Search Results (65)

Background: Chronic lymphocytic leukemia (CLL) is a prevalent hematologic malignancy that predominantly affects elderly individuals, posing significant clinical challenges due to patient comorbidities and inherent resistance to conventional chemotherapy. The emergence of targeted therapies combining venetoclax, a selective inhibitor of the anti-apoptotic protein BCL-2, with anti-CD20 monoclonal antibodies has dramatically transformed the treatment landscape. Methods: This retrospective observational study analyzed the differential impacts of first-line venetoclax-obinutuzumab (VenO) and second-line venetoclax-rituximab (VenR) on immunoglobulin G (IgG) levels and absolute neutrophil count (ANC) in CLL patients. Results: Our findings indicate that during first-line VenO therapy, a significant improvement in ANC levels from baseline was observed, whereas patients undergoing second-line VenR therapy demonstrated limited impact on ANC and the decreasing tendency in IgG levels. Patients treated with VenR had a longer disease history and previous exposure to other treatment regimens, primarily chemoimmunotherapy, which could negatively influence immune recovery, making direct comparisons between these two treatment lines challenging. Although this observational study did not directly compare infection rates, the observed enhancement of ANC levels in patients receiving VenO suggests a potential for lower infection risk compared to pretreated VenR patients. Conclusions: These results underscore the clinical significance of considering both the treatment line and the patient’s prior therapeutic history when selecting venetoclax-based regimens for CLL. The potential association of first-line VenO with improved immunological parameters and the complex impact of prior therapies on immunological recovery with second-line VenR warrant further prospective investigation into the correlation between treatment regimen, patient history, immune function, and infectious complications. Full article

Red blood cell (RBC) aggregation and disaggregation are key factors in microcirculatory flow, and their disturbance can lead to alterations in the rheological properties of blood in disorders such as chronic lymphocytic leukemia (CLL). This study aimed to determine the critical shear rate required to fully disaggregate RBC aggregates using samples from healthy individuals, providing a reference point for evaluating pathological changes. Using a microfluidic system and software-image-based flow analysis, RBC disaggregation was assessed by the Aggregation-Area Indicator at a high shear rate (AAI_H) changes and the number of undestroyed aggregates. The defined critical shear rate at 446 s⁻¹ was applied to assess RBC disaggregation in CLL patients, both untreated and treated with Obinutuzumab/Venetoclax or Ibrutinib. CLL samples exhibited significantly elevated AAI_H values compared to controls, indicating a greater resistance to shear-induced dispersion. Although both treatments reduced the number of stable aggregates, neither therapy fully normalized RBC disaggregation to the levels observed in healthy controls. Moreover, there was a notable heterogeneity among Ibrutinib-treated patients, revealing different therapeutic effects on RBC rheology. These findings suggest alterations in the RBC rheology in CLL despite therapy and support the use of a shear-dependent disaggregation analysis as a complementary tool for understanding and monitoring CLL-related hematologic abnormalities. Full article

Monoclonal antibodies (mAbs) have become a cornerstone in the treatment of follicular lymphoma (FL), offering highly specific therapeutic targeting that enhances efficacy while minimizing systemic toxicity. Their mechanisms of action include antibody-dependent cellular cytotoxicity (ADCC), complement-dependent cytotoxicity (CDC), and direct apoptotic signaling, effectively mediating malignant B-cell depletion. Anti-CD20 mAbs, such as rituximab and obinutuzumab, have significantly improved progression-free survival (PFS) and overall survival (OS), establishing immunochemotherapy as the standard of care for FL. However, the emergence of treatment resistance, often characterized by CD20 antigen downregulation or immune escape, has prompted the development of next-generation mAbs with enhanced effector functions. Bispecific antibodies (BsAbs), which simultaneously engage CD20-expressing tumor cells and CD3-positive cytotoxic T cells, have emerged as a novel immunotherapeutic strategy, redirecting T-cell activity to eliminate malignant B cells independently of major histocompatibility complex (MHC) antigen presentation. Additionally, antibody–drug conjugates (ADCs) offer a targeted cytotoxic approach by delivering potent chemotherapeutic payloads directly to tumor cells while limiting off-target effects. The integration of mAbs with immune checkpoint inhibitors and immunomodulatory agents is further enhancing treatment outcomes by overcoming immunosuppressive mechanisms within the tumor microenvironment. Despite these advancements, challenges remain, including optimizing the treatment sequence, mitigating immune-related toxicities—particularly cytokine release syndrome (CRS)—and identifying predictive biomarkers to guide patient selection. As the role of monoclonal antibodies continues to expand, their integration into therapeutic regimens is transforming the management of FL, paving the way for chemotherapy-free treatment approaches and long-term disease control. This review provides an updated overview of mAbs therapies for FL, emphasizing the advances brought by BsAbs and ADCs toward more tailored and effective treatments. Full article

