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Annals of Clinical and Translational... May 2024Observational real-world study to analyze the clinical effects of alemtuzumab (ALEM) and subsequent disease-modifying therapy (DMT) usage in multiple sclerosis (MS).
BACKGROUND/OBJECTIVE
Observational real-world study to analyze the clinical effects of alemtuzumab (ALEM) and subsequent disease-modifying therapy (DMT) usage in multiple sclerosis (MS).
METHODS
Data retrieved from the Austrian MS treatment registry (AMSTR) included baseline (BL) characteristics (at ALEM start), annualized relapse rate (ARR), 6-month confirmed progression independent of relapse activity (PIRA; ≥ 0.5-point Expanded Disability Status Scale (EDSS) score increase), 6-month confirmed disability improvement (CDI; ≥ 0.5-point EDSS decrease), and safety outcomes until initiation of a subsequent DMT. The EDSS was re-baselined at 30 days from ALEM start (BL EDSS).
RESULTS
Eighty-seven ALEM-treated patients (median age: 32 years, 72% female, 14% treatment-naïve) were followed for a median of 55 (interquartile range 31-68) months. We found significant reductions in the ARR from 1.16 before ALEM to 0.15 throughout Years 1-9 (p < 0.001). Subsequent DMTs were initiated in 19 patients (22%, 74% anti-CD20 monoclonal antibodies). At Year 5 (n = 53), more patients achieved CDI (58%, 95% confidence interval (CI) 45%-71%) than had experienced PIRA (14%, CI 7.5%-24%), and 58% remained relapse-free. Shorter MS duration (p < 0.001, hazard ratio (HR) 0.86 (CI 0.80-0.93)) and no previous high-efficacy treatment (p < 0.001, HR 5.16 (CI 2.66-10.0)) were the best predictors of CDI, while PIRA was associated with a higher number of previous DMTs (p = 0.04, HR 3.06, CI 1.05-8.89). We found no new safety signals.
INTERPRETATION
ALEM had long-lasting beneficial effects on the ARR and disability improvement, especially when initiated early in the course of the disease. Only a subset of patients received subsequent DMTs.
PubMed: 38715245
DOI: 10.1002/acn3.52056 -
Frontiers in Immunology 2024The objective of this study is to evaluate the risk of secondary autoimmune diseases in multiple sclerosis (MS) patients treated with alemtuzumab (ALZ) through a... (Meta-Analysis)
Meta-Analysis
BACKGROUND AND PURPOSE
The objective of this study is to evaluate the risk of secondary autoimmune diseases in multiple sclerosis (MS) patients treated with alemtuzumab (ALZ) through a meta-analysis.
METHODS
PubMed, Web of Science, OVID, EMBASE, and Cochrane central register of controlled trials were searched. Information and data were screened and extracted by 2 researchers. The obtained data were analyzed using the R software meta package. Quality assessment was conducted using the Newcastle-Ottawa Scale (NOS). The causes of heterogeneity were analyzed using subgroup analysis and sensitivity analysis. Publication bias was evaluated using funnel plots and Egger's test.
RESULTS
The search retrieved a total of 3530 papers from the databases. After screening, a total of 37 studies were included in the meta-analysis. The analysis results indicate that the pooled incidence rate of overall secondary autoimmune events (SAEs) in the included studies was 0.2824 [0.2348, 0.3300] (I²=94%, p<0.01). The overall incidence of autoimmune thyroid events (ATE) was 0.2257 [0.1810, 0.2703] (I²=94%, p<0.01). Among them, the rate of serious autoimmune thyroid events (SATE) was 0.0541 [0.0396, 0.0687] (I²=0%, p=0.44). The incidence rates of different thyroid events were as follows: Graves' disease (GD), 0.2266 [0.1632, 0.2900] (I²=83%, p<0.01); Hashimoto thyroiditis (HT), 0.0844 [0.0000, 0.2262] (I²=81%, p=0.02); Hashimoto thyroiditis with hypothyroidism (HTwH), 0.0499 [0.0058, 0.0940] (I²=37%, p=0.21); fluctuating thyroid dysfunction (FTD), 0.0219 [0.0015, 0.0424] (I²=0%, p=0.40); transient thyroiditis (TT), 0.0178 [0.0062, 0.0295] (I²=0%, p=0.94). The overall incidence of hematological events was 0.0431 [0.0274, 0.0621] (I²=70%, p<0.01). The incidence rates from high to low were as follows: lymphopenia, 0.0367 [0.0000, 0.0776] (I²=81%, p=0.02); Idiopathic thrombocytopenic purpura (ITP), 0.0258 [0.0199, 0.0323] (I²=25%, p=0.15); Hemolytic anemia (HA), 0.0177 [0.0081, 0.0391] (I²=29%, p=0.23); pancytopenia, 0.0136 [0.0000, 0.0314] (I²=0%, p=0.67); Neutropenia, 0.0081 [0.0000, 0.0183] (I²=0%, p=0.42). After excluding thyroid and hematological diseases, the combined incidence of other related SAEs was 0.0061 [0.0014, 0.0109] (I²=50%, p=0.02). The incidence of each disease ranked from highest to lowest as: skin psoriasis (SP), 0.0430 [0.0000, 0.0929] (I²=0%, p=0.57); alopecia areata (AA), 0.0159 [0.0024, 0.0372] (I²=19%, p=0.29); vitiligo, 0.0134 [0.0044, 0.0223] (I²=0%, p=0.81); inflammatory atrichia (IA), 0.0103 [0.0000, 0.0232] (I²=0%, p=0.43); chronic urticaria (CU), 0.0107 [0.0000, 0.0233] (I²=0%, p=0.60); and nephropathy, 0.0051 [0.0000, 0.0263] (I²=62%, p=0.02).
