Spontaneous development of myasthenia gravis and myositis following treatment with pembrolizumab: a case report.

BACKGROUND: Immune checkpoint inhibitors are a relatively new advancement in the world of cancer therapy. As such, their adverse effects have yet to be fully understood, with only recent literature documenting autoimmune phenomena secondary to their utilization. Specific immune checkpoint inhibitors have recently been linked with the development of myasthenia gravis, which is classically known to manifest spontaneously in patients. Given the relative rarity of this presentation, the risk of misdiagnosis and subsequent mortality and morbidity is concerning. CASE PRESENTATION: We discuss the case of a 73-year-old male who presented with clinical symptoms of myasthenia gravis and myositis shortly after beginning treatment with Pembrolizumab. The diagnosis of myasthenia gravis was initially missed at an outside hospital, which delayed initiation of proper treatment. CONCLUSION: While the incidence of "de-novo" diseases secondary to immune checkpoint inhibitors might be increasing, guidelines regarding best treatment options do not yet exist, leaving many providers at a loss when faced with making clinical decisions surrounding patients with De novo myasthenia gravis. Thus, our goal is to underscore the importance of early recognition of this disease, and emphasize the need for a standard of care as immune checkpoint inhibitors usage becomes more prevalent.

Psoriasis vulgaris patient with psoriatic arthritis managed with interleukin-17A inhibitor: Balancing benefits and adverse effects.

Psoriasis vulgaris is a significant health problem and up to 30% of the patients are most likely to develop psoriatic arthritis. Secukinumab, an interleukin-17A (IL-17A) inhibitor, is used to treat patients with moderate-to-severe plaques associated with psoriatic arthritis. The aim of this case report was to highlight the efficacy of secukinumab treatment in a patient with both psoriasis vulgaris and psoriatic arthritis focusing the how to balance the benefits and adverse effects. A 36-year-old female came to Dr. Zainoel Abidin Hospital, Banda Aceh, Indonesia with chief complaint of itchy and scaly red plaques almost all over the body. The patient also experienced pain in both knees, both ankle joints and index finger as well as thumb in the right hand in the last year. The patient was diagnosed with psoriasis vulgaris and psoriatic arthritis, then treated with phototherapy and 15 mg of oral methotrexate each week for four weeks. Due to no improvement of the initial treatment, the patient received emollient and secukinumab at a dose of 300 mg/week subcutaneously for five weeks. The lesions began to disappear and the joint pain began to relieve. Secukinumab therapy was continued with a dose of 300 mg/month for six months. However, after six months, the patient complained of acnes appeared on the face. Therefore, the maintenance dose of secukinumab was decreased to 150 mg/month. After the reduced maintenance therapy was given, the patient came back with no complained of acnes. The erythematous plaques on trunk, back, arms and legs have subsided, as well as the joint pain. This case highlights that in a moderate-to-severe psoriasis associated with psoriatic arthritis, secukinumab is highly effective. However, since the potential adverse effects, education and regular follow-up are needed to analyze the success of the treatment and to be able to manage the adverse effects.

The real life experience goes on: update after 4 years on the first cohort treated with lanadelumab at our center.

