Autologous enzyme-linked immunosorbent facilitated antigen binding detects IgE-blocking activity based on direct competition between allergen-specific IgE and non-IgE

Aim: To measure IgE-blocking activity induced by allergen immunotherapy (AIT) by an enzyme-linked immunosorbent facilitated antigen binding (ELIFAB) assay based on autologous immunoglobulin competition. Methods: The developed ELIFAB assay was used to investigate the kinetics of IgE-blocking activity in 87 patients at multiple AIT treatment time points, in comparison to the changes in IgG4. Results: High ELIFAB response was observed until 2.5 months of AIT, then significantly decreased after 4 months and remained suppressed during the 3-year AIT period. After treatment cessation, the ELIFAB response was maintained at the level seen at the 4–6 month treatment time point, similar to IgG4, indicating sustained IgE-blocking activity related to IgG4. Conclusion: This ELIFAB assay measures the IgE-blocking activity for autologous allergen-specific IgE and non-IgE during and after immunotherapy. It is suited for measuring the sustained IgE-blocking activity induced by AIT.

A Validated Risk Prediction Model for Bone Fragility in Children with Acute Lymphoblastic Leukemia

Introduction Due to bone fragility, children with acute lymphoblastic leukemia (ALL) have a 6-fold greater fracture risk during therapy compared to peers. Osteoporotic fractures are a concern, as they lead to adverse health outcomes including pain, loss of height due to vertebral deformity, and (transient) disability. In previous studies, lower lumbar spine bone mineral density (LS BMD) at ALL diagnosis was found to be prognostic for the occurrence of future fractures. However, routinely performing dual-energy X-ray absorptiometry (DXA) in each newly diagnosed child is not universally feasible. The aim of this study is to develop and validate an easy to use clinical risk prediction model for low lumbar spine bone mineral density (LS BMD Z-score ≤-2.0) at diagnosis, as an important indicator for fracture risk and further treatment-related BMD aggravation. Methods Children treated for ALL according to the Dutch Childhood Oncology Group (DCOG-ALL9; model development) protocol (n=249; median age: 7.6 years [range: 4.0-16.6 years]) and children from the Canadian STeroid-Associated Osteoporosis in the Pediatric Population (STOPP; model validation) cohort (n=99; median age: 7.3 years [range: 4.0-16.6 years]) were included in this study. Multivariable logistic regression analyses were used to develop the prediction model for low LS BMD at diagnosis, defined as a Z-score ≤-2.0 (evaluated with DXA). Candidate predictors included sex, age, height and weight Z-scores at diagnosis of ALL. The receiver operating characteristic area under the curve (AUC) was assessed for model performance. To confirm the association between low LS BMD at diagnosis and bone fragility during and shortly following ALL therapy, we performed multivariable logistic regression analyses. The dependent variables were: one or more symptomatic fractures from ALL diagnosis to 12 months following treatment cessation and low LS BMD at cessation of treatment. In addition, because of homogeneity in the intended glucocorticoid doses, we combined data from the DCOG-ALL9 and STOPP cohorts and performed multivariable pooled cohort analyses (meta-analysis). Potential associations between the six-month cumulative glucocorticoid dose and fractures that occurred in the first year of therapy, were explored. Furthermore, we assessed potential associations between the cumulative glucocorticoid dose at cessation of therapy, and the endpoints 'low LS BMD at therapy cessation' and 'fractures that occurred during treatment and within 12 months following treatment cessation'. Results The prediction model for low LS BMD at diagnosis included weight Z-scores (β = -0.70) and age (β = -0.10) at diagnosis. This model had an AUC of 0.71 (0.63 to 0.78) in the DCOG-ALL9 cohort, and resulted in correct identification of 71% of patients with low LS BMD at ALL diagnosis. Validation on the STOPP cohort showed an AUC of 0.74 (95% CI = 0.63 to 0.84). To calculate the probability of low LS BMD at ALL diagnosis for an individual patient, an online calculator is available at http://lsbmd-risk-calculator.azurewebsites.net/ We confirmed that low LS BMD at diagnosis is associated with LS BMD at treatment cessation (OR = 5.9; 95% CI = 3.2 to 10.9) and with symptomatic fractures (OR = 1.7; 95% CI = 1.3 to 2.4) that occurred from diagnosis until 12 months following treatment cessation. In pooled meta-analysis, lower LS BMD at diagnosis (OR = 1.6, 95% CI = 1.1 to 2.4) and six-month cumulative glucocorticoid dose (OR = 1.9, 95% CI = 1.1 to 3.3, for every gram increase) were associated with symptomatic fractures that occurred in the first year of therapy. Higher cumulative glucocorticoid dose at cessation of therapy (OR = 1.5, 95% CI = 1.2 to 2.0, for every gram increase), lower LS BMD Z-scores at diagnosis (OR = 7.9, 95% CI = 4.8 to 13.1) and higher age at diagnosis (OR = 1.6, 95% CI = 1.4 to 1.8), were associated with low LS BMD at cessation of therapy. Conclusion We developed and successfully validated a risk prediction model for low LSBMD at diagnosis in children aged 4-18 years with ALL. This is important because low LS BMD at diagnosis was strongly associated with bone fragility and fractures during and shortly following treatment for ALL. Our easy to use prediction model, can facilitate awareness and early identification of bone fragility in individual pediatric ALL patients, without performing DXA examination. Disclosures No relevant conflicts of interest to declare.