Background: Obinutuzumab is a glycoengineered type II anti-CD-20 monoclonal antibody, which can be applied as immunotherapy in patients with follicular lymphoma. To our knowledge, this is the first reported case in the literature describing osteonecrosis of the jaw associated with CD20 monoclonal antibody therapy. Methods: The following case report describes a 39-year-old female patient under maintaining therapy with Obinutuzumab developing osteonecrosis of the jaw after tooth extraction. The necrotic area was located in the right mandible and was rated as a stage II osteonecrosis. Results: This case report should draw attention to the importance of dental follow-ups during aftercare of patients with Non-Hodgkin’s Lymphoma as well as to the relevant precautions for performing tooth extractions in such patients. Conclusions: As Obinutuzumab seems to be a contributing factor in the development of MRONJ, special attention has to be drawn to tooth extractions in such patients, which should only be performed with perioperative antibiosis, the least amount of trauma possible, always including the smoothening of sharp residual bone segments and a saliva-proof wound closure, as well as constant dental follow-ups. Full article

Background: The long-term follow-up of clinical trials of novel first-line (1L) therapies for chronic lymphocytic leukemia (CLL) demonstrates 6–10-year progression-free survival. We describe the effectiveness of 1L CLL treatments in real-world settings, with an emphasis on the important real-world outcome of time to next treatment or death (TTNT-D). Methods: This retrospective, observational study utilized de-identified electronic health records from the ConcertAI RWD360™ database with linked administrative open claims. Adults with CLL who initiated an approved 1L CLL therapy (June 2019–March 2023) were included. Duration of therapy (DoT), TTNT-D, and overall survival were assessed. Results: At 1L, 39.8% of 1843 patients received first-generation covalent Bruton tyrosine kinase inhibitors (cBTKis), 23.0% second-generation cBTKis, 12.4% venetoclax-obinutuzumab (VenO), 7.4% chemotherapy/chemoimmunotherapy (CT/CIT), and 17.4% anti-CD20 monotherapy. Median (range) follow-up in months was 24.9 (13.1–36.6) for first-generation cBTKis, 13.4 (7.3–21.7) for second-generation cBTKis, 16.0 (8.4–27.8) for VenO, 21.8 (11.2–32.7) for CT/CIT, and 19.7 (10.0–33.4) for anti-CD20 monotherapy. Median (range) DoT was 11.5 (4.2–25.0) and 8.6 (3.0–16.1), 9.1 (5.9–12.2), 5.6 (3.2–5.8), and 1.6 (1.6–4.5) months for first- and second-generation cBTKis, VenO, CT/CIT, and anti-CD20 monotherapy, respectively. Regarding TTNT-D, at 2 years’ follow-up, 69.1%, 82.5%, 86.3%, 79.1%, and 53.0% of patients treated with first- and second-generation cBTKis, VenO, CT/CIT, and anti-CD20 monotherapy, respectively, had not initiated subsequent treatment or experienced death. Conclusions: TTNT-D is an important real-world outcome in CLL. Our findings demonstrated the utility of time-limited VenO, with potentially more time off treatment, relative to continuous 1L cBTKi therapies. Full article

