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Multiple Sclerosis (Houndmills,... Nov 2018Despite proven efficacy of alemtuzumab in multiple sclerosis (MS), approximately 50% of individuals will develop a new autoimmune disease following treatment. To date,...
Despite proven efficacy of alemtuzumab in multiple sclerosis (MS), approximately 50% of individuals will develop a new autoimmune disease following treatment. To date, these have largely been antibody mediated and organ specific (primarily affecting the thyroid gland). In a retrospective case series of 187 patients from two UK specialist centres (Cardiff and Cambridge) followed up for a median of 10 years, we report three (1.6%) cases of sarcoidosis following alemtuzumab treatment of MS. This report increases the spectrum of auto-inflammatory disease following alemtuzumab and should be considered by clinicians when using this therapeutic agent for MS.
Topics: Adult; Alemtuzumab; Antibodies, Monoclonal, Humanized; Autoimmune Diseases; Female; Humans; Male; Multiple Sclerosis; Retrospective Studies; Sarcoidosis; Treatment Outcome; Young Adult
PubMed: 30307364
DOI: 10.1177/1352458518790391 -
Transplant Immunology Dec 2023Blood group B kidney transplant candidates have lower transplantation rates and longer waiting times compared to other blood groups. Kidney transplantation from blood...
Comparative analysis of Basiliximab and Alemtuzumab induction therapies in blood type A2-to-B kidney transplantation: Impact on kidney function and de novo donor-specific HLA antibodies.
PURPOSE
Blood group B kidney transplant candidates have lower transplantation rates and longer waiting times compared to other blood groups. Kidney transplantation from blood group A2-to-B has offered a solution for these patients. This study aimed to investigate the impact of Basiliximab and Alemtuzumab induction therapies on kidney function and de novo donor-specific antibodies (DSA) in blood type A2-to-B kidney transplant recipients within the first 12 months of post-transplant.
METHODS
A retrospective analysis was conducted on 110 consecutive A2-to-B kidney transplant recipients between January 2015 and December 2022. Of these, 46 (41.8%) received Basiliximab, while 64 (58.2%) received Alemtuzumab as induction therapy. Demographics and comorbidities data were collected and compared between the two groups. Serum samples collected at 4- and 12-month intervals post-transplant were used to assess the presence of de novo DSA. Kidney allograft function was evaluated by monitoring serum creatinine levels and assessing Creatinine Clearance based on 24-h urine collection at various time points.
RESULTS
During the follow-up period, 20.00% of patients who received Alemtuzumab developed de novo DSA, whereas none of the patients induced with Basiliximab developed de novo DSA (p = 0.038). Recipients who received Basiliximab were older (mean age = 72.00) and received higher Kidney Donor Profile Index (KDPI) kidneys (mean = 75) compared to those induced with Alemtuzumab (mean age = 58.00, mean KDPI = 49) (p < 0.001), with no significant difference observed in the last follow-up creatinine clearance or creatinine levels between the two groups (p = 0.28).
CONCLUSION
The use of Basiliximab as induction immunosuppression in A2-to-B kidney transplant recipients is associated with a lower incidence of de novo HLA DSA formation without significant differences in overall renal function compared to Alemtuzumab.
Topics: Humans; Aged; Middle Aged; Basiliximab; Alemtuzumab; Immunosuppressive Agents; Kidney Transplantation; Antibodies, Monoclonal; Retrospective Studies; Creatinine; Kidney; Blood Group Antigens; Graft Rejection; Graft Survival
PubMed: 37949378
DOI: 10.1016/j.trim.2023.101958 -
Blood Advances Feb 2023Interleukin-15 (IL-15) monotherapy substantially increases the number and activity of natural killer (NK) cells and CD8+ T cells but has not produced clinical responses....
Interleukin-15 (IL-15) monotherapy substantially increases the number and activity of natural killer (NK) cells and CD8+ T cells but has not produced clinical responses. In a xenograft mouse model, IL-15 enhanced the NK cell-mediated antibody-dependent cell cytotoxicity (ADCC) of the anti-CD52 antibody alemtuzumab and led to significantly more durable responses than alemtuzumab alone. To evaluate whether IL-15 potentiates ADCC in humans, we conducted a phase 1 single-center study of recombinant human IL-15 and alemtuzumab in patients with CD52-positive mature T-cell malignances. We gave IL-15 subcutaneously 5 days per week for 2 weeks in a 3 + 3 dose escalation scheme (at 0.5, 1, and 2 μg/kg), followed by standard 3 times weekly alemtuzumab IV for 4 weeks. There were no dose-limiting toxicities or severe adverse events attributable to IL-15 in the 11 patients treated. The most common adverse events were lymphopenia (100%), alemtuzumab-related infusion reactions (90%), anemia (90%), and neutropenia (72%). There were 3 partial and 2 complete responses, with an overall response rate of 45% and median duration of response 6 months. Immediately after 10 days of IL-15, there was a median 7.2-fold increase in NK cells and 2.5-fold increase in circulating CD8+ T cells, whereas the number of circulating leukemic cells decreased by a median 38% across all dose levels. Treatment with IL-15 was associated with increased expression of NKp46 and NKG2D, markers of NK-cell activation, and increased ex vivo ADCC activity of NK cells, whereas inhibitory receptors PD1 and Tim3 were decreased. This trial was registered at www.clinicaltrials.gov as #NCT02689453.
