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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 -
Neurology and Therapy Jun 2024Over the past few years, anti-CD20 therapies like rituximab, ocrelizumab or ofatumumab have seen an increase in interest in the treatment of neurological autoimmune...
INTRODUCTION
Over the past few years, anti-CD20 therapies like rituximab, ocrelizumab or ofatumumab have seen an increase in interest in the treatment of neurological autoimmune disorders such as multiple sclerosis (MS), neuromyelitis optica spectrum disorders (NMOSD), or resistant forms of generalized myasthenia gravis (MG). They are generally well-tolerated, but recent reports have highlighted severe dental disorders in patients undergoing anti-CD20 therapies. The aim was to describe a series of cases and to compare with the available scientific literature.
METHODS
We reviewed 6 patient cases with dental disorders during anti-CD20 therapy that were reported to the pharmacovigilance center. A disproportionality analysis was also conducted on Vigibase® for each anti-CD20 and each adverse effect described in the cases.
RESULTS
Six cases of dental and gingival conditions in relatively young patients were reported (median age: 40.5 years old [min: 34; max: 79]). Oral conditions were developed in four patients with MS treated with ocrelizumab and in two patients receiving rituximab (one patient with MG and one with NMOSD). The onset of oral conditions ranged from 10 days to 2 years after treatment initiation. Notably, all patients treated with ocrelizumab experienced gingival recession. Various dental pathologies were observed, including tooth loss, dental pain, caries, brittle teeth, dental fractures, dental abscesses, and periodontitis. Analysis of Vigibase® revealed 284 worldwide cases of dental and gingival conditions under ocrelizumab, 386 cases under rituximab, and 80 under ofatumumab. Significant associations were found between these therapies and dental pathologies, particularly tooth abscesses and infections.
CONCLUSION
To our knowledge, this is the first case series reporting dental conditions developed in patients long-term treated with anti-CD20 treatments. This issue, literature data, and Vigilyze® analysis might be considered a safety signal that necessitates being confirmed with more robust data, such as a retrospective study with a control group. Meanwhile, proactive measures are essential like frequent dental checkups and dental hygienic measures to prevent oral health problems associated with anti-CD20 therapies.
PubMed: 38668835
DOI: 10.1007/s40120-024-00616-7 -
Therapeutic Advances in Neurological... 2024Evidence from network meta-analyses (NMAs) and real-world propensity score (PS) analyses suggest monoclonal antibodies (mAbs) offer a therapeutic advantage over...
BACKGROUND
Evidence from network meta-analyses (NMAs) and real-world propensity score (PS) analyses suggest monoclonal antibodies (mAbs) offer a therapeutic advantage over currently available oral therapies and, therefore, warrant consideration as a distinct group of high-efficacy disease-modifying therapies (DMTs) for patients with relapsing multiple sclerosis (RMS). This is counter to the current perception of these therapies by some stakeholders, including payers.
OBJECTIVES
A multifaceted indirect treatment comparison (ITC) approach was undertaken to clarify the relative efficacy of mAbs and oral therapies.
DESIGN
Two ITC methods that use individual patient data (IPD) to adjust for between-trial differences, PS analyses and simulated treatment comparisons (STCs), were used to compare the mAb ofatumumab the oral therapies cladribine, fingolimod, and ozanimod.
DATA SOURCES AND METHODS
As IPD were available for trials of ofatumumab and fingolimod, PS analyses were conducted. Given summary-level data were available for cladribine, fingolimod, and ozanimod trials, STCs were conducted between ofatumumab and each of these oral therapies. Three efficacy outcomes were compared: annualized relapse rate (ARR), 3-month confirmed disability progression (3mCDP), and 6-month CDP (6mCDP).
RESULTS
The PS analyses demonstrated ofatumumab was statistically superior to fingolimod for ARR and time to 3mCDP but not time to 6mCDP. In STCs, ofatumumab was statistically superior in reducing ARR and decreasing the proportion of patients with 3mCDP compared with cladribine, fingolimod, and ozanimod and in decreasing the proportion with 6mCP compared with fingolimod and ozanimod. These findings were largely consistent with recently published NMAs that identified mAb therapies as the most efficacious DMTs for RMS.
CONCLUSION
Complementary ITC methods showed ofatumumab was superior to cladribine, fingolimod, and ozanimod in lowering relapse rates and delaying disability progression among patients with RMS. Our study supports the therapeutic superiority of mAbs over currently available oral DMTs for RMS and the delineation of mAbs as high-efficacy therapies.
PubMed: 38525490
DOI: 10.1177/17562864241239453 -
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 -
International Journal of Infectious... Jun 2024Yellow fever (YF) is a potentially lethal viral hemorrhagic fever that can be prevented with the 17D live attenuated YF vaccine. However, this vaccination can cause...
Yellow fever (YF) is a potentially lethal viral hemorrhagic fever that can be prevented with the 17D live attenuated YF vaccine. However, this vaccination can cause severe adverse reactions including vaccine-associated YF. Here, we describe the case of a 32-year-old female who was permanently immunosuppressed with an anti-CD20 antibody due to multiple sclerosis. Following YF vaccination, the patient developed a variety of symptoms such as febrile temperatures, muscle and joint pain, headaches, and dysuria. A vaccine-associated YF with viremia was diagnosed. To avoid a potentially severe course of the disease, sofosbuvir was used as antiviral treatment followed by the resolution of symptoms and serological response. As travelers with chronic diseases and immunosuppression will increasingly engage in long distance travel, this case demonstrates the importance of assessing patient history prior to the administration of live vaccines and points towards a possible therapeutic approach in those suffering from vaccine-associated YF.
Topics: Adult; Female; Humans; Antiviral Agents; Immunocompromised Host; Rituximab; Sofosbuvir; Yellow Fever; Yellow Fever Vaccine; Antigens, CD20; Multiple Sclerosis
PubMed: 38521450
DOI: 10.1016/j.ijid.2024.107017