Antibody therapies are a crucial component of modern lymphoid malignancy treatment and an exciting area of active research. We performed a review of modern antibody therapies used in the treatment of lymphoid malignancies, with an emphasis on landmark studies and current directions. We describe the indications for rituximab, obinutuzumab, ADCs, and bispecific antibody therapies. Finally, we summarize early data from ongoing trials on emerging novel therapy combination regimens and discuss the role of machine learning in future therapy development. Full article

In treating cancer, immunotherapy has been established as a later-line treatment option in clinical practice. That includes stem cell transplantation, modified or activated immune cells, and antibodies directed against aberrant cells. As an unconventional immune cell subgroup, γδ T cells have been shown to provide effects against malignant cells. They exhibit an MHC-independent activation process, which could diminish graft-versus-host disease after an adoptive transfer of allogeneic cells. Over the last years, the efficacy of therapeutic antibodies has been improved. As a bi-specific antibody, mosunetuzumab binds to both CD3 and CD20, thereby providing close proximity between effector and target cells. Here, we set out to analyze the efficiency of γδ T cells’ anti-tumor effects in combination with mosunetuzumab vs. the monoclonal anti-CD20 antibody obinutuzumab. Mosunetuzumab revealed improved responses of γδ T cells regarding their expression of IFN-γ and CD107a and their cytotoxicity towards malignant B cells from lymphoma B cell lines. In comparison to obinutuzumab, mosunetuzumab led to an equivalent or enhanced cytotoxicity against B cell lymphoma cell lines and primary patient samples, where this effect was even more prominent. In summary, we consider the combination of stimulated γδ T cells and mosunetuzumab to be a promising therapeutic approach for future clinical trials. Full article

Lupus nephritis is one of the most severe manifestations of systemic lupus erythematosus, affecting roughly 40% of all lupus patients. With the introduction of cyclophosphamide and mycophenolate mofetil, outcomes have dramatically improved. However, 10% of patients still progress towards end-stage kidney disease, which carries an elevated mortality rate. In recent years, several novel agents have been approved for use or have shown preliminary evidence of efficacy in lupus nephritis. These agents include belimumab, voclosporin, and obinutuzumab, among others. Efficacy has also been demonstrated in recent trials combining older drugs. However, determining which patients would benefit the most from novel agents or combined drug regimens and whether these drugs might serve as an alternative to current remission-induction drug regimens rather than as add-on therapies remain unresolved issues. In this review, we will explore the current evidence regarding the efficacy of novel agents. Full article

Chronic lymphocytic leukemia (CLL), the most common type of leukemia, remains incurable with conventional therapy. Despite advances in therapies targeting Bruton’s tyrosine kinase and anti-apoptotic protein BCL-2, little is known about their effect on red blood cell (RBC) aggregation in blood flow. In this study, we applied a microfluidic device and a newly developed Software Image Flow Analysis to assess the extent of RBC aggregation in CLL patients and to elucidate the hemorheological effects of the commonly applied therapeutics Obinutuzumab/Venetoclax and Ibrutinib. The results revealed that, in RBC samples from untreated CLL patients, complex 3D clusters of large RBC aggregates are formed, and their number is significantly increased compared to healthy control samples. The application of the Obinutuzumab/Venetoclax combination did not affect this aspect of RBCs’ rheological behavior. In contrast, targeted therapy with Ibrutinib preserves the aggregation state of CLL RBCs to levels seen in healthy controls, demonstrating that Ibrutinib mitigates the alterations in the rheological properties of RBCs associated with CLL. Our findings highlight the alterations in RBC aggregation in CLL and the impact of different targeted therapies on RBCs’ rheological properties, which is critical for predicting the potential complications and side effects of CLL treatments, particularly concerning blood flow dynamics. Full article