Introduction: Lanadelumab is a first-line long-term prophylaxis (LTP) in hereditary angioedema (HAE). Real-life data on its long-term efficacy and safety are limited. It is unknown whether patients using lanadelumab need short-term prophylaxis (STP). Objectives: To provide 4-year follow-up data for our first 34 patients treating with lanadelumab. Methods: Patients were assessed for their current injection interval, attacks, treatment satisfaction, disease control (AECT), quality of life impairment (AE-QoL), events that can induce attacks, and the use of STP since the start of their treatment with lanadelumab. Results: Of 34 patients who started lanadelumab treatment, 32 were still using it after 4 years, with a median injection interval of 33 (range 14-90) days. HAE patients (n=28) reported longer intervals, i.e. 35 (14-90) days, than patients with angioedema due to acquired C1 inhibitor deficiency (n=4, 23 (14-31) days). With their current injection intervals, used for a mean duration of 29 ± 17 months, patients reported a yearly attack rate of 0.3 ± 0.1. More than 70% of patients were attack-free since starting their current injection interval. All patients reported well-controlled disease, i.e. ≥10 points in the AECT; 21 patients had complete control (16 points). AE-QoL scores improved further compared to our initial report, most prominently in the fears/shame domain (-6 points). Treatment satisfaction was very high. No angioedema occurred after 146 of 147 potentially attack-inducing medical procedures without STP. Conclusions: Our results demonstrate the long-term efficacy and safety of lanadelumab in real-life and question the need for STP in patients who use effective LTP.

Good clinical response to cemiplimab in a young patient with locally advanced cutaneous squamous cell carcinoma on preexisting recessive dystrophic epidermolysis bullosa.

Recessive dystrophic epidermolysis bullosa (RDEB) is a rare genetic skin disease caused by mutations in the type VII collagen gene (COL7A1; 3p21.31). Mutations in this gene lead to an alteration in function or reduced amounts of collagen VII. This alteration of collagen VII leads to skin fragility and lesions at minor injuries with difficult healing. Cutaneous squamous cell carcinoma (cSCC) is more frequent in patients with RDEB than in the general population because of chronic wound formation; it constitutes a major cause of morbidity and is often cited as a cause of death for these patients. There is little experience with the treatment of cSCC in patients with RDEB. We report the case of a 19-year-old female patient with RDBE and inoperable locally advanced cSCC of the left arm. Because of the lack of therapy options, therapy with cemiplimab was started at a dose of 350 mg administered intravenously every 3 weeks. A confirmed clinical response was observed after the second cycle of treatment with no toxicity. During follow-up, the patient had a notable clinical response with no auto-immune adverse reactions. This shows that cemiplimab has a good safety profile for cSCC in patients with RDEB and is a valuable therapy option.

Prognostic impact of corticosteroid and tocilizumab use following chimeric antigen receptor T-cell therapy for multiple myeloma.

Despite being the mainstay of management for cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS), there is limited data regarding the impact of tocilizumab (TCZ) and corticosteroids (CCS) on chimeric antigen receptor (CAR) T-cell efficacy in multiple myeloma (MM). The present study aims to evaluate the prognostic impact of these immunosuppressants in recipients of BCMA- or GPRC5D-directed CAR T cells for relapsed/refractory MM. Our retrospective cohort involved patients treated with commercial or investigational autologous CAR T-cell products at a single institution from March 2017-March 2023. The primary endpoint was progression-free survival (PFS). Secondary endpoints included overall response rate (ORR), complete response rate (CRR), and overall survival (OS). In total, 101 patients (91% treated with anti-BCMA CAR T cells and 9% treated with anti-GPRC5D CAR T cells) were analyzed. Within 30 days post-infusion, 34% received CCS and 49% received TCZ for CRS/ICANS management. At a median follow-up of 27.4 months, no significant difference in PFS was observed between CCS and non-CCS groups (log-rank p = 0.35) or between TCZ and non-TCZ groups (log-rank p = 0.69). ORR, CRR, and OS were also comparable between evaluated groups. In our multivariable model, administering CCS with/without TCZ for CRS/ICANS management did not independently influence PFS (HR, 0.74; 95% CI, 0.36-1.51). These findings suggest that, among patients with relapsed/refractory MM, the timely and appropriate use of CCS or TCZ for mitigating immune-mediated toxicities does not appear to impact the antitumor activity and long-term outcomes of CAR T-cell therapy.

Epitope binning for multiple antibodies simultaneously using mammalian cell display and DNA sequencing.

