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BMJ Open Feb 2024Autologous haematopoietic stem cell transplantation (aHSCT) is increasingly used as treatment for patients with active multiple sclerosis (MS), typically after failure...
Efficacy and safety of autologous haematopoietic stem cell transplantation versus alemtuzumab, ocrelizumab, ofatumumab or cladribine in relapsing remitting multiple sclerosis (StarMS): protocol for a randomised controlled trial.
INTRODUCTION
Autologous haematopoietic stem cell transplantation (aHSCT) is increasingly used as treatment for patients with active multiple sclerosis (MS), typically after failure of disease-modifying therapies (DMTs). A recent phase III trial, 'Multiple Sclerosis International Stem Cell Transplant, MIST', showed that aHSCT resulted in prolonged time to disability progression compared with DMTs in patients with relapsing remitting MS (RRMS). However, the MIST trial did not include many of the current high-efficacy DMTs (alemtuzumab, ocrelizumab, ofatumumab or cladribine) in use in the UK within the control arm, which are now offered to patients with rapidly evolving severe MS (RES-MS) who are treatment naïve. There remain, therefore, unanswered questions about the relative efficacy and safety of aHSCT over these high-efficacy DMTs in these patient groups. The StarMS trial (Autologous Stem Cell Transplantation versus Alemtuzumab, Ocrelizumab, Ofatumumab or Cladribine in Relapsing Remitting Multiple Sclerosis) will assess the efficacy, safety and long-term impact of aHSCT compared with high-efficacy DMTs in patients with highly active RRMS despite the use of standard DMTs or in patients with treatment naïve RES-MS.
METHODS AND ANALYSIS
StarMS is a multicentre parallel-group rater-blinded randomised controlled trial with two arms. A total of 198 participants will be recruited from 19 regional neurology secondary care centres in the UK. Participants will be randomly allocated to the aHSCT arm or DMT arm in a 1:1 ratio. Participants will remain in the study for 2 years with follow-up visits at 3, 6, 9, 12, 18 and 24 months postrandomisation. The primary outcome is the proportion of patients who achieve 'no evidence of disease activity' during the 2-year postrandomisation follow-up period in an intention to treat analysis. Secondary outcomes include efficacy, safety, cost-effectiveness and immune reconstitution of aHSCT and the four high-efficacy DMTs.
ETHICS AND DISSEMINATION
The study was approved by the Yorkshire and Humber-Leeds West Research Ethics Committee (20/YH/0061). Participants will provide written informed consent prior to any study specific procedures. The study results will be submitted to a peer-reviewed journal and abstracts will be submitted to relevant national and international conferences.
TRIAL REGISTRATION NUMBER
ISRCTN88667898.
Topics: Humans; Cladribine; Alemtuzumab; Multiple Sclerosis, Relapsing-Remitting; Multiple Sclerosis; Hematopoietic Stem Cell Transplantation; Transplantation, Autologous; Randomized Controlled Trials as Topic; Multicenter Studies as Topic; Antibodies, Monoclonal, Humanized
PubMed: 38316583
DOI: 10.1136/bmjopen-2023-083582 -
Multiple Sclerosis and Related Disorders May 2019Efficacy and safety profiles of alemtuzumab for relapsing-remitting multiple sclerosis (RRMS) mainly come from Western countries and have not been reported in Asian...
BACKGROUND
Efficacy and safety profiles of alemtuzumab for relapsing-remitting multiple sclerosis (RRMS) mainly come from Western countries and have not been reported in Asian populations. The aim of this study was to report the efficacy and safety of alemtuzumab for RRMS patients in a Korean population.
METHODS
We retrospectively reviewed RRMS patients treated with alemtuzumab. Study outcomes included annualized relapse rate (ARR), expanded disability status scale (EDSS) score, 6-month confirmed disability worsening (CDW), confirmed disability improvement (CDI), MRI lesion activity (new/enlarging T2 hyperintense and gadolinium-enhancing T1 lesions), no evidence of disease activity (NEDA), and adverse events.