CONCLUSION
The occurrence of secondary autoimmune diseases in patients with MS treated with ALZ is noteworthy, particularly in the form of thyroid events and hematological events. Clinicians should monitor the overall condition of patients promptly for early management and avoid delayed diagnosis and treatment.
SYSTEMATIC REVIEW REGISTRATION
inplasy.com/inplasy-2024-4-0048/, identifier INPLASY202440048.
Topics: Humans; Alemtuzumab; Multiple Sclerosis; Autoimmune Diseases; Incidence; Hashimoto Disease
PubMed: 38690271
DOI: 10.3389/fimmu.2024.1343971 -
Medicina (Kaunas, Lithuania) Mar 2024: Multiple sclerosis (MS) is a chronic inflammatory demyelinating disorder of the central nervous system characterized by autoimmune-mediated damage to oligodendrocytes... (Review)
Review
: Multiple sclerosis (MS) is a chronic inflammatory demyelinating disorder of the central nervous system characterized by autoimmune-mediated damage to oligodendrocytes and subsequent myelin destruction. : Clinically, the disease presents with many symptoms, often evolving over time. The insidious onset of MS often manifests with non-specific symptoms (prodromal phase), which may precede a clinical diagnosis by several years. Among them, headache is a prominent early indicator, affecting a significant number of MS patients (50-60%). : Headache manifests as migraine or tension-type headache with a clear female predilection (female-male ratio 2-3:1). Additionally, some disease-modifying therapies in MS can also induce headache. For instance, teriflunomide, interferons, ponesimod, alemtuzumab and cladribine are associated with an increased incidence of headache. : The present review analyzed the literature data on the relationship between headache and MS to provide clinicians with valuable insights for optimized patient management and the therapeutic decision-making process.
Topics: Humans; Multiple Sclerosis; Headache; Female; Migraine Disorders; Toluidines; Crotonates; Hydroxybutyrates; Nitriles; Tension-Type Headache; Male; Cladribine
PubMed: 38674218
DOI: 10.3390/medicina60040572 -
Glomerular Diseases 2024Alemtuzumab, a humanized monoclonal antibody indicated for the treatment of adult patients with active relapsing-remitting multiple sclerosis (MS), has been associated...
INTRODUCTION
Alemtuzumab, a humanized monoclonal antibody indicated for the treatment of adult patients with active relapsing-remitting multiple sclerosis (MS), has been associated with increased risk of autoimmune adverse events, including thyroid disorders, immune thrombocytopenia, and renal diseases. Renal immune-mediated adverse events, which have been reported in 0.3% of patients treated with alemtuzumab in MS clinical trials, typically occur within 39 months after the last drug administration. However, no consensus has been reached regarding the management of patients who develop glomerulonephritis after treatment with alemtuzumab.
CASE PRESENTATION
We report the cases of two young adults with MS who developed biopsy-proven severe glomerulonephritis after alemtuzumab treatment. Both patients, including a 32-year-old female patient who developed membranous nephropathy and a 31-year-old male who developed drug-induced podocytopathy, were treated successfully with the calcineurin inhibitor tacrolimus followed by the anti-CD20 antibody rituximab.
