissions (ranging from 50% to 70% disease-free survival at 5 years) associated with qualitative immunological changes not seen with other forms of treatment. However, this clinical benefit is associated with an increase in short-term mortality in most studies. Improving patient selection, long-term follow-up of patients after AHSCT, optimisation of induction and maintenance treatment together with detailed analysis of the immune system are identified as key areas for future research. Optimally, AHSCT should be compared with conventional treatment in randomised controlled trials. Development of stronger transplant registries, defining a core set of clinical data and standardising biological sample collections would make future collaborations and comparison of studies more feasible.
| S-EPMC3923531 | biostudies-literature
Project description:IntroductionAutologous haematopoietic stem cell transplantation improves event-free survival and lung function and reduces skin thickening in patients with progressive diffuse cutaneous systemic sclerosis. Anti-thymocyte globulin is a key lymphoablative constituent of conditioning protocols and is administered in a weight-based dosage. However, whether anti-thymocyte globulin exposure contributes to response to autologous haematopoietic stem cell transplantation and lymphocyte reconstitution in diffuse cutaneous systemic sclerosis patients is unknown. We aimed to explore the relationship between anti-thymocyte globulin exposure, lymphocyte reconstitution and treatment response in diffuse cutaneous systemic sclerosis patients undergoing autologous haematopoietic stem cell transplantation.MethodsA retrospective cohort of 15 diffuse cutaneous systemic sclerosis patients undergoing autologous haematopoietic stem cell transplantation was performed. Clinical characteristics and routine laboratory results were retrieved from electronic medical records. Anti-thymocyte globulin concentrations were measured in cryopreserved plasma samples at four time points (day 1 and week 1, 2 and 4) after stem cell reinfusion. Anti-thymocyte globulin exposure was estimated using a validated population pharmacokinetic model.ResultsDuring a median follow-up of 45 months (interquartile range 19-66), 11 (73%) patients had a treatment response, and 4 (27%) were non-responders. Although all patients received the same weight-based anti-thymocyte globulin dosage, 7.5 mg/kg divided over 3 days, anti-thymocyte globulin exposure varied. Anti-thymocyte globulin exposure was higher in responders than in non-responders (163 AU*day/mL (interquartile range 153-183) and 137 AU*day/mL (interquartile range 101-149), respectively, p = .026). Anti-thymocyte globulin exposure was not correlated with lymphocyte reconstitution or infection rate.ConclusionWeight-based dosing of anti-thymocyte globulin results in variable anti-thymocyte globulin exposure and treatment response across individuals.
| S-EPMC10515999 | biostudies-literature
Project description:Three randomised controlled trials of haematopoietic stem cell transplantation (HSCT) in systemic sclerosis (SSc) demonstrated long-term survival benefits, induction of clinically meaningful, sustained improvement of forced vital capacity with improvements in skin thickening, vasculopathy and health-related quality of life, in contrast to a clinical decline in standard of care control groups. These benefits, however, must be weighed against the increased risk of transplant-related mortality. Further, with disease progression, severe extensive internal organ involvement and damage ensues, constituting an exclusion criterion for safety reasons, leaving a limited window whereby patients with SSc are eligible for HSCT. Although autologous HSCT offers the possibility of drug-free remission, relapse can occur, requiring re-initiation of disease modifying antirheumatic drugs. HSCT is also associated with secondary autoimmune diseases and gonadal failure. HSCT should be proposed for carefully selected patients with early rapidly progressive diffuse SSc whose clinical picture portends a poor prognosis for survival, but yet lacks advanced organ involvement.
| S-EPMC6045702 | biostudies-literature
Project description:BackgroundAutologous haematopoietic stem cell transplantation (AHSCT) is increasingly used as a treatment for aggressive multiple sclerosis (MS) and has the potential to induce long-term remission and resolution of disease activity. Despite the extensive research on treatment outcome after AHSCT, the experience of living with MS after AHSCT has not been previously described in the scientific literature. The aim of this study was to explore long-term lived experience of people with MS treated with AHSCT.Methods and findingsTo exclude selection bias, all persons treated with AHSCT for MS at Uppsala University Hospital, Sweden, between 2004 and 2007 (n = 10), were asked to participate in the study, and all accepted. Open-ended interviews were conducted, digitally recorded, transcribed verbatim, and then subjected to qualitative content analysis with an inductive approach. Five main themes emerged from the interviews: (I) being diagnosed with MS-an unpredictable existence; (II) a new treatment-a possibility for a new life; (III) AHSCT-a transition; (IV) reclaiming life; and (V) a bright future accompanied by insecurity. AHSCT was described by the participants in terms of a second chance and an opportunity for a new life. The treatment became a transition from a state of illness to a state of health, enabling a previous profound uncertainty to wane and normality to be restored. Although participants of different age and sex were included, the main limitation of this study is the relatively small number of participants. Also, the inclusion of persons from one centre alone could restrict transferability of the results.ConclusionsThe results give a first insight into lived experience following a highly effective induction treatment for MS, and the experience of not having MS anymore. Underpinned by previously described outcome following AHSCT, the results of this study challenge the current view on MS as a chronic disease with no possible cure.
| S-EPMC10849216 | biostudies-literature