RESULTS
Nineteen patients were identified and mean follow-up was 1.5 years after alemtuzumab initiation. Mean ARR fell from 1.20 pre-treatment to 0.30 post-treatment (p < 0.001). Mean EDSS score remained stable, with a change from baseline of -0.08 at 1 year. After treatment, 16 patients (84.2%) had freedom from 6-month CDW, 3 (15.8%) had 6-month CDI, 11 (57.9%) had freedom from new/enlarging T2 hyperintense lesions, 13 (68.4%) had freedom from gadolinium-enhancing lesions, and 10 (52.6%) had NEDA. Four patients (21.1%) developed relapses after alemtuzumab therapy.
CONCLUSION
Alemtuzumab efficacy and safety were similar to that reported previously in Western populations. Severe relapses can occur after alemtuzumab administration.
Topics: Adult; Alemtuzumab; Antineoplastic Agents, Immunological; Brain; Disability Evaluation; Female; Follow-Up Studies; Humans; Magnetic Resonance Imaging; Male; Multiple Sclerosis; Republic of Korea; Retrospective Studies; Spinal Cord
PubMed: 30849681
DOI: 10.1016/j.msard.2019.03.001 -
British Journal of Clinical Pharmacology Apr 2023Alemtuzumab is a monoclonal antibody used as induction immunosuppressive therapy in kidney transplantation. It targets CD52 on lymphocytes, inducing profound immune cell...
AIM
Alemtuzumab is a monoclonal antibody used as induction immunosuppressive therapy in kidney transplantation. It targets CD52 on lymphocytes, inducing profound immune cell depletion upon administration. Owing to its off-label status in kidney transplantation, its pharmacokinetic characteristics are largely unknown in this setting, and its current fixed dosing algorithm originates from other populations. We developed a population pharmacokinetic model for alemtuzumab in kidney transplant recipients and investigated the potential of personalized alemtuzumab therapy.
METHODS
In total, 362 pharmacokinetic observations drawn 0-165 days after transplantation were available from 61 adult kidney transplant recipients who received two consecutive doses of 15 mg alemtuzumab subcutaneously. A population pharmacokinetic model was developed using nonlinear mixed-effects modelling and applied to simulate various dosing regimens.
RESULTS
The alemtuzumab concentration-time data were best described by a two-compartmental model with first-order absorption and parallel first-order and time-varying concentration-dependent elimination, with between-subject variability on the first-order elimination (39.6%) and central distribution volume (39.6%). Alemtuzumab pharmacokinetics varied with body size, rendering lighter individuals exposed to lympholytic alemtuzumab concentrations (>0.1 mg/L) for prolonged durations as compared to their heavier peers. This between-subject variability could be reduced through lean bodyweight-adjusted dosing, showing a twofold to threefold reduction in the slope of the median alemtuzumab exposure over the bodyweight range.
CONCLUSION
Alemtuzumab displays substantial pharmacokinetic variability in kidney transplant recipients, which may warrant a personalized treatment strategy. Lean bodyweight-adjusted dosing poses an option for individualized dosing, but further evaluation of its potential clinical benefit is warranted.
Topics: Adult; Humans; Alemtuzumab; Kidney Transplantation; Immunosuppressive Agents; Antibodies, Monoclonal; Immunosuppression Therapy
PubMed: 36408784
DOI: 10.1111/bcp.15608 -
Transplantation Proceedings Dec 2020Variability in tacrolimus levels has been associated with increased rejection, graft loss, and de novo donor-specific antibody (dnDSA) development in kidney transplant...
PURPOSE
Variability in tacrolimus levels has been associated with increased rejection, graft loss, and de novo donor-specific antibody (dnDSA) development in kidney transplant recipients (KTRs); however, limited data on alemtuzumab induction or infection exist. We sought to determine the impact of tacrolimus variability in KTRs on dnDSAs, graft outcomes, and infections 3 years posttransplant after alemtuzumab induction.
METHODS
Adult KTRs from January 1, 2013, to December 31, 2017, receiving alemtuzumab and tacrolimus-based immunosuppression at a single center were included. Tacrolimus variability was calculated using coefficient of variability (CV), and high CV was defined as ≥30%. Graft and infectious outcomes were assessed between high and low CV groups.
