Relative Treatment Effects Research Articles

Neoadjuvant immunotherapy and chemotherapy regimens for the treatment of high-risk, early-stage triple-negative breast cancer: a systematic review and network meta-analysis

BackgroundPatients with triple-negative breast cancer (TNBC) are generally younger and more likely to experience disease recurrence and have the shortest survival among all breast cancer patients. Recently, neoadjuvant delivery of the programmed cell death protein-1 inhibitor pembrolizumab plus chemotherapy followed by adjuvant pembrolizumab was approved for patients with high-risk, early-stage TNBC, but this treatment regimen has not been evaluated in head-to-head trials with other neoadjuvant treatment regimens. Therefore, the objective of this study was to estimate the relative efficacy of neoadjuvant pembrolizumab + chemotherapy followed by adjuvant pembrolizumab versus other neoadjuvant treatments for early-stage TNBC through a systematic review and network meta-analysis (NMA).MethodsEMBASE, MEDLINE, Cochrane Central Register of Controlled Trials, conference abstracts, and clinical trial registries were searched for randomized controlled trials evaluating neoadjuvant treatments for early-stage TNBC. NMA was performed to estimate relative treatment effects among evaluated interventions.ResultsFive trials met the inclusion criteria and were included in the NMA. The relative efficacy of neoadjuvant pembrolizumab + chemotherapy followed by adjuvant pembrolizumab was favorable to paclitaxel followed by anthracycline + cyclophosphamide in terms of pathologic complete response (pCR), event-free survival (EFS), and overall survival; paclitaxel + carboplatin followed by anthracycline + cyclophosphamide in terms of pCR and EFS; paclitaxel + bevacizumab followed by anthracycline + cyclophosphamide + bevacizumab in terms of pCR; and paclitaxel + carboplatin + veliparib followed by anthracycline + cyclophosphamide in terms of EFS.ConclusionsNeoadjuvant pembrolizumab + chemotherapy followed by adjuvant pembrolizumab confers benefits in response and survival outcomes versus alternative neoadjuvant treatments for early-stage TNBC.

Sex-Specific Effects of Blood Pressure Lowering Pharmacotherapy for the Prevention of Cardiovascular Disease: An Individual Participant-Level Data Meta-Analysis.

Whether the relative effects of blood pressure (BP)-lowering treatment on cardiovascular outcomes differ by sex, particularly when BP is not substantially elevated, has been uncertain. We conducted an individual participant-level data meta-analysis of randomized controlled trials of pharmacological BP lowering. We pooled the data and categorized participants by sex, systolic BP categories in 10-mm Hg increments from <120 to ≥170 mm Hg, and age categories spanning from <55 to ≥85 years. We used fixed-effect one-stage individual participant-level data meta-analyses and applied Cox proportional hazard models, stratified by trial, to analyze the data. We included data from 51 randomized controlled trials involving 358 636 (42% women) participants. Over 4.2 years of median follow-up, a 5-mm Hg reduction in systolic BP decreased the risk of major cardiovascular events both in women and men (hazard ratio [95% CI], 0.92 [0.89-0.95] for women and 0.90 [0.88-0.93] for men; P for interaction, 1). There was no evidence for heterogeneity of relative treatment effects by sex for the major cardiovascular disease, its components, or across the different baseline BP categories (all P for interaction, ≥0.57). The effects in women and men were consistent across age categories and the types of antihypertensive medications (all P for interaction, ≥0.14). The effects of BP reduction were similar in women and men across all BP and age categories at randomization and with no evidence to suggest that drug classes had differing effects by sex. This study does not substantiate sex-based differences in BP-lowering treatment.

Comparative Effectiveness of Anticoagulants in Patients With Cancer-Associated Thrombosis