Time-Limited Venetoclax and Ibrutinib for Patients with Relapsed/Refractory Chronic Lymphocytic Leukemia (R/R CLL) Who Have Undetectable MRD - Primary Analysis from the Randomized Phase II Vision HO141 Trial

Background: For patients with Relapsed/Refractory Chronic Lymphocytic Leukemia (R/R CLL), targeted time-limited treatment options are warranted. Thus far, therapeutic options are based on a (one-size-fits-all) fixed treatment duration or treatment until progression independent of individualized responsiveness. Post-treatment minimal residual disease (MRD) predicts outcome for patients receiving venetoclax-based therapy. Aim: To evaluate Progression-Free Survival (PFS) for patients with R/R CLL 12 months after MRD guided treatment cessation of venetoclax + ibrutinib (V+I) treatment (arm B) with the option to reinitiate V+I based on MRD reappearance. Methods: Patients (BTK inhibitor naïve) received ibrutinib lead-in (420 mg daily) for two (28-day) cycles. Venetoclax ramp-up was initiated during cycle 3, reaching 400 mg daily at cycle 4 with continued V+I during cycle 4-15. Patients reaching at least partial remission (PR) and undetectable (u)MRD (<10 -4) in blood (PB) and bone marrow (BM, by central 8-color flow cytometry) at cycle 15 day 15 were randomized 1:2 between ibrutinib maintenance (arm A) or treatment cessation (arm B). Patients later becoming MRD positive (>10 -2) in arm B reinitiated V+I. MRD positive patients at cycle 15 remained on ibrutinib until progression. Results: 225 patients were enrolled: median age 68 years (range 36-87), median CIRS score 2 (range 0-12), Binet stage B/C 84%, IGHV unmutated: 64%, TP53 aberrations (deletions and/or mutations): 24%. Planned treatment until randomization was completed by 194 (86%) patients, 8 patients went off protocol due to toxicity, 5 (2%) patients died during the first two cycles of ibrutinib lead-in (unknown cause, myocardial infarction, intracranial hemorrhage, Richter's transformation and tick-borne viral encephalitis), 15 patients went off protocol due to refusal to continue or other reasons and 3 patients progressed. At cycle 15, 81 (36%) patients achieved uMRD in both PB (112, 50%) and BM (84, 37%) and overall responses were 86%, of which 145 pts (64%) CR(i). Patients with uMRD were randomized to ibrutinib maintenance arm A (n 24 11%) or observation arm B (n 48 21%). Patients who did not achieve uMRD (n 125, 56%) continued ibrutinib maintenance without randomization while 5 patients went off protocol. The primary endpoint of the trial was met; PFS was achieved for 47 (98%) of 48 patients randomized to observation arm B at 12 months after randomization (27 months after starting therapy). One patient died during observation due to myelodysplastic syndrome and 1 patient, without sign of progression, reinitiated per protocol due to MRD positivity. A similar proportion of uMRD patients randomized to ibrutinib maintenance (arm A) or observation (arm B) remained uMRD after 12 months (month 27 after treatment start); 75% and 71%, respectively; see figure. No difference in blood uMRD at cycle 15 was seen neither between TP53 aberrated/wildtype (uMRD: 46%, 52%) nor between IGHV unmutated/mutated patients (uMRD: 50%, 50%). The most frequent adverse event (AE, only grade ≥2) was infections with 68 (30%) grade 2 and 62 (28%) grade ≥3 during the first 15 cycles, while 14 (58%) and 6 (12%) infections appeared after randomization in the treatment arm A and observation arm B, respectively. Atrial fibrillation was reported for 29 (13%) patients during the first 15 cycles, for 4 (3%) during ibrutinib maintenance (arm A + non-randomized) while no patients were reported with atrial fibrillation in arm B. Hypertension was reported for 23 (10%) patients