RESULTS
Two hundred fourteen KTRs were included. The median tacrolimus CV from 0 to 3 months and from 3 to 12 months was 28.1% and 25.8%, respectively. Recipients with high CV had decreased glomerular filtration rate at 3 and 12 months (67.7 ± 35.48 vs 80.7 ± 29.3, P = .01 and 70.9 ± 35.4 vs 83.3 ± 30.2, P = .015). High CV was also associated with increased cytomegalovirus viremia and disease (19.6% vs 9.3%, P = .046 and 6.4% vs 17.9%, P = .015). No difference in biopsy-proven acute rejection, survival, or dnDSA development at 3 years was observed.
CONCLUSIONS
High tacrolimus variability was associated with significantly reduced graft function and increased cytomegalovirus viremia and disease but not biopsy-proven acute rejection, survival, or dnDSA development.
Topics: Adult; Alemtuzumab; Cytomegalovirus Infections; Female; Graft Rejection; Graft Survival; Humans; Immunosuppressive Agents; Kidney Transplantation; Male; Middle Aged; Tacrolimus
PubMed: 32896383
DOI: 10.1016/j.transproceed.2020.07.016 -
Current Opinion in Neurology Jun 2019To critically assess the current landscape of disease-modifying agents for multiple sclerosis (MS). Treatment algorithms will be discussed and studies for new agents in... (Review)
Review
PURPOSE OF REVIEW
To critically assess the current landscape of disease-modifying agents for multiple sclerosis (MS). Treatment algorithms will be discussed and studies for new agents in late development or recently approved are analyzed in terms of their impact on current treatment strategies.
RECENT FINDINGS
A real-world study from Wales suggests that early initiation of highly effective therapy may provide more benefit that an escalation approach in relapsing MS. A study from the MSBase dataset found evidence that early treatment with highly effective therapies decreased the risk of developing secondary progressive MS. Ocrelizumab is highly efficacious in relapsing MS and in a group of patients with primary progressive MS. Another CD20 directed mAb, ofatumumab, is in phase 3. A large study examining extended interval dosing of natalizumab in an attempt to decrease the risk of developing progressive multifocal leukoencephalopathy is underway. Cladribine and alemtuzumab may work by immune reconstitution. Siponimod was recently approved by United States Federal Drug Administration for relapsing MS and active secondary progressive MS. Other S1P receptor modulators are being studied in phase 3 trials for relapsing MS. Cladribine received FDA approval as treatment for relapsing and active secondary progressive MS. Autologous hematopoetic stem-cell transplantation may be an option for treatment-refractory MS.
SUMMARY
Development of disease-modifying agents in MS continues to be successful. Treatment algorithms need to take new developments into account.
Topics: Alemtuzumab; Antibodies, Monoclonal, Humanized; Drug Development; Humans; Immunosuppressive Agents; Multiple Sclerosis; Natalizumab
PubMed: 30985372
DOI: 10.1097/WCO.0000000000000700 -
Transplant International : Official... 2023Alemtuzumab is used as lymphocyte-depleting therapy for severe or glucocorticoid-resistant kidney transplant rejection. However, the long-term efficacy and toxicity of...
Alemtuzumab is used as lymphocyte-depleting therapy for severe or glucocorticoid-resistant kidney transplant rejection. However, the long-term efficacy and toxicity of alemtuzumab therapy are unclear. Therefore, all cases of alemtuzumab anti-rejection therapy between 2012 and 2022 in our institution were investigated. Graft survival, graft function, lymphocyte depletion, serious infections, malignancies, and patient survival were analyzed and compared with a reference cohort of transplanted patients who did not require alemtuzumab anti-rejection therapy. A total of 225 patients treated with alemtuzumab were identified and compared with a reference cohort of 1,668 patients. Over 60% of grafts was salvaged with alemtuzumab therapy, but graft survival was significantly poorer compared to the reference cohort. The median time of profound T- and B lymphocyte depletion was 272 and 344 days, respectively. Serious infection rate after alemtuzumab therapy was 54.1/100 person-years. The risk of death (hazard ratio 1.75, 95%-CI 1.28-2.39) and infection-related death (hazard ratio 2.36, 95%-CI 1.35-4.11) were higher in the alemtuzumab-treated cohort. In conclusion, alemtuzumab is an effective treatment for severe kidney transplant rejection, but causes long-lasting lymphocyte depletion and is associated with frequent infections and worse patient survival outcomes.