CONCLUSION
Regular renal function monitoring is required in patients who may rarely develop glomerulonephritis following treatment with alemtuzumab. There is no clear consensus on case management. In both cases, immunosuppressive therapy, which was necessary due to disease severity, resulted in successful remission, highlighting the potential utility of this approach.
PubMed: 38660579
DOI: 10.1159/000538492 -
Frontiers in Neurology 2024The purpose of this study was to evaluate the risk of secondary immune thrombocytopenia in multiple sclerosis patients treated with alemtuzumab through a meta-analysis.
OBJECT
The purpose of this study was to evaluate the risk of secondary immune thrombocytopenia in multiple sclerosis patients treated with alemtuzumab through a meta-analysis.
METHODS
We searched databases including PubMed, Web of Science, OVID and EMBASE for studies reporting changes in platelet levels in MS patients treated with alemtuzumab from their inception until May 2023 and performed a meta-analysis. Information and data were screened and extracted by two researchers. The inclusion and exclusion criteria were established according to the PICOS principle. The obtained data were analyzed using the R software meta package and the quality assessment was conducted using Newcastle-Ottawa Scale (NOS). The causes of heterogeneity were analyzed using subgroup analysis and sensitivity analysis. Publication bias was evaluated using funnel plots and Egger test.
RESULTS
A total of 15 studies were included, encompassing 1,729 multiple sclerosis patients. Meta-analysis of overall secondary ITP in the included studies yielded a pooled rate of 0.0243. The overall incidence of secondary autoimmune events was 0.2589. In addition, subgroup analysis was applied using study regions and study types. The results showed that the incidence rate of secondary ITP in Europe was about 0.0207, while the incidence of autoimmune events (AEs) was 0.2158. The incidence rate of secondary ITP and AEs in North America was significantly higher than in Europe, being 0.0352 and 0.2622. And the analysis showed that the incidence rates of secondary ITP and AEs in prospective studies were 0.0391 and 0.1771. Retrospective studies had an incidence rate of secondary ITP at 2.16, and an incidence rate of AEs at 0.2743.
CONCLUSION
This study found that there was a certain incidence of Immune thrombocytopenia in multiple sclerosis patients after treatment with alemtuzumab. Alemtuzumab may have some interference with platelet levels, and the mechanism may be associated with Treg cells. But due to the absence of a control group in the included literature, we cannot determine the specific impact of Alemtuzumab on platelet levels in patients with MS. Therefore, clinical physicians should perform a comprehensive assessment of the patient's benefit-to-risk ratio before initiating alemtuzumab.
SYSTEMATIC REVIEW REGISTRATION
Inplasy website, DOI number is 10.37766/inplasy2024.3.0007.
PubMed: 38660089
DOI: 10.3389/fneur.2024.1375615 -
Transplant Immunology Jun 2024Allogeneic stem cell transplantation (SCT) is a critical therapy for haematological malignancy but may lead to acute and chronic graft versus host disease (GvHD). T-cell...
BACKGROUND
Allogeneic stem cell transplantation (SCT) is a critical therapy for haematological malignancy but may lead to acute and chronic graft versus host disease (GvHD). T-cell depletion with alemtuzumab, either in vivo or ex vivo, reduces the incidence of GvHD but is a risk factor for disease relapse and poor immune reconstitution. Natural killer (NK) cells are the first lymphocytes to recover. Classical NK cells make up >90% of the normal circulating population and can directly kill neoplastic or virally infected cells while the regulatory subset makes up <10%, secretes cytokines and is not cytotoxic. The recovery and balance of these subsets post SCT remains controversial, with most studies analysing patients who received unmanipulated grafts and in vivo immunosuppression.
OBJECTIVE
The aim was to assess the early recovery of NK cells in 18 consecutive patients receiving ex vivo T-cell depleted SCT and to compare the results to 25 individuals receiving haploidentical non-T cell depleted grafts.
METHODS
All patients received myeloablative conditioning. After stem cell collection, the stem cells of the T cell depleted group were treated "in the bag" with alemtuzumab (CAMPATH 1H) at a concentration of 1mg/10 mononuclear cells and thereafter immediately infused. For those receiving non-T cell depleted grafts, GvHD prophylaxis was with post infusion therapeutic doses of cyclophosphamide. Blood samples were collected at days 21, 28 and 90. Complete blood counts were performed on an automated analyser while lymphocyte and NK subsets were examined using multiparameter flowcytometry. NK cells were defined as lymphocytes which were CD3-/CD56+. The classical subset was recognised as CD56/CD16+ while the regulatory population as CD56/CD16-. The results for both transplant types were compared at all time points using SPSS v8 statistical software.
