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Neurology. Clinical Practice Oct 2024Disease-modifying therapy (DMT) for multiple sclerosis (MS) after natalizumab-associated progressive multifocal leukoencephalopathy (PML) is controversial due to concern...
OBJECTIVES
Disease-modifying therapy (DMT) for multiple sclerosis (MS) after natalizumab-associated progressive multifocal leukoencephalopathy (PML) is controversial due to concern for recurrent PML. We describe DMT utilization for over a decade in a patient with MS who survived PML.
METHODS
Case report.
RESULTS
A 36-year-old woman was diagnosed with MS in 2002 and treated with interferon beta-1a until 2006, when she transitioned to natalizumab due to relapses. She presented in 2012 with 2 months of progressive cognitive and gait concerns and was diagnosed with PML by positive CSF JC virus testing with concordant clinical and MRI findings. She was treated with plasma exchange and then corticosteroids for PML immune reconstitution inflammatory syndrome before starting glatiramer acetate for DMT. She transitioned to dimethyl fumarate in 2013 after MS activity on MRI with negative CSF JC virus testing. Owing to worsening footdrop consistent with progression, she transitioned to ocrelizumab in 2017 and then to ofatumumab in 2020 due to logistics of medication administration. There has been no clinicoradiographic or CSF evidence of recurrent PML.
DISCUSSION
DMT selection is challenging for patients with MS who survive PML. We used an escalation approach extending to ocrelizumab and ofatumumab due to MS progression. Anti-CD20 DMTs are a high-efficacy option post-PML.
CLASSIFICATION OF EVIDENCE
This provides Class IV evidence. It is a single observational study without controls.
PubMed: 38919933
DOI: 10.1212/CPJ.0000000000200330 -
Multiple Sclerosis and Related Disorders Jun 2024In December 2021, the U.S. Food and Drug Administration issued emergency use authorization for the combination monoclonal antibodies tixagevimab and cilgavimab (Evusheld...
BACKGROUND
In December 2021, the U.S. Food and Drug Administration issued emergency use authorization for the combination monoclonal antibodies tixagevimab and cilgavimab (Evusheld - AstraZeneca) for COVID-19 pre-exposure prophylaxis. While COVID-19 vaccination is recommended for multiple sclerosis (MS) patients, there is concern for insufficient antibody response in patients receiving B-cell depleting therapies. The literature is sparse regarding the safety and efficacy of Evusheld use in MS patients.
OBJECTIVE
We sought to investigate the administration, safety, and efficacy of Evusheld in MS patients.
METHODS
Participants were consecutively recruited from the UCSD MS Center from July 2022 to October 2022. We conducted both a review of medical records and a prospective cohort study. Inclusion criteria included prior diagnosis of MS and eligibility for Evusheld injection due to use of B-cell depleting disease modifying therapy (DMT). All eligible patients were evaluated to determine uptake of Evusheld use. Participant surveys were distributed to Evusheld recipients that evaluated for potential Evusheld side effects and COVID-19 vaccination and infection history. The proportion of COVID-19 infections among participants with or without Evusheld use were compared using Fisher's exact test, and a negative binomial regression analysis was used to evaluate risk for COVID-19 infection after Evusheld administration.
RESULTS
A review of medical records showed that 79 MS patients were offered Evusheld by their clinicians during the recruitment period; 48 patients ultimately received the injection. Forty-two participants consented to the prospective cross-sectional study (mean age 46.4 years, 71.8 % female), of which 33 individuals received Evusheld. All participants received at least one COVID-19 vaccination dose, with 92.3 % receiving the initial series and at least one booster dose. One-third (30.8 %) of participants had a previous COVID-19 infection. DMTs included ocrelizumab, rituximab, and ofatumumab. Of the 33 participants who received Evusheld, 10 (30.3 %) reported experiencing at least one side effect. Injection site reactions included pain (most common), itchiness, and redness. General side effects included fatigue (most common), headache, muscle pain, and weakness. Of the 33 participants who received Evusheld, seven participants (21.2 %) tested positive for COVID-19 within 6 months of Evusheld injection. In an unadjusted binomial regression analysis, Evusheld administration was associated with a reduction in COVID-19 infection risk (OR 0.22, 95 % CI 0.05 - 1.02, p = 0.05). After adjusting for age and sex, Evusheld administration was still associated with a lower COVID-19 infection risk though it did not achieve nominal significance (OR 0.21, 95 % CI 0.04 - 1.09, p = 0.06). Of the 9 participants who were offered but did not receive Evusheld, five (55.6 %) tested positive for COVID-19 (p = 0.04 with Pearson's chi square test and p = 0.09 on Fisher's exact test).
CONCLUSIONS
Our medical records data demonstrated that only 61 % of MS patients offered Evusheld received the injection. Evusheld seems to be largely well-tolerated. No serious adverse effects were reported. The use of Evusheld was associated with fewer COVID-19 infections, but this did not reach nominal statistical significance in the modest sample size. The lessons learned from the initial Evusheld experience may be applied to future interventions directed at infection prevention in MS patients on immunomodulatory therapies.