Epitope binning, an approach for grouping antibodies based on epitope similarities, is a critical step in antibody drug discovery. However, conventional methods are complex, involving individual antibody production. Here, we established Epitope Binning-seq, an epitope binning platform for simultaneously analyzing multiple antibodies. In this system, epitope similarity between the query antibodies (qAbs) displayed on antigen-expressing cells and a fluorescently labeled reference antibody (rAb) targeting a desired epitope is analyzed by flow cytometry. The qAbs with epitope similar to the rAb can be identified by next-generation sequencing analysis of fluorescence-negative cells. Sensitivity and reliability of this system are confirmed using rAbs, pertuzumab and trastuzumab, which target human epidermal growth factor receptor 2. Epitope Binning-seq enables simultaneous epitope evaluation of 14 qAbs at various abundances in libraries, grouping them into respective epitope bins. This versatile platform is applicable to diverse antibodies and antigens, potentially expediting the identification of clinically useful antibodies.

Cost-effectiveness analysis of tislelizumab vs. camrelizumab for the treatment of second-line locally advanced or metastatic esophageal squamous cell carcinoma.

BACKGROUND: Esophageal carcinoma is a type of cancer that occurs in the esophagus. For patients with locally advanced or metastatic esophageal squamous cell carcinoma who have either experienced disease progression following first-line standard chemotherapy or are intolerant to it, the prognosis is typically poor. Additionally, these patients often bear a substantial economic burden during the course of their treatment. Tislelizumab is a selective PD-1 inhibitor with efficacy proven in locally advanced or metastatic esophageal squamous cell carcinoma. The study aims to evaluate the cost-effectiveness of tislelizumab versus camrelizumab as the second-line treatment in locally advanced or metastatic esophageal squamous cell carcinoma (ESCC) patients in China. METHODS: From the perspective of China's healthcare system, the partitioned survival model with three health states was established in a 3-week cycle and a lifetime horizon. Anchored matching adjusted indirect comparison was used for survival analyses based on individual patient data from RATIONALE 302 trial and the published ESCORT study due to the lack of head-to-head clinical trials. Only direct medical costs were included. Costs and utility values were derived from local charges, the published literature, and related databases. Sensitivity analyses and a scenario analysis were also performed to verify the robustness of the model results. RESULTS: Compared with camrelizumab monotherapy, tislelizumab monotherapy incurred a lower lifetime cost ($8,346 vs. $8,851) and yielded higher quality-adjusted life-years (QALYs) (0.87 vs. 0.63), which resulted in an incremental cost-effectiveness ratio (ICER) of -$2,051/QALY. Tislelizumab monotherapy is a dominant option over camrelizumab monotherapy in China. The three primary parameters upon which this result was most sensitive were the unit cost of camrelizumab, the unit cost of tislelizumab, and the duration of reactive cutaneous capillary endothelial proliferation (RCCEP). According to the probabilistic sensitivity analysis (PSA), tislelizumab monotherapy was 100% cost-effective when the WTP was 1-3 times GDP per capita in China($11,207/QALY∼$33,621/QALY). Scenario analysis showed that the result was consistent. CONCLUSION: Tislelizumab monotherapy is a dominant option compared with camrelizumab monotherapy as the second-line treatment for locally advanced or metastatic ESCC in China.

Neoadjuvant Treatment for a cT4cN+ HER2+ Breast Cancer: Case Report of a Therapeutic Success.

BACKGROUND: HER2 positive disease accounts for 15-20% of early breast cancer. Achieving a pathological complete response after neoadjuvant chemotherapy (NACT) improves prognosis and decreases risk of recurrence. CASE REPORT: Our case report aimed to highlight an emblematic clinical success and benefit of NACT with the addition of pertuzumab to the standard trastuzumab/taxane/anthracycline combination in a patient with a 9 cm breast neoplasm and extensive lymph node involvement (>4 pathological lymph nodes). CONCLUSION: Achieving a complete pathological response with NACT, should be the main goal, especially in patients with triple negative and HER2 positive breast cancer.