Topics: Humans; Animals; Mice; Alemtuzumab; Interleukin-15; Antibodies, Monoclonal; Killer Cells, Natural; Antibody-Dependent Cell Cytotoxicity; Immunologic Factors; Neoplasms; CD52 Antigen
PubMed: 35475910
DOI: 10.1182/bloodadvances.2021006440 -
Medicina Clinica Dec 2014Until the mid 1990s, with the appearance of interferon beta and glatiramer acetate, there was no treatment for multiple sclerosis (MS). However, due to their moderate... (Review)
Review
Until the mid 1990s, with the appearance of interferon beta and glatiramer acetate, there was no treatment for multiple sclerosis (MS). However, due to their moderate therapeutic potential in some patients, a broad search was continued to find new and more effective treatment strategies, largely concentrated on monoclonal antibodies (MOAB). Natalizumab, the first MOAB for the treatment of MS, was approved at the end of 2004, representing a major advance in the field of neuroimmunology. Today, there is broad experience with natalizumab and other MOAB (alemtuzumab, daclizumab, rituximab, ocrelizumab, ofatumumab and anti-lingo-1) that are pending commercialization or are under phase II or III of development with promising results. The present review analyzes the efficacy and safety results of all these drugs.
Topics: Alemtuzumab; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Daclizumab; Humans; Immunoglobulin G; Multiple Sclerosis
PubMed: 25732947
DOI: 10.1016/S0025-7753(15)30007-5 -
Journal of Neurology Jun 2019No postmarketing randomised clinical trials are available about alemtuzumab, and real-world data are limited. We aimed to analyse the efficacy and safety of alemtuzumab... (Observational Study)
Observational Study
BACKGROUND
No postmarketing randomised clinical trials are available about alemtuzumab, and real-world data are limited. We aimed to analyse the efficacy and safety of alemtuzumab in a single-centre cohort of patients with relapsing-remitting MS.
METHODS
Patients who took alemtuzumab were enrolled. We collected the following data: age, sex, MS history, expanded disability status scale (EDSS), relapses, magnetic resonance imaging (MRI) parameters after alemtuzumab, and adverse events. EDSS scores before alemtuzumab and at the last follow-up were compared by Wilcoxon test. Time to first relapse was analysed after dividing the cohort on the basis of previous treatment.
RESULTS
Ninety patients were enrolled [women 74.4%; naïve 7; mean follow-up 27 months (SD 23)]. The EDSS was reduced from a median of 2.5 (IQR 1.5-4) before alemtuzumab to 2.0 (IQR 1.5-3.5) after (p = 0.025). The time to first relapse was shorter in patients shifting from a second-line therapy (p = 0.011). Over 2 years, 43.7% had no evidence of disease activity. We observed infusion-related reactions in 95.5% patients, including 11.1% with pneumonitis, thyroiditis in 11%, and thrombocytopenia in 3.3%.
CONCLUSIONS
We confirmed the clinical and MRI efficacy of alemtuzumab in the clinical setting and the frequency of infusion-related reactions. Compared with that in clinical trials, higher number of patients developed pneumonitis during infusion.
Topics: Adult; Alemtuzumab; Drug-Related Side Effects and Adverse Reactions; Female; Follow-Up Studies; Humans; Immunologic Factors; Magnetic Resonance Imaging; Male; Multiple Sclerosis, Relapsing-Remitting; Pneumonia; Severity of Illness Index; Thrombocytopenia; Thyroiditis
PubMed: 30863891
DOI: 10.1007/s00415-019-09272-6 -
Neurology Dec 2018To report 3 patients with relapsing-remitting multiple sclerosis (RRMS) showing vitiligo after treatment with alemtuzumab.
OBJECTIVE
To report 3 patients with relapsing-remitting multiple sclerosis (RRMS) showing vitiligo after treatment with alemtuzumab.
METHODS
Retrospective case series including flow cytometric analyses and T-cell receptor (TCR) sequencing of peripheral blood mononuclear cells.