RESULTS
The recovery of lymphocytes was slow in both groups. Those receiving non-T cell depleted grafts had significantly higher T cell counts at day 21 and 28 when compared to the T cell depleted group (P < 0.05). In contrast, NK cells in the ex vivo T-cell depleted patients recovered rapidly and by day 21 was no different to normal (p > 0.05), while the non-T cell depleted group had significantly decreased numbers (p < 0.001), only recovering at day 90. Both groups had abnormal NK cell subset ratios with significantly elevated percentages of regulatory cells (p < 0.05). However, significant differences were observed between the two groups with those receiving T cell depleted grafts having lower percentages of regulatory cells as well as higher numbers of classical NK cells at day 21 and 28 (p < 0.01).
CONCLUSION
This study of ex vivo T-cell depleted SCT's demonstrates that NK cells recover quicker when compared to those receiving unfractionated grafts. These results may have implications for GvHD and the GvL effect which warrants further study.
Topics: Humans; Alemtuzumab; Killer Cells, Natural; Male; Adult; Female; Middle Aged; Graft vs Host Disease; Lymphocyte Depletion; Hematopoietic Stem Cell Transplantation; Transplantation, Homologous; Transplantation Conditioning; T-Lymphocytes; Hematologic Neoplasms; Young Adult; Aged
PubMed: 38641148
DOI: 10.1016/j.trim.2024.102045 -
Human Immunology Apr 2024Intestinal allografts are the most immunologically complex and carry the highest risk of rejection among solid organ transplantation, necessitating complex... (Review)
Review
Intestinal allografts are the most immunologically complex and carry the highest risk of rejection among solid organ transplantation, necessitating complex immunosuppressive management. We evaluated the latest information regarding induction immunosuppression, with an emphasis on established, novel, and emergent therapies. We also reviewed classic and novel induction immunosuppression strategies for highly sensitized recipients. Comparable progress has been made in intestinal transplantation clinical outcomes since the implementation of induction strategies. This review shows a clear diversity of induction protocols can be observed across different centers. The field of intestinal transplantation is still in its early stages, which is further complicated by the limited number of institutions capable of intestinal transplantation and their geographical variation, which further hinders the development of adequately powered studies in comparison to other organs. As the implementation of institution-specific induction protocols becomes more refined and results are disseminated, future research efforts should be directed towards the development of efficacious induction strategies.
PubMed: 38599892
DOI: 10.1016/j.humimm.2024.110800 -
Frontiers in Immunology 2024Unmodified donor lymphocyte infusions (DLI) after allogeneic stem cell transplantation (alloSCT) can boost the beneficial Graft-versus-Leukemia (GvL) effect but may also...
INTRODUCTION
Unmodified donor lymphocyte infusions (DLI) after allogeneic stem cell transplantation (alloSCT) can boost the beneficial Graft-versus-Leukemia (GvL) effect but may also induce severe Graft-versus-Host-Disease (GvHD). To improve the balance between GvL and GvHD, it is crucial to identify factors that influence the alloreactivity of DLI.
METHODS
We investigated the effects of the presence of patient-derived antigen-presenting cells at time of DLI as estimated by the bone marrow (BM) chimerism status, lymphopenia as measured by the absolute lymphocyte count (ALC) at time of DLI, and the presence of a viral infection ( or reactivation) close to DLI on the risk of GvHD after DLI. The cohort consisted of patients with acute leukemia or myelodysplastic syndrome who prophylactically or pre-emptively received DLI as standard care after alemtuzumab-based alloSCT. In patients at high risk for relapse, DLI was administered at 3 months after alloSCT (n=88) with a dose of 0.3x10 or 0.15x10 T cells/kg in case of a related or unrelated donor, respectively. All other patients (n=76) received 3x10 or 1.5x10 T cells/kg, respectively, at 6 months after alloSCT.
RESULTS
For both DLIs, patients with reduced-intensity conditioning and an unrelated donor had the highest risk of GvHD. For DLI given at three months, viral infection within 1 week before and 2 weeks after DLI was an additional significant risk factor (hazard ratio (HR) 3.66 compared to no viral infection) for GvHD. At six months after alloSCT, viral infections were rare and not associated with GvHD. In contrast, mixed BM chimerism (HR 3.63 for ≥5% mixed chimerism compared to full donor) was an important risk factor for GvHD after DLI given at six months after alloSCT. ALC of <1000x10/l showed a trend for association with GvHD after this DLI (HR 2.05 compared to ≥1000x106/l, 95% confidence interval 0.94-4.45). Furthermore, the data suggested that the presence of a viral infection close to the DLI at three months or ≥5% mixed chimerism at time of the DLI at six months correlated with the severity of GvHD, thereby increasing their negative impact on the current GvHD-relapse-free survival.