Background: Idiopathic nephrotic syndrome (INS) is the most common cause of nephrotic syndrome in children. A hallmark of the disease is the rapid remission of proteinuria following a high dose of steroids. Recurrent disease or steroid dependence are common, leading to a high steroid burden and the introduction of steroid sparing therapy. Anti-CD20 antibodies have been increasingly used with excellent results in complicated INS. Nevertheless, their use can be limited by the occurrence of infusion-related reactions (IRRs). Methods: This report discusses further treatment options for children who are intolerant to RTX and presents the first report of a successful switch to obinutuzumab (OBI) for a child with difficult-to-treat steroid-dependent nephrotic syndrome (SDNS) and RTX intolerance who was unresponsive to a desensitization protocol. Results: A 12-year-old boy with SDNS since the age of 2, was treated with steroids, cyclophosphamide and cyclosporine A (CsA). Because of the prolonged use of calcineurin inhibitors, a course of rituximab (RTX) was planned. Unfortunately, during first infusion, the boy presented with IRR. A desensitization protocol following the first unsuccessful infusion also failed. Facing the risks of long-term cyclosporine therapy, a decision was made to switch to another type of anti-CD20 antibody. Obinutuzumab infusion with a modified premedication scheme was uneventful. Conclusions: Switching therapy to obinutuzumab may be considered an option in nephrotic children who are intolerant to RTX when alternative therapies have been exhausted. The addition of montelukast to premedication and employment of desensitization protocols may decrease the risk of infusion-related reactions to anti-CD20 agents. Full article

Background/Objectives: Obinutuzumab was approved for front-line treatment of chronic lymphocytic leukemia in combination with chlorambucil pulses administered every 2 wks. Alternative schedules of chlorambucil enable the administration of higher total chlorambucil doses, and have better antileukemia activity. So far, evidence on the feasibility of combining obinutuzumab with alternative chlorambucil schedules is lacking. We performed this retrospective analysis to analyze real life outcomes in chronic lymphocytic leukemia patients receiving a combination of obinutuzumab with different chlorambucil schedules. Methods: This was a retrospective survey performed in order to analyze the feasibility and efficacy of different obinutuzumab and chlorambucil combinations in a real-life setting. Patients receiving this combination as a front-line therapy for chronic lymphocytic leukemia in participating centers, outside of clinical trials, in 2017 and 2018 were included. Results: Seventy-three patients fulfilling entry criteria were identified. Their median age was 76 years, and ranged from 58 to 90 years. The median follow up time was 59 months. The response rate was 89%, with a median progression-free survival time of 27 months, and an overall survival time of 49 months. Chlorambucil was administered as planned in 15 of the 22 (79%) patients treated with chlorambucil pulses every 2 weeks; in 15 of the 42 (34%) patients treated with 7-day courses of chlorambucil administered every 4 weeks; and in 0 of the 10 patients treated with a continuous high dose of chlorambucil (p = 0.002). Changes in treatment schedules were made due to side effects. The progression-free and overall survival rates were similar between the three groups. Conclusions: The combinations of obinutuzumab with more intensive chlorambucil schedules are less feasible, preventing the administration of the intended higher total dose of chlorambucil, and do not improve outcomes in comparison to chlorambucil pulses administered every 2 weeks. Full article

Background/Objectives: Patients with chronic lymphocytic leukemia (CLL) are susceptible to infections that can affect their clinical outcomes. Aims: The aims of this study were to assess the following: (1) the incidence of pneumonia in CLL patients treated with venetoclax-based regimens in a real-world setting, (2) the risk factors for event-free survival (EFS), and (3) overall survival (OS). Methods: This multicenter study included 322 patients from eight centers. Univariable and multivariable analyses (MVA) were performed, with the development of pneumonia during venetoclax-based treatment and OS as outcomes. Results: The most common complication was neutropenia (59%). During treatment with venetoclax-based regimens, 66 (20%) patients developed pneumonia—50 (23%) patients in the rituximab-plus-venetoclax (R-VEN) group and 13 (16%) patients in the obinutuzumab-plus-venetoclax (O-VEN) group (p = 0.15). Chronic obstructive pulmonary disease (COPD)/asthma, splenomegaly, elevated creatinine, and anemia < 8 g/dL were the risk factors for EFS in MVA (HR = 2.08, 95%CI 1.16–3.74, p = 0.014; HR 1.73, 95%CI 1.08–2.78, p = 0.02; HR 2.13, 95%CI 1.10–4.11, p = 0.03, HR 3.58, 95%CI 2.18–5.89, p < 0.001, respectively). Relapsed/refractory (R/R) CLL patients treated with R-VEN with pneumonia had worse OS than those without (p < 0.001). In patients treated with O-VEN, median OS did not differ between patients with and without pneumonia (p = 0.45). Conclusions: Our real-world study showed that pneumonia during venetoclax treatment occurs more frequently than reported in registration trials and has a negative impact on OS, especially in patients with R/R CLL who are treated with R-VEN. Neutropenia is not a risk factor for pneumonia. Full article