RESULTS
We describe 3 cases of alemtuzumab-treated patients with RRMS developing vitiligo 52, 18, and 14 months after alemtuzumab initiation. Histopathology shows loss of epidermal pigmentation with absence of melanocytes and interface dermatitis with CD8 T-cell infiltration. Also compatible with pathophysiologic concepts of vitiligo, peripheral blood mononuclear cells of one patient showed high proportions of CD8 T cells with an activated (human leukocyte antigen-DR), memory (CD45RO), and type 1 cytokine (interferon-γ + tumor necrosis factor-α) phenotype at vitiligo onset compared to a control cohort of alemtuzumab-treated patients with RRMS (n = 30). Of note, analysis of CD8 TCR repertoire in this patient revealed a highly increased clonality and reduced repertoire diversity compared to healthy controls and treatment-naive patients with RRMS. We observed a predominance of single clones at baseline in this patient and alemtuzumab treatment did not substantially affect the proportions of most abundant clones over time.
CONCLUSION
The 3 cases represent a detailed description of vitiligo as a T-cell-mediated secondary autoimmune disease following alemtuzumab treatment. The prevailing concept of unleashed B-cell responses might therefore not cover all facets of alemtuzumab-related secondary autoimmunity. Mechanistic studies, especially on TCR repertoire, might help clarify the underlying mechanisms.
Topics: Adult; Alemtuzumab; Autoimmune Diseases; Autoimmunity; B-Lymphocytes; CD8-Positive T-Lymphocytes; Female; Humans; Male; Multiple Sclerosis, Relapsing-Remitting; Retrospective Studies; Treatment Outcome; Vitiligo
PubMed: 30404783
DOI: 10.1212/WNL.0000000000006648 -
Current Hematologic Malignancy Reports Apr 2020T cell prolymphocytic leukemia (T-PLL) is a rare mature T cell tumor. Available treatment options in this aggressive disease are largely inefficient and patient outcomes...
PURPOSE OF REVIEW
T cell prolymphocytic leukemia (T-PLL) is a rare mature T cell tumor. Available treatment options in this aggressive disease are largely inefficient and patient outcomes are highly dissatisfactory. Current therapeutic strategies mainly employ the CD52-antibody alemtuzumab as the most active single agent. However, sustained remissions after sole alemtuzumab-based induction are exceptions. Responses after available second-line strategies are even less durable. More profound disease control or rare curative outcomes can currently only be expected after a consolidating allogeneic hematopoietic stem cell transplantation (allo-HSCT) in best first response. However, only 30-50% of patients are eligible for this procedure. Major advances in the molecular characterization of T-PLL during recent years have stimulated translational studies on potential vulnerabilities of the T-PLL cell. We summarize here the current state of "classical" treatments and critically appraise novel (pre)clinical strategies.
RECENT FINDINGS
Alemtuzumab-induced first remissions, accomplished in ≈ 90% of patients, last at median ≈ 12 months. Series on allo-HSCT in T-PLL, although of very heterogeneous character, suggest a slight improvement in outcomes among transplanted patients within the past decade. Dual-action nucleosides such as bendamustine or cladribine show moderate clinical activity as single agents in the setting of relapsed or refractory disease. Induction of apoptosis via reactivation of p53 (e.g., by inhibitors of HDAC or MDM2) and targeting of its downstream pathways (i.e., BCL2 family antagonists, CDK inhibitors) are promising new approaches. Novel strategies also focus on inhibition of the JAK/STAT pathway with the first clinical data. Implementations of immune-checkpoint blockades or CAR-T cell therapy are at the stage of pre-clinical assessments of activity and feasibility. The recommended treatment strategy in T-PLL remains a successful induction by infusional alemtuzumab followed by a consolidating allo-HSCT in eligible patients. Nevertheless, long-term survivors after this "standard" comprise only 10-20%. The increasingly revealed molecular make-up of T-PLL and the tremendous expansion of approved targeted compounds in oncology represent a "never-before" opportunity to successfully tackle the voids in T-PLL. Approaches, e.g., those reinstating deficient cell death execution, show encouraging pre-clinical and first-in-human results in T-PLL, and urgently have to be transferred to systematic clinical testing.
Topics: Alemtuzumab; Animals; Antineoplastic Agents, Immunological; Diffusion of Innovation; Forecasting; Hematopoietic Stem Cell Transplantation; Humans; Immunotherapy, Adoptive; Leukemia, Prolymphocytic, T-Cell; Molecular Targeted Therapy; Receptors, Chimeric Antigen; Treatment Outcome
PubMed: 32034661
DOI: 10.1007/s11899-020-00566-5 -
Autoimmunity Reviews Apr 2020Immune reconstitution therapy (IRT) is an emerging concept for the treatment of multiple sclerosis (MS) that is given intermittently and can induce long-term remission...