PubMed: 38901372
DOI: 10.1016/j.msard.2024.105733 -
Multiple Sclerosis (Houndmills,... Jun 2024
PubMed: 38877846
DOI: 10.1177/13524585241260564 -
Neurological Sciences : Official... Jun 2024
PubMed: 38861049
DOI: 10.1007/s10072-024-07614-5 -
EClinicalMedicine Jul 2024BTK inhibitors have been concurrently administered with anti-CD20 monoclonal antibodies (mAbs) in chronic lymphocytic leukemia (CLL). However, the optimal regimen for...
Ibrutinib followed by ofatumumab consolidation in previously untreated patients with chronic lymphocytic leukemia (CLL): GELLC-7 trial from the Spanish group of CLL (GELLC).
BACKGROUND
BTK inhibitors have been concurrently administered with anti-CD20 monoclonal antibodies (mAbs) in chronic lymphocytic leukemia (CLL). However, the optimal regimen for combining these two drugs remains pending.
METHODS
This multi-center phase 2 study aimed to analyze whether consolidation with ofatumumab improved the response in patients with CLL receiving front-line treatment with ibrutinib. Patients received 12 cycles of ibrutinib monotherapy. Those who achieved CR after this induction were maintained on ibrutinib. Conversely, those who did not attain CR continued with ibrutinib in addition to a consolidation, which involved 7 doses of ofatumumab. The primary objective was the complete response (CR) rate at cycle 20. This study is registered within the EU Clinical Trials Register (EudraCT 2016-004937-26).
FINDINGS
Between September 8, 2017, and May 21, 2018, 84 patients (median age, 69 years) were included. After completion of 12 cycles of ibrutinib (n = 80), 4 patients (5%) were in CR, 67 (84%) in partial response (PR), and 6 patients (7%) had a PR with lymphocytosis (PRL). After consolidation with ofatumumab, 20 patients improved the response from PR to CR and 6 patients with PRL obtained a PR. Seventy-one patients (85%) completed 20 cycles of treatment, with a CR rate of 24/71 (34%). According to the intention-to-treat analysis at cycle 20, the ORR was 69/84 (82.2%), with a CRR of 24/84 (28.6%). Progression-free survival and overall survival at 48-months were 89.9% (CI: 82.4-95.5) and 92.2% (CI: 85.3-97.1), respectively.
INTERPRETATION
These findings underscore the potential for a consolidation strategy in CLL, wherein the addition of a mAb in patients with low tumor burden might enhance the quality of the response.
FUNDING
The study was funded by Janssen that also supplied ibrutinib, whereas ofatumumab was supplied by Novartis.
PubMed: 38841711
DOI: 10.1016/j.eclinm.2024.102642 -
Haematologica May 2024Not available.
The phase III DUO trial of PI3K inhibitor duvelisib versus ofatumumab in relapsed/refractory chronic lymphocytic leukemia/small lymphocytic lymphoma: final analysis including overall survival.
Not available.
PubMed: 38813715
DOI: 10.3324/haematol.2024.285043 -
Cureus Apr 2024Pemphigus, an autoimmune blistering disorder, poses significant therapeutic challenges due to dysregulated B cells and the involvement of CD20. This review assesses the... (Review)
Review
Pemphigus, an autoimmune blistering disorder, poses significant therapeutic challenges due to dysregulated B cells and the involvement of CD20. This review assesses the efficacy of anti-CD20 therapies, including rituximab, ofatumumab, ocrelizumab, and obinutuzumab, in pemphigus treatment. Mechanisms of action, clinical studies, and safety profiles were analyzed, revealing diverse impacts on disease severity. B cell depletion emerged as a pivotal factor, disrupting the autoimmune process and reducing pathogenic antibodies. Varied efficacy and safety profiles among agents underscore the need for personalized treatment strategies guided by biomarkers. Challenges such as resistance and long-term safety concerns necessitate continued research and vigilance. In clinical practice, insights from this review inform nuanced, tailored approaches for improved pemphigus management. The dynamic landscape of emerging therapies and personalized medicine emphasizes the need for ongoing research and strategic clinical decision-making. This review is a foundation for future investigations, providing insights for clinicians and researchers in optimizing pemphigus treatment.
PubMed: 38784354
DOI: 10.7759/cureus.58834 -
The Lancet. Neurology Jun 2024Neuroimmunology research and development has been marked by substantial advances, particularly in the treatment of neuroimmunological diseases, such as multiple... (Review)
Review
BACKGROUND
Neuroimmunology research and development has been marked by substantial advances, particularly in the treatment of neuroimmunological diseases, such as multiple sclerosis, myasthenia gravis, neuromyelitis optica spectrum disorders, and myelin oligodendrocyte glycoprotein antibody disease. With more than 20 drugs approved for multiple sclerosis alone, treatment has become more personalised. The approval of disease-modifying therapies, particularly those targeting B cells, has highlighted the role of immunotherapeutic interventions in the management of these diseases. Despite these successes, challenges remain, particularly for patients who do not respond to conventional therapies, underscoring the need for innovative approaches.