Topics: Humans; Alemtuzumab; Immunosuppressive Agents; Glucocorticoids; Kidney Transplantation; Antibodies, Monoclonal, Humanized; Graft Survival; Graft Rejection
PubMed: 38020744
DOI: 10.3389/ti.2023.11834 -
Annals of Clinical and Translational... Jun 2021Autologous hematopoietic stem cell transplantation (aHSCT) is increasingly recognized as a potential therapy for patients with highly active multiple sclerosis (MS).... (Comparative Study)
Comparative Study
OBJECTIVE
Autologous hematopoietic stem cell transplantation (aHSCT) is increasingly recognized as a potential therapy for patients with highly active multiple sclerosis (MS). This study aims to assess outcome differences in disease activity in MS patients treated either with aHSCT or alemtuzumab.
METHODS
We conducted a monocentric registry-based cohort study by recording the clinical course (EDSS and relapses), MRI parameters (new T2 lesions), and neuropsychological assessment in all 19 MS patients receiving aHSCT, and all 21 patients receiving alemtuzumab between 2007 and 2018. We used survival analyses of no evidence of disease activity (NEDA) as the primary objective which was defined by no EDSS progression, no relapse, and no new T2 lesion on MRI. Secondary objectives were EDSS improvement and neurocognitive performance.
RESULTS
Both treatment groups were similar in respect of age, gender, disability, and neurocognitive performance except for significantly longer disease duration in the alemtuzumab group. Mean follow-up was 58.8 [range 29-140] months in the aHSCT group compared to 27.6 [range 11-52] months in the alemtuzumab-treated group. We observed significantly more patients maintaining NEDA in the aHSCT group (p = 0.048) compared to the alemtuzumab-treated patients. Furthermore, 37% of the aHSCT patients showed an improvement of EDSS compared to none in the alemtuzumab-treated group (p = 0.033). It is of note that cognitive function was significantly improved in the aHSCT-treated patients.
INTERPRETATION
aHSCT suppresses inflammatory activity more effectively than alemtuzumab and might enable improvement of overall disability and cognition in MS.
Topics: Adult; Alemtuzumab; Cognitive Dysfunction; Disease Progression; Female; Follow-Up Studies; Hematopoietic Stem Cell Transplantation; Humans; Magnetic Resonance Imaging; Male; Middle Aged; Multiple Sclerosis; Neuropsychological Tests; Outcome Assessment, Health Care; Patient Acuity; Registries; Transplantation, Autologous; Young Adult
PubMed: 33949790
DOI: 10.1002/acn3.51366 -
The Journal of Allergy and Clinical... May 2022Treatment of hypereosinophilic syndrome (HES) often requires the use of immunomodulators with substantial side effect profiles. The emergence of biologics offers an...
BACKGROUND
Treatment of hypereosinophilic syndrome (HES) often requires the use of immunomodulators with substantial side effect profiles. The emergence of biologics offers an alternative treatment modality.
OBJECTIVE
To examine real-world practice data to describe the safety and consequences of various biologics suspected to directly or indirectly affect eosinophilic inflammation for the treatment of HES.
METHODS
Retrospective data from 13 centers were collected via an online Research Electronic Data Capture repository. Inclusion criteria included (1) peripheral eosinophil count of 1,500/mm or greater without a secondary cause; (2) clinical manifestations attributable to the eosinophilia; and (3) having received mepolizumab (anti-IL-5), benralizumab (afucosylated anti-IL-5 receptor α), omalizumab (anti-IgE), alemtuzumab (anti-CD52), dupilumab (anti-IL-4 receptor α), or reslizumab (anti-IL-5) outside a placebo-controlled clinical trial.