Immune reconstitution therapy (IRT) is an emerging concept for the treatment of multiple sclerosis (MS) that is given intermittently and can induce long-term remission of MS that is sustained in treatment-free periods. A systematic literature review was performed to identify and summarize current knowledge regarding the short- and long-term immunological consequences of different IRTs and CD20 depleting therapies on the cellular level in patients with MS. A total of 586 articles published between January 2010 and September 2019 were identified and screened; 44 studies met inclusion criteria for the review. All the treatments considered appeared to produce both qualitative and quantitative changes in the immune cell populations of patients with MS that resulted in a more anti-inflammatory immune profile. Autologous hematopoietic stem cell transplantation produced the longest-lasting and greatest effects on a wide range of immune cells. Many patients achieved prolonged depletion of the adaptive immune system when alemtuzumab and cladribine tablets were administered as short courses of therapy; however, a proportion of patients required retreatment to maintain these effects. Alemtuzumab may produce greater depletion of both CD4+ and CD8+ T cells than cladribine tablets, although both treatments similarly deplete B cells. Recovery of B cells before T cell recovery and hyperpopulation of B cells after alemtuzumab may contribute to secondary autoimmunity. Cladribine tablets had a greater effect on B cells than T cells, and no hyperpopulation of B cells was observed after treatment with cladribine tablets. Ocrelizumab and rituximab require regular repeated treatment every 6 months to maintain depletion of B and T cells. Effects of the drug treatments on the innate immune system were minor compared with those on the adaptive immune system. Additional characterization of the cellular changes occurring during IRT and CD20 depletion may lead to further improvement in the understanding of the pathogenesis of MS and the future development of therapies with even longer lasting effects. Although the treatments considered in this review improve quality of life and outcomes for patients with MS, a cure for this debilitating disease is not yet in sight.
Topics: Alemtuzumab; Autografts; Cladribine; Hematopoietic Stem Cell Transplantation; Humans; Immune Reconstitution; Multiple Sclerosis; Quality of Life
PubMed: 32062028
DOI: 10.1016/j.autrev.2020.102492 -
Immunity, Inflammation and Disease Aug 2022After lung transplantation (LuTX), lower respiratory tract infections (LRTI) and acute cellular rejection (ACR) are associated with changes in peripheral blood and...
BACKGROUND
After lung transplantation (LuTX), lower respiratory tract infections (LRTI) and acute cellular rejection (ACR) are associated with changes in peripheral blood and bronchoalveolar lavage fluid mononuclear cell profile (PBMC and BALIC). PBMC is also influenced by immunosuppressive regimen and its changes with postoperative time. First-year PBMC and BALIC changes were evaluated in this study with rabbit anti-thymocyte globulin (ATG) and alemtuzumab (AL) induction therapy.
METHODS
In total, 64 LuTX recipients were included, 53 of them received AL and 11 ATG as induction therapy. PBMC and BALIC were examined routinely and in cases suspicious of infection and/or rejection. A PBMC- and BALIC-based algorithm for infection and rejection prediction was also tested.
RESULTS
In the AL group, peripheral blood lymphocyte and basophil cell numbers were significantly reduced, while the neutrophil cell number elevation during LRTI was significantly higher compared to the control. Early postoperative measurements showed a lower BALIC lymphocyte count. The algorithm had 17% sensitivity and 94% specificity for ACR in all patients and 33% sensitivity and 95% specificity for ACR with coexisting LRTI.
CONCLUSION
BALIC is not significantly influenced by the immunosuppressive regimen. PBMC- and BALIC-based algorithm may improve the differential diagnosis of ACR.
Topics: Alemtuzumab; Graft Rejection; Humans; Immunosuppressive Agents; Leukocytes, Mononuclear; Lung; Transplant Recipients
PubMed: 35894710
DOI: 10.1002/iid3.673 -
American Journal of Transplantation :... Aug 2014This editorial puts into perspective the findings of the first randomized, controlled trial examining alemtuzumab induction for lung transplantation, and highlights the...
This editorial puts into perspective the findings of the first randomized, controlled trial examining alemtuzumab induction for lung transplantation, and highlights the challenges encountered with alemtuzumab induction in other solid organs. See article by Jaksch et al on page 1839.
Topics: Alemtuzumab; Antibodies, Monoclonal, Humanized; Female; Humans; Lung Transplantation; Male
PubMed: 25039475
DOI: 10.1111/ajt.12825