Adverse Event Profile of Atezolizumab, Bevacizumab, Carboplatin, and Paclitaxel Combination Therapy Based on JADER.

BACKGROUND/AIM: There have been advances in the development of immune checkpoint inhibitors for monotherapy and combination therapy with other anticancer agents in recent years. The combination of bevacizumab, carboplatin, and paclitaxel with atezolizumab, an anti-programmed death ligand 1 antibody (ABCP therapy), has been reported to be effective for treating non-small cell lung cancer. However, reports on its adverse events are limited. In this study, a survey and disproportionality analysis based on the Japanese Adverse Drug Event Report (JADER) database was conducted to elucidate the adverse event profile of ABCP therapy. MATERIALS AND METHODS: The reporting odds ratio (ROR) and information component were used as indicators for the disproportionality analysis. The ROR was also used to assess the changes in the reporting intensity with combination therapy, and the mutual exclusivity of the 95% confidence interval between the compared groups was considered. RESULTS: The reported adverse events of ABCP therapy mirrored those of the individual drugs that constituted it. ABCP therapy enhanced the reporting intensity of adverse events related to leukocytes and the skin, while decreased those related to interstitial lung disease and hepatic function abnormality as immune-related adverse events caused by atezolizumab, and gastrointestinal perforation caused by bevacizumab. CONCLUSION: Our analysis of data from the JADER database has revealed the adverse event profile of ABCP therapy. Our findings emphasize the importance of effectively managing febrile neutropenia and skin-related adverse events in ABCP therapy.

Real Clinical Practice of Combined Atezolizumab Plus Chemotherapy in Patients With Small Cell Lung Cancer.

BACKGROUND/AIM: Atezolizumab, an anti-PD-L1 antibody, has been increasingly administered in combination with chemotherapy to patients with small cell lung cancer (SCLC). This study aimed to determine how patients with extensive disease (ED) -SCLC responded to atezolizumab with chemotherapy and found factors affecting long-term response and survival. PATIENTS AND METHODS: This study focused on patients with SCLC who were treated with a combination of atezolizumab and chemotherapy in Japan between 2019 and 2023. Patient information and tumor response were analyzed, along with adverse events. We compared data and estimated survival probabilities. RESULTS: In our clinical trial, 95 patients with SCLC who received this treatment had a median progression-free survival of 6.0 months and a median overall survival of 15.0 months. Immune-related adverse events were observed in 13.7% of the patients, with grade 3 or higher in 5.3%. The efficacy and immune-related adverse events associated with this treatment regimen were comparable to those reported in previous clinical trials. Progression-free survival >2 years was observed in a small number of patients (5.3%). CONCLUSION: Our research will offer important insights for the future care of patients with extensive-stage SCLC by utilizing atezolizumab in combination with chemotherapy. Accumulation and confirmation of clinical practice results will have important implications for the future implementation of this therapy.

Photoimmunotherapy of Prostate Cancer With Antibody and Fab Fragments Targeting the Prostate Specific Membrane Antigen.

BACKGROUND/AIM: The standard treatment for localized prostate cancer involves surgical removal of the prostate with curative intent. However, when tumor cells persist in the operation site, there is high risk of local recurrence and tumor spread, leading to stressful follow-up treatments, impaired quality of life, and reduced overall survival. This study examined photoimmunotherapy (PIT) as a new treatment option for prostate cancer cells. MATERIALS AND METHODS: We generated conjugates consisting of either a humanized antibody or Fab fragments thereof targeting the prostate specific membrane antigen (PSMA), along with our silicon phthalocyanine photosensitizer dye WB692-CB1. PSMA-expressing prostate cancer cells were incubated with the antibody dye or Fab dye conjugates and cell binding was measured using flow cytometry. Cells were irradiated with varying doses of red light for dye activation, and cytotoxicity was determined by erythrosin B staining and subsequent analysis using a Neubauer counting chamber. RESULTS: Specific cytotoxicity was induced with the antibody dye conjugate in the prostate cancer cells in a light dose-dependent manner. Treatment of the cells with the Fab dye conjugate resulted in lower cytotoxicity, which could be attributed to a reduced binding affinity and a reduced dye uptake of the Fab fragment. CONCLUSION: Our new antibody dye and Fab dye conjugates offer potential for future intraoperative PIT in patients with localized prostate cancer, with the aim to ensure complete removal of tumor cells from the surgical area, to avoid local recurrence, and to improve clinical outcome.