during the first 15 cycles and for 10 (7%) patients during ibrutinib maintenance while no events were reported in arm B. One fatal bleeding event was reported in addition to 32 (14%) grade 2-3 bleeding events during the first 15 cycles; 12 (9%) grade 2-3 bleeding events were reported during ibrutinib maintenance, while no events were reported in arm B. Laboratory tumor lysis grades 2-3 was reported for 11 (5%) of patients. Conclusion: MRD guided time-limited treatment with ibrutinib and venetoclax in the setting of R/R CLL is feasible and demonstrates a favorable benefit-risk profile. No new safety signals were detected. No patients progressed after treatment cessation while patients becoming MRD positive successfully reinitiated therapy, thus proving MRD-guided cessation and reinitiation of targeted therapy feasible in CLL. Figure 1 Figure 1. Disclosures Niemann: CSL Behring, Genmab, Takeda, Octapharma: Consultancy; Abbvie, AstraZeneca, Janssen: Consultancy, Research Funding; Novo Nordisk Foundation: Research Funding. Dubois: Abbvie: Research Funding; Genentech: Research Funding; Roche: Research Funding. Brieghel: AstraZeneca: Consultancy. Kersting: Cellgene: Other: travel grant. Enggaard: Abbvie: Consultancy; Janssen: Consultancy. Mellink: Financial support related to microarray analysis of Murano samples: Research Funding; Genome Diagnostics Laboratory, AUMC: Current Employment; Cytogenetic Field: Consultancy. Poulsen: Janssen: Consultancy; Abbvie: Consultancy. Frederiksen: Abbvie: Research Funding; Janssen Pharmaceuticals: Research Funding; Gilead: Research Funding; Alexion: Research Funding; Novartis: Research Funding. Janssens: Sanofi: Consultancy; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Abbvie, Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Trael Grant, Speakers Bureau; Beigene, AstraZeneca: Consultancy, Speakers Bureau. Mattsson: Gilead: Research Funding. Bellido: Janssen: Other: educational funding. Tran: Novartis, Janssen, Abbvie, Takeda, CSL Bering: Consultancy; Astra Zeneca: Consultancy. Levin: Roche, Janssen, Abbvie: Other: Travel Expenses, Ad-Board. Kater: Genmab, LAVA: Other: Ad Board, Steering Committee; BMS, Roche/Genentech: Other: Ad Board, , Research Funding; Janssen, AstraZeneca: Other: Ad Board, steering committee, Research Funding; Abbvie: Honoraria, Other: Ad Board, Research Funding. OffLabel Disclosure: The combination of ibrutinib and venetoclax is not registered for treatment of CLL, both drugs are separately registered for treatment of CLL

The Contribution of Physiological and Accelerated Aging to Cancer Progression Through Senescence-Induced Inflammation

Senescent cells are found to accumulate in aged individuals, as well as in cancer patients that receive chemotherapeutic treatment. Although originally believed to halt cancer progression due to their characteristic growth arrest, senescent cells remain metabolically active and secrete a combination of inflammatory agents, growth factors and proteases, collectively known as the senescence-associated secretory phenotype (SASP). In this review, we discuss the contribution of senescent cells to cancer progression through their ability to alter cancer cells’ properties and to generate a microenvironment that promotes tumor growth. Furthermore, recent evidence suggests that senescent cells are able resume proliferation and drive cancer relapse, pointing to the use of senolytics and SASP modulators as a potential approach to prevent tumor resurgence following treatment cessation. Thus, a better understanding of the hallmarks of senescence and the impact of the SASP will allow the development of improved targeted therapeutic strategies to leverage vulnerabilities associated with this cellular state.