Background: Bruton tyrosine kinase inhibitors (BTKis) represent an advancement in chronic lymphocytic leukemia; however, these agents are administered continuously until disease progression or unacceptable toxicity, raising concerns about their affordability. Venetoclax in combination with obinutuzumab (VO) is a fixed-duration (12-month) treatment, approved in Canada in 2020. This study estimated the total cumulative cost of different treatment sequences and evaluated the economic impact of introducing treatment sequences with/without VO, from a Canadian health care system perspective. Methods: A 10-year partitioned survival model was developed, considering key clinical parameters and direct medical costs. Results were stratified by TP53 aberration. Results: Treatment sequences starting with first-line (1L) VO resulted in lower 10-year cumulative costs compared to sequences starting with BTKis administered until disease progression, across both TP53 aberration subgroups. With a maximum of three lines of treatment over a 10-year period, cumulative costs were largely determined by the first two lines of treatment. When comparing sequences with the same 1L treatment, sequences with BTKis in second-line incurred greater costs compared to fixed-duration regimens. Conclusions: Overall, the economic impact of treating all patients with VO led to 10-year cumulative savings of CAD 169,341 and CAD 293,731 per patient, without and with TP53 aberration, respectively. These savings are mainly due to reductions in treatment costs associated with fixed treatment duration. Full article

Introduction: Systemic lupus erythematosus (SLE) is a multifaceted autoimmune disorder characterized by significant autoantibodies, particularly targeting nuclear antigens. SLE pathogenesis involves genetic, environmental, and hormonal factors. The disease course includes flares and remission and involves various organs. Recent therapeutic progresses, including biologics, have improved management and prognosis, though the long-term impact of novel therapies remains to be determined. Biologics in SLE: Rituximab, the earliest B-cell-oriented biologic, binds CD20 and depletes CD20+ B cells, leading to remission in some SLE patients. Belimumab is a B-cell-activating factor (BAFF) inhibitor with a recent additional indication for lupus nephritis. The CALIBRATE and BLISS-BELIEVE studies investigated combinations of these drugs with conventional therapies, showing varied efficacy. Ocrelizumab and obinutuzumab, newer CD20-oriented SLE therapies, together with ofatumumab and veltuzumab, are also promising. The latest trials highlight their efficacy and safety. Anifrolumab, targeting type-I interferon receptors, was evaluated in the TULIP 1/2 trials. The ongoing TULIP LTE trial supports the long-term safety and efficacy of anifrolumab. Additionally, the IRIS Phase III trial is exploring anifrolumab for lupus nephritis, showing favorable renal responses. Tocilizumab and secukinumab are being assessed for SLE, with mixed outcomes. Several biologics targeting the C5 complement protein, together with immunomodulators and immunotherapeutics, are also under investigation for potential benefits in SLE. Discussion: Biologics in SLE target specific immune components, aiming to improve disease control and reduce the side effects of conventional therapy. However, trial outcomes vary due to factors like inclusion criteria and trial design. Conclusions: Biotechnology progress enables targeted biologic therapies for SLE, reducing disease activity and improving patients’ quality of life. Full article