Cardiovascular health in pediatric patients with X-linked hypophosphatemia under two years of burosumab therapy.

Introduction: X-linked hypophosphatemia (XLH) is caused by an inactivating mutation in the phosphate-regulating endopeptidase X-linked (PHEX) gene whose defective product fails to control phosphatonin fibroblast growth factor 23 (FGF23) serum levels. Although elevated FGF23 levels have been linked with detrimental cardiac effects, the cardiologic outcomes in XLH patients have been subject to debate. Our study aimed to evaluate the prevalence and severity of cardiovascular morbidity in pediatric XLH patients before, during, and after a 2-year treatment period with burosumab, a recombinant anti-FGF23 antibody. Methods: This prospective observational study was conducted in a tertiary medical center, and included 13 individuals with XLH (age range 0.6-16.2 years) who received burosumab every 2 weeks. Clinical assessment at treatment initiation and after .5, 1, and 2 years of uninterrupted treatment included anthropometric measurements and cardiologic evaluations (blood pressure [BP], electrocardiogram, conventional echocardiography, and myocardial strain imaging). Results: The linear growth of all patients improved significantly (mean height z-score: from -1.70 ± 0.80 to -0.96 ± 1.08, P=0.03). Other favorable effects were decline in overweight/obesity rates (from 46.2% to 23.1%) and decreased rates of elevated BP (systolic BP from 38.5% to 15.4%; diastolic BP from 38.5% to 23.1%). Electrocardiograms revealed no significant abnormality throughout the study period. Cardiac dimensions and myocardial strain parameters were within the normative range for age at baseline and remained unchanged during the study period. Conclusion: Cardiologic evaluations provided reassurance that 2 years of burosumab therapy did not cause cardiac morbidity. The beneficial effect of this treatment was a reduction in cardiovascular risk factors, as evidenced by the lower prevalence of both overweight/obesity and elevated BP.

Projected environmental and public health benefits of extended-interval dosing: an analysis of pembrolizumab use in a US national health system.

BACKGROUND: Health care is a major source of greenhouse gas emissions, leading to climate change and public health harms. Changes are needed to improve the environmental sustainability of health-care practices, but such changes should not sacrifice patient outcomes or financial sustainability. Alternative dosing strategies that reduce the frequency with which specialty drugs are administered, without sacrificing patient outcomes, are an attractive possibility for improving environmental sustainability. We sought to inform environmentally sustainable cancer care by estimating and comparing the environmental and financial effects of alternative, clinically equivalent strategies for pembrolizumab administration. METHODS: We conducted a retrospective analysis using a cohort of patients from the Veterans Health Administration (VHA) in the USA who received one or more pembrolizumab doses between May 1, 2020, and Sept 30, 2022. Using baseline, real-world administration of pembrolizumab, we generated simulated pembrolizumab use data under three near-equivalent counterfactual pembrolizumab administration strategies defined by combinations of weight-based dosing, pharmacy-level vial sharing and dose rounding, and extended-interval dosing (ie, every 6 weeks). For each counterfactual dosing strategy, we estimated greenhouse gas emissions related to pembrolizumab use across the VHA cohort using a deterministic environmental impact model that estimated greenhouse gas emissions due to patient travel, drug manufacture, and medical waste as the primary outcome measure. FINDINGS: We identified 7813 veterans who received at least one dose of pembrolizumab-containing therapy in the VHA during the study period. 59 140 pembrolizumab administrations occurred in the study period, of which 46 255 (78·2%) were dosed at 200 mg every 3 weeks, 12 885 (21·8%) at 400 mg every 6 weeks, and 14 955 (25·3%) were coadministered with infusional chemotherapies. Adoption of weight-based, extended-interval pembrolizumab dosing (4 mg/kg every 6 weeks) and pharmacy-level stewardship strategies (ie, dose rounding and vial sharing) for all pembrolizumab infusions would have resulted in 24·7% fewer administration events than baseline dosing (44 533 events vs 59 140 events) and an estimated 200 metric tons less CO2 emitted per year as a result of pembrolizumab use within the VHA (650 tons vs 850 tons of CO2, a relative reduction of 24%), largely due to reductions in distance travelled by patients to receive treatment. Similar results were observed when weight-based and extended-interval dosing were applied only to pembrolizumab monotherapy and pembrolizumab in combination with oral therapies. INTERPRETATION: Alternative pembrolizumab administration strategies might have environmental advantages over the current dosing and compounding paradigms. Specialty medication dosing can be optimised for health-care spending and environmental sustainability without sacrificing clinical outcomes. FUNDING: None.