Anti-drug antibodies to antibody-based therapeutics in multiple sclerosis

Multiple sclerosis is the major demyelinating autoimmune disease of the central nervous system. Relapsing MS can be treated by a number of approved monoclonal antibodies that currently target: CD20, CD25 (withdrawn), CD49d and CD52. These all target potentially pathogenic memory B cell subsets and perhaps functionally inhibit pathogenic T cell function. These consist of chimeric, humanized and fully human antibodies. However, despite humanization it is evident that all of these monoclonal antibodies can induce binding and neutralizing antibodies ranging from < 1% to over 80% within a year of treatment. Importantly, it is evident that monitoring these allow prediction of future treatment-failure in some individuals and treatment cessation and switching therefore potentially limiting disease breakthrough and disability accumulation. In response to the COVID-19 pandemic and the need to avoid hospitals, shortened infusion times and extended dose intervals have been implemented, importantly, subcutaneous delivery of alternative treatments or formulations have been developed to allow for home treatment. Therefore, hospital-based and remote monitoring of ADA could therefore be advantageous to optimize patient responses in the future.

Flupentixol/melitracen for chronic refractory cough after treatment failure with other neuromodulators

BACKGROUND: Gabapentin and baclofen are recommended for the treatment of chronic refractory cough (CRC). We investigated the efficacy of flupentixol/melitracen in patients unresponsive to these neuromodulators.METHODS: A total of 101 patients with CRC who failed to respond to gabapentin and baclofen were recruited, and treated with flupentixol/melitracen. The prevalence of cough resolution and changes in the Cough Symptom Score (CSS), cough thresholds to capsaicin, Hull Airway Reflux Questionnaire (HARQ), Leicester Cough Questionnaire (LCQ), Generalized Anxiety Disorder-7, Hamilton Anxiety Rating Scale, Patient Health Questionnaire-9, and Hamilton Depression Rating Scale-24 were evaluated after treatment.RESULTS: Ninety-eight patients (97.0%) completed the study. The overall successful cough resolution rate was 62.4% (63/101). Cough resolution was accompanied by an obvious decrease in the CSS and HARQ score and a remarkable increase in cough thresholds to capsaicin challenge and LCQ score, whereas anxiety and depression scores did not change significantly. The prevalence of adverse effects (e.g., insomnia and dizziness) was 21.8%. The prevalence of cough recurrence within 2 weeks after treatment cessation was 17.8%.CONCLUSION: Flupentixol/melitracen may be an efficacious option for CRC unresponsive to other neuromodulators.

Is It Really Safe to Discontinue Anticoagulant/antiplatelet Treatment Before Ptosis Surgery From Serious Bleeding?

PurposeTo evaluate the effects of discontinuing anticoagulants(ACs)/antiplatelets(APs) preoperatively on surgery for blepharoptosisMethodA retrospective analysis included patients with acquired blepharoptosis who underwent surgical correction, and were followed for more than one month. Patients were classified into two groups depending on AC/AP treatment or otherwise. All patients taking AC/AP discontinued with the treatment one week prior to surgery in accordance with our clinical guidelines. Preoperative and postoperative marginal reflex distance 1(MRD1) and ecchymosis grade were evaluated and compared.ResultsGroup 1 (AC/AP treatment cessation) included 47 patients with 93 eyelids, and group 2 (control) included 51 patients with 98 eyelids. The preoperative MRD1 showed no significant difference between groups. Group 1 showed a significantly higher rate of severe ecchymosis (41.8 vs. 22.4%, p = 0.004) at 1 week of surgery as well as 'persistent ecchymosis (58.8 vs. 7.3%, p=0.000) compared with group 2 postoperatively at 1 month. Postoperative MRD1 was significantly lower in group 1 at 1 week (p=0.019). However, the MRD1 and degree of improvement in lid height (postoperative MRD1–preoperative MRD1) was not significantly different between the two groups (p = 0.499, p = 0.058) at 1 month postoperatively.ConclusionPostoperative ecchymosis was more severe in group 1 at one month after ptosis surgery even though the ACs/APs were discontinued. Surgeons should be careful about this before operation.