RESULTS
Of the 151 courses of biologics prescribed for 121 patients with HES, 59% resulted in improved HES symptoms and 77% enabled tapering of other HES medications. Overall, 105 patients were receiving daily systemic glucocorticoids at the time of a biologic initiation and were able to reduce the glucocorticoid dose by a median reduction of 10 mg of daily prednisone equivalents. Biologics were generally safe and well-tolerated other than infusion reactions with alemtuzumab. Thirteen of 24 patients had clinical improvement after switching biologics and nine patients responded to increasing the dose of mepolizumab after a lack of response to a lower dose.
CONCLUSIONS
Biologics may offer a safer treatment alternative to existing therapies for HES, although the optimal dosing and choice for each subtype of HES remain to be determined. Limitations of this study include its retrospective nature and intersite differences in data collection and availability of each biologic.
Topics: Alemtuzumab; Biological Products; Glucocorticoids; Humans; Hypereosinophilic Syndrome; Interleukin-5; Off-Label Use; Retrospective Studies
PubMed: 35181548
DOI: 10.1016/j.jaip.2022.02.006 -
Neurology Mar 2021To assess safety outcomes for the induction therapies alemtuzumab and autologous hematopoietic stem cell transplantation (AHSCT) compared to noninduction...
OBJECTIVE
To assess safety outcomes for the induction therapies alemtuzumab and autologous hematopoietic stem cell transplantation (AHSCT) compared to noninduction disease-modifying therapies.
METHODS
We performed a population-based cohort study linking the Swedish Multiple Sclerosis Register to national health care registers. Alemtuzumab, AHSCT, and a matched reference group of noninduction therapies (natalizumab, dimethyl fumarate, rituximab, fingolimod) were included if started between 2008 and 2017. Main outcomes were death, thyroid disease, nonthyroid autoimmune disease, and infection.
RESULTS
We identified 132 alemtuzumab-treated and 139 AHSCT-treated (68% high-dose cyclophosphamide and anti-thymocyte globulin [ATG], 32% BCNU, etoposide, cytosine-arabinoside, and melphalan/ATG) patients, together with 2,486 matched patients treated with noninduction therapies. Four patients in the alemtuzumab group died (incidence rate [IR] per 1,000 person-years 8.6, 95% confidence interval [CI] 2.3-22.0) compared to 1 patient in the AHSCT group (IR 1.7, 95% CI 0.0-9.6), and the mortality rate in the reference group was 0.7 (95% CI 0.3-1.3). Thyroid disease was most frequent in the alemtuzumab group (IR 109, 95% CI 75-154) but also occurred more often for AHSCT (IR 34, 95% CI 18-56) compared to the reference (IR 5.3 95% CI 3.9-7.1). The incidence of nonthyroid autoimmune disease was similar in all groups. IR for infection diagnosed ≥6 months from therapy initiation was 53 (95% CI 30-87) for alemtuzumab, 108 (95% CI 75-150) for AHSCT, and 51 (95% CI 46-57) for the reference.
CONCLUSION
We confirmed a high incidence of thyroid disease in alemtuzumab- and, to a smaller extent, AHSCT-treated patients and found a higher incidence of infection for AHSCT compared to both alemtuzumab and noninduction therapies. The incidence of nonthyroid autoimmune disease was low for both therapies.
CLASSIFICATION OF EVIDENCE
This study provides Class III evidence of an increased risk of thyroid disease with alemtuzumab and an increased risk of infection with AHSCT treatment.
Topics: Adult; Alemtuzumab; Cohort Studies; Female; Hematopoietic Stem Cell Transplantation; Humans; Immunologic Factors; Infections; Male; Middle Aged; Multiple Sclerosis, Relapsing-Remitting; Registries; Sweden; Thyroid Diseases; Transplantation, Autologous
PubMed: 33514645
DOI: 10.1212/WNL.0000000000011545 -
Pharmacogenomics Jul 2022
Topics: Alemtuzumab; Graft Rejection; Graft Survival; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Kidney Transplantation
PubMed: 35763447
DOI: 10.2217/pgs-2022-0071