First-line venetoclax combinations versus chemoimmunotherapy in fit patients with chronic lymphocytic leukaemia (GAIA/CLL13): 4-year follow-up from a multicentre, open-label, randomised, phase 3 trial.

BACKGROUND: In the primary analysis report of the GAIA/CLL13 trial, we found that venetoclax-obinutuzumab and venetoclax-obinutuzumab-ibrutinib improved undetectable measurable residual disease (MRD) rates and progression-free survival compared with chemoimmunotherapy in patients with previously untreated chronic lymphocytic leukaemia. However, to our knowledge, no data on direct comparisons of different venetoclax-based combinations are available. METHODS: GAIA/CLL13 is an open-label, randomised, phase 3 study conducted at 159 sites in ten countries in Europe and the Middle East. Eligible patients were aged 18 years or older, with a life expectancy of at least 6 months, an Eastern Cooperative Oncology group performance status of 0-2, a cumulative illness rating scale score of 6 or lower or a single score of 4 or lower, and no TP53 aberrations. Patients were randomly assigned (1:1:1:1), with a computer-generated list stratified by age, Binet stage, and regional study group, to either chemoimmunotherapy, venetoclax-rituximab, venetoclax-obinutuzumab, or venetoclax-obinutuzumab-ibrutinib. All treatments were administered in 28-day cycles. Patients in the chemoimmunotherapy group received six cycles of treatment, with patients older than 65 years receiving intravenous bendamustine (90 mg/m2, days 1-2), whereas patients aged 65 years or younger received intravenous fludarabine (25 mg/m2, days 1-3) and intravenous cyclophosphamide (250 mg/m2, days 1-3). Intravenous rituximab (375 mg/m2, day 1 of cycle 1; 500 mg/m2, day 1 of cycles 2-6) was added to chemotherapy. In the experimental groups, patients received daily venetoclax (400 mg orally) for ten cycles after a 5-week ramp-up phase starting on day 22 of cycle 1. In the venetoclax-rituximab group, intravenous rituximab (375 mg/m2, day 1 of cycle 1; 500 mg/m2, day 1 of cycles 2-6) was added. In the obinutuzumab-containing groups, obinutuzumab was added (cycle 1: 100 mg on day 1, 900 mg on day 2, and 1000 mg on days 8 and 15; cycles 2-6: 1000 mg on day 1). In the venetoclax-obinutuzumab-ibrutinib group, daily ibrutinib (420 mg orally, from day 1 of cycle 1) was added until undetectable MRD was reached in two consecutive measurements (3 months apart) or until cycle 36. The planned treatment duration was six cycles in the chemoimmunotherapy group, 12 cycles in the venetoclax-rituximab and the venetoclax-obinutuzumab group and between 12 and 36 cycles in the venetoclax-obinutuzumab-ibrutinib group. Coprimary endpoints were the undetectable MRD rate in peripheral blood at month 15 for the comparison of venetoclax-obinutuzumab versus standard chemoimmunotherapy and investigator-assessed progression-free survival for the comparison of venetoclax-obinutuzumab-ibrutinib versus standard chemoimmunotherapy, both analysed in the intention-to-treat population (ie, all patients randomly assigned to treatment) with a split α of 0·025 for each coprimary endpoint. Both coprimary endpoints have been reported elsewhere. Here we report a post-hoc exploratory analysis of updated progression-free survival results