RECENT DEVELOPMENTS
The approval of monoclonal antibodies, such as ocrelizumab and ofatumumab, which target CD20, and inebilizumab, which targets CD19, for the treatment of various neuroimmunological diseases reflects progress in the understanding and management of B-cell activity. However, the limitations of these therapies in halting disease progression or activity in patients with multiple sclerosis or neuromyelitis optica spectrum disorders have prompted the exploration of cell-based therapies, particularly chimeric antigen receptor (CAR) T cells. Initially successful in the treatment of B cell-derived malignancies, CAR T cells offer a novel therapeutic mechanism by directly targeting and eliminating B cells, potentially overcoming the shortcomings of antibody-mediated B cell depletion. WHERE NEXT?: The use of CAR T cells in autoimmune diseases and B cell-driven neuroimmunological diseases shows promise as a targeted and durable option. CAR T cells act autonomously, penetrating deep tissue and effectively depleting B cells, especially in the CNS. Although the therapeutic potential of CAR T cells is substantial, their application faces hurdles such as complex logistics and management of therapy-associated toxic effects. Ongoing and upcoming clinical trials will be crucial in determining the safety, efficacy, and applicability of CAR T cells. As research progresses, CAR T cell therapy has the potential to transform treatment for patients with neuroimmunological diseases. It could offer extended periods of remission and a new standard in the management of autoimmune and neuroimmunological disorders.
Topics: Humans; B-Lymphocytes; Receptors, Chimeric Antigen; Immunotherapy, Adoptive; T-Lymphocytes; Receptors, Antigen, T-Cell; Animals; Autoimmune Diseases of the Nervous System
PubMed: 38760099
DOI: 10.1016/S1474-4422(24)00140-6 -
Multiple Sclerosis Journal -... 2024Many patients report a wearing-off phenomenon with monoclonal antibody treatment for multiple sclerosis in which perceived benefits wear off before the next dose is due.
BACKGROUND
Many patients report a wearing-off phenomenon with monoclonal antibody treatment for multiple sclerosis in which perceived benefits wear off before the next dose is due.
OBJECTIVES
To determine prevalence of the wearing-off effect, symptoms experienced, impact on treatment satisfaction, and associated patient characteristics.
METHODS
Patients receiving natalizumab, ocrelizumab, ofatumumab, or rituximab at a tertiary multiple sclerosis center were invited to take an online survey interrogating their monoclonal antibody experience. Additional history and patient characteristic data were collected. Logistic regression was used to determine if patient characteristics predicted the wearing-off effect and linear regression to evaluate the impact of the wearing-off effect on treatment satisfaction. The models were adjusted for age, disease duration, race, sex, body mass index, education, and depression as measured by the Patient Health Questionnaire-9.
RESULTS
We received 258 qualifying responses and 141 (54.7%) patients reported the wearing-off phenomenon. The most common symptom was fatigue (47.7%). Higher Patient Health Questionnaire-9 scores were significantly associated with the wearing-off phenomenon (OR = 1.02, = 0.005). The wearing-off effect (β = -0.52, = 0.04) and higher Patient Health Questionnaire-9 (β = -0.09, < 0.01) scores were associated with significantly reduced treatment satisfaction.
CONCLUSION
The wearing-off phenomenon is common, associated with depression, and reduces treatment satisfaction. Research addressing mitigation strategies is needed.
PubMed: 38715893
DOI: 10.1177/20552173241251707 -
Journal of Central Nervous System... 2024Patients with Multiple Sclerosis (pwMS) treated with anti-CD20 (cluster of differentiation) monoclonal antibodies (mAbs) such as ocrelizumab (OCR) and ofatumumab (OFA)...
INTRODUCTION
Patients with Multiple Sclerosis (pwMS) treated with anti-CD20 (cluster of differentiation) monoclonal antibodies (mAbs) such as ocrelizumab (OCR) and ofatumumab (OFA) show a reduction mainly of B-lymphocytes, but also other lymphocyte subsets can be affected by these treatments. There is limited data on differences between lymphocyte subset counts of pwMS after treatment initiation with OCR or OFA.
OBJECTIVE
To compare lymphocyte subset counts after treatment initiation in pwMS treated with OCR and OFA.
METHODS
We analyzed 22 pwMS initiated on OFA and 56 sex-, age- and MS course matched pwMS initiated on OCR from 2 prospectively collected observational MS databases (Bern [n: OFA 14, OCR 44] and Vienna [n: OFA 8, OCR 12]) statistically comparing lymphocyte subset counts (Mann Whitney Test).
RESULTS
We found that pwMS treated with OCR showed a stronger reduction of CD20 B-lymphocytes ( = .001), and a trend towards lower counts of CD8 T cells ( = .056) compared to pwMS treated with OFA, whereas reduction of total lymphocyte, CD4 lymphocyte and NK cell count was equally distributed between both treatments.
CONCLUSION
Different effects on lymphocyte subpopulations appear to be present in pwMS after treatment initiation with different anti-CD20 mAbs. Further studies are needed to determine potential effects on anti-CD20 treatment efficacy as well as treatment associated risks such as failed vaccinations and infections.
PubMed: 38711956
DOI: 10.1177/11795735241249644