CONCLUSION
These data demonstrate that the risk factors for GvHD after DLI depend on the setting of the DLI.
Topics: Humans; T-Lymphocytes; Lymphocyte Transfusion; Hematopoietic Stem Cell Transplantation; Graft vs Host Disease; Leukemia, Myeloid, Acute; Unrelated Donors; Virus Diseases
PubMed: 38545096
DOI: 10.3389/fimmu.2024.1335341 -
Therapeutic Advances in Neurological... 2024While evidence highlights the effectiveness of initiating disease-modifying therapy with a high-efficacy medication for multiple sclerosis (MS) patients with poor...
BACKGROUND
While evidence highlights the effectiveness of initiating disease-modifying therapy with a high-efficacy medication for multiple sclerosis (MS) patients with poor prognostic factors, it remains unclear whether this approach has been adopted by a broad range of MS providers in Germany yet.
OBJECTIVE
To assess the adoption of the early highly effective treatment (EHT) compared to the treat-to-target treatment approach with the option of escalating treatment efficacy over time in Germany based on real-world evidence data.
DESIGN
Patient-level pharmacy dispensing data from the Permea platform were analysed from 2020 to 2022.
METHODS
In total, 29,529 therapy beginners (>18 years) were included to analyse shifts in treatment approaches over time and switching behaviour. Medication classification adhered to the German Society of Neurology guidelines and designated fumarates, glatiramer acetate, teriflunomide and interferons as low-efficacy category 1 medications; cladribine and S1P-modulators as medium-efficacy category 2 medications; and alemtuzumab, natalizumab, ocrelizumab, ofatumumab and rituximab (off-label) as high-efficacy category 3 medications.
RESULTS
Our results show that 70.0% of patients redeemed their first prescription for category 1 medication, 16.3% for category 2 and 13.7% for category 3 medications. The proportion of prescriptions filled shifted from 2020 to 2022 with a decrease of 14.7% for category 1 drugs and an increase of 12.5% for category 3 drugs. 93.2% of patients stayed on their initially prescribed medication category. 3.2% of category 1 and 3.7% of category 2 therapy beginners escalated to category 3 medication. 3.4% of category 3 medication users de-escalated their treatment to category 1 or category 2.
CONCLUSION
While most individuals started their treatment according to the treat-to-target approach and remained on their initially prescribed medication category, there has been a steadily increasing shift towards the EHT approach since 2020. These insights demonstrate that, while not officially recommended by German guidelines, MS providers increasingly adopt the EHT approach.
PubMed: 38525488
DOI: 10.1177/17562864241237857 -
European Thyroid Journal Apr 2024Secondary thyroid autoimmunity, especially Graves' disease (GD), frequently develops in patients with multiple sclerosis (MS) following alemtuzumab treatment (ALTZ;...
INTRODUCTION
Secondary thyroid autoimmunity, especially Graves' disease (GD), frequently develops in patients with multiple sclerosis (MS) following alemtuzumab treatment (ALTZ; anti-CD52). Thyroid eye disease (TED) can also develop, and rituximab (RTX; anti-CD20) is a suitable treatment.
CASE PRESENTATION
A 37-year-old woman with MS developed steroid-resistant active moderate-to-severe TED 3 years after ALTZ, that successfully responded to a single 500 mg dose of i.v. RTX. Before RTX peripheral B-cells were low, and were totally depleted immediately after therapy. Follow-up analysis 4 years post ALTZ and 1 year post RTX showed persistent depletion of B cells, and reduction of T regulatory cells in both peripheral blood and thyroid tissue obtained at thyroidectomy.
CONCLUSION
RTX therapy successfully inactivated TED in a patient with low B-cell count derived from previous ALTZ treatment. B-cell depletion in both thyroid and peripheral blood was still present 1 year after RTX, indicating a likely cumulative effect of both treatments.
Topics: Female; Humans; Adult; Rituximab; Graves Ophthalmopathy; Alemtuzumab; Antibodies, Monoclonal, Murine-Derived; Graves Disease; Multiple Sclerosis
PubMed: 38471303
DOI: 10.1530/ETJ-23-0236