after a 4-year follow-up of our study population. Safety analyses included all patients who received at least one dose of study treatment. This study is registered with ClinicalTrials.gov, NCT02950051, recruitment is complete, and all patients are off study treatment. FINDINGS: Between Dec 13, 2016, and Oct 13, 2019, 1080 patients were screened and 926 were randomly assigned to treatment (chemoimmunotherapy group n=229; venetoclax-rituximab group n=237; venetoclax-obinutuzumab group n=229; and venetoclax-obinutuzumab-ibrutinib group n=231); mean age 60·8 years (SD 10·2), 259 (28%) of 926 patients were female, and 667 (72%) were male (data on race and ethnicity are not reported). At data cutoff for this exploratory follow-up analysis (Jan 31, 2023; median follow-up 50·7 months [IQR 44·6-57·9]), patients in the venetoclax-obinutuzumab group had significantly longer progression-free survival than those in the chemoimmunotherapy group (hazard ratio [HR] 0·47 [97·5% CI 0·32-0·69], p<0·0001) and the venetoclax-rituximab group (0·57 [0·38-0·84], p=0·0011). The venetoclax-obinutuzumab-ibrutinib group also had a significantly longer progression-free survival than the chemoimmunotherapy group (0·30 [0·19-0·47]; p<0·0001) and the venetoclax-rituximab group (0·38 [0·24-0·59]; p<0·0001). There was no difference in progression-free survival between the venetoclax-obinutuzumab-ibrutinib and venetoclax-obinutuzumab groups (0·63 [0·39-1·02]; p=0·031), and the proportional hazards assumption was not met for the comparison between the venetoclax-rituximab group versus the chemoimmunotherapy group (log-rank p=0·10). The estimated 4-year progression-free survival rate was 85·5% (97·5% CI 79·9-91·1; 37 [16%] events) in the venetoclax-obinutuzumab-ibrutinib group, 81·8% (75·8-87·8; 55 [24%] events) in the venetoclax-obinutuzumab group, 70·1% (63·0-77·3; 84 [35%] events) in the venetoclax-rituximab group, and 62·0% (54·4-69·7; 90 [39%] events) in the chemoimmunotherapy group. The most common grade 3 or worse treatment-related adverse event was neutropenia (114 [53%] of 216 patients in the chemoimmunotherapy group, 109 [46%] of 237 in the venetoclax-rituximab group, 127 [56%] of 228 in the venetoclax-obinutuzumab group, and 112 [48%] of 231 in the venetoclax-obinutuzumab-ibrutinib group). Deaths determined to be associated with study treatment by the investigator occurred in three (1%) patients in the chemoimmunotherapy group (n=1 due to each of sepsis, metastatic squamous cell carcinoma, and Richter's syndrome), none in the venetoclax-rituximab and venetoclax-obinutuzumab groups, and four (2%) in the venetoclax-obinutuzumab-ibrutinib group (n=1 due to each of acute myeloid leukaemia, fungal encephalitis, small-cell lung cancer, and toxic leukoencephalopathy). INTERPRETATION: With more than 4 years of follow-up, venetoclax-obinutuzumab and venetoclax-obinutuzumab-ibrutinib significantly extended progression-free survival compared with both chemoimmunotherapy and venetoclax-rituximab in previously untreated, fit patients with chronic lymphocytic leukaemia, thereby supporting their use and further evaluation in this patient group, while still considering the higher toxicities observed with the triple combination. FUNDING: AbbVie, Janssen, and F Hoffmann-La Roche.

Preclinical development of humanized monoclonal antibodies against CD169 as a broad antiviral therapeutic strategy.

New therapies to treat or prevent viral infections are essential, as recently observed during the COVID-19 pandemic. Here, we propose a therapeutic strategy based on monoclonal antibodies that block the specific interaction between the host receptor Siglec-1/CD169 and gangliosides embedded in the viral envelope. Antibodies are an excellent option for treating infectious diseases based on their high specificity, strong targeting affinity, and relatively low toxicity. Through a process of humanization, we optimized monoclonal antibodies to eliminate sequence liabilities and performed biophysical characterization. We demonstrated that they maintain their ability to block viral entry into myeloid cells. These molecular improvements during the discovery stage are key if we are to maximize efforts to develop new therapeutic strategies. Humanized monoclonal antibodies targeting CD169 provide new opportunities in the treatment of infections caused by ganglioside-containing enveloped viruses, which pose a constant threat to human health. In contrast with current neutralizing antibodies that bind antigens on the infectious particle, our antibodies can prevent several types of enveloped viruses interacting with host cells because they target the host CD169 protein, thus becoming a potential pan-antiviral therapy.

Long-term therapy with itolizumab is safe and effective for patients with moderate to severe psoriasis: Results from an expanded-access program.

Itolizumab is a humanized monoclonal antibody that selectively targets the CD6-ALCAM pathway. This article reports on the safety and efficacy of itolizumab in the treatment of moderate-to-severe plaque psoriasis in a clinical study conducted in Cuba in the setting of an expanded-access program (EAP). The study included 84 patients who had previously received conventional anti-psoriatic systemic therapies but were either intolerant, had an inadequate response, or had contraindications to these therapies. It consisted of multiple phases, including a 12-week induction phase, a 40-week maintenance phase, and a 24-week off-treatment follow-up phase, using either a 0.4 or 1.6 mg/Kg dose. The results showed that itolizumab monotherapy was safe and effective during 52 weeks of continuous treatment and the subsequent 24 follow-up weeks. Itolizumab treatment resulted in a significant improvement (PASI 75) in 80 % of patients at the end of the induction phase, and this effect was sustained till week 52 during the maintenance phase. Moreover, 24 weeks after treatment stopped nearly two-thirds of patients still showed a PASI ≥ 75. The observed effects were dose-dependent, with 1.6 mg/kg being the most convenient dose. This study further supports the strategy of targeting the CD6-ALCAM signaling pathway for the treatment of psoriasis and the use of itolizumab as a valuable asset in the armamentarium of anti-psoriasis drugs.

[Swelling on the neck]. / Schwellung am Hals.

INTRODUCTION: A 30-year-old female patient presented with a swelling of a cervical left lymph node measuring 1x3 cm, which had been presenting for three weeks. Lymph node excision revealed a metastasis of a malignant melanoma, but the primary tumor was not found. The guidelines recommend neck dissection and adjuvant systemic or immunotherapy. The patient opted for immunotherapy with pembrolizumab and was tumor-free one year later.

Systemic Biologic Management of Atopic Dermatitis.

Dupilumab and tralokinumab are currently the only FDA-approved biologic therapies for the treatment of moderate-to-severe atopic dermatitis. Tralokinumab is approved for patients greater than 18 years old, and dupilumab is approved for patients as young as 6 months old. Both medications are effective in clinical trials at improving atopic dermatitis. With a good safety profile and low-risk adverse events, dupilumab and tralokinumab are generally excellent treatment options for patients with severe or refractory atopic dermatitis.