Patterns of clinical utilization and comparative effectiveness of anticoagulants for cancer-associated thrombosis (CAT) remain largely unexplored. To assess patterns of and factors associated with anticoagulant use and to evaluate the comparative effectiveness of contemporary anticoagulants in patients with active cancer in a clinical setting. This retrospective cohort study obtained deidentified OptumLabs electronic health record claims data from January 1, 2012, to September 30, 2019. Adult patients (≥18 years of age) with a primary cancer diagnosis (except skin cancer) during at least 1 inpatient or 2 outpatient visits within 6 months before the venous thromboembolism (VTE) date were included. Data were analyzed from April 2020 to September 2021. The patients were grouped according to the anticoagulant prescribed: (1) direct oral anticoagulants (DOACs), (2) low-molecular-weight heparin (LMWH), and (3) warfarin. Odds ratios (ORs) were used to present the association between factors of interest and utilization of anticoagulants. Main efficacy outcomes included risk of VTE recurrence and all-cause mortality. Main safety outcomes included the risk of hospitalization due to major bleeding. Relative treatment effect estimates were expressed as hazard ratios (HRs) with 95% CIs. This study included 5100 patients (mean [SD] age, 66.3 [12.3] years; 2670 [52.4%] women; 799 [15.7%] Black, 389 [7.6%] Hispanic, and 3559 [69.8%] White individuals). Overall, 2512 (49.3%), 1488 (29.2%), and 1460 (28.6%) filled prescriptions for DOACs, LMWH, and warfarin, respectively. The median (IQR) treatment duration was 3.2 (1.0-6.5) months for DOACs, 3.1 (1.0-6.8) months for warfarin, and 1.8 (0.9-3.8) months for LWMH. Patients with lung (OR, 2.07; 95% CI, 1.12-3.65), urological (OR, 1.94; 95% CI,1.08-3.49), gynecological (OR, 4.25; 95% CI, 2.31-7.82), and colorectal (OR, 2.26; 95% CI, 1.20-4.32) cancer were associated with increased prescriptions for LMWH compared with DOACs. LMWH (HR, 1.47; 95% CI, 1.14-1.90) and warfarin (HR, 1.46; 95% CI, 1.13-1.87) were associated with an increased risk of VTE recurrences compared with DOACs. LMWH was associated with an increased risk of major bleeding (HR, 2.27; 95% CI, 1.62-3.20) and higher all-cause mortality (HR, 1.61; 95% CI, 1.15-2.25) compared with DOACs. In this comparative effectiveness study of claims-based data, patients with CAT received anticoagulation for a remarkably short duration in clinical settings. DOACs was associated with a lower risk of VTE recurrence, major bleeding, and mortality. Warfarin may still be considered for patients with contraindications to DOACs and those with poor persistence on LMWH.

Effect of Dietary Approaches on Glycemic Control in Patients with Type 2 Diabetes: A Systematic Review with Network Meta-Analysis of Randomized Trials.

Dietary patterns play a critical role in diabetes management, while the best dietary pattern for Type 2 diabetes (T2DM) patients is still unclear. The aim of this network meta-analysis was to compare the impacts of various dietary approaches on the glycemic control of T2DM patients. Relevant studies were retrieved from PubMed, Embase, Web of Knowledge, Cochrane Central Register of Controlled Trials (CENTRAL), and other additional records (1949 to 31 July 2022). Eligible RCTs were those comparing different dietary approaches against each other or a control diet in individuals with T2DM for at least 6 months. We assessed the risk of bias of included studies with the Cochrane risk of bias tool and confidence of estimates with the Grading of Recommendations Assessment, Development, and Evaluation approach for network meta-analyses. In order to determine the pooled effect of each dietary approach relative to each other, we performed a network meta-analysis (NMA) for interventions for both HbA1c and fasting glucose, which enabled us to estimate the relative intervention effects by combing both direct and indirect trial evidence. Forty-two RCTs comprising 4809 patients with T2DM were included in the NMA, comparing 10 dietary approaches (low-carbohydrate, moderate-carbohydrate, ketogenic, low-fat, high-protein, Mediterranean, Vegetarian/Vegan, low glycemic index, recommended, and control diets). In total, 83.3% of the studies were at a lower risk of bias or had some concerns. Findings of the NMA revealed that the ketogenic, low-carbohydrate, and low-fat diets were significantly effective in reducing HbA1c (viz., -0.73 (-1.19, -0.28), -0.69 (-1.32, -0.06), and -1.82 (-2.93, -0.71)), while moderate-carbohydrate, low glycemic index, Mediterranean, high-protein, and low-fat diets were significantly effective in reducing fasting glucose (viz., -1.30 (-1.92, -0.67), -1.26 (-2.26, -0.27), -0.95 (-1.51, -0.38), -0.89 (-1.60, -0.18) and -0.75 (-1.24, -0.27)) compared to a control diet. The clustered ranking plot for combined outcomes indicated the ketogenic, Mediterranean, moderate-carbohydrate, and low glycemic index diets had promising effects for controlling HbA1c and fasting glucose. The univariate meta-regressions showed that the mean reductions of HbA1c and fasting glucose were only significantly related to the mean weight change of the subjects. For glycemic control in T2DM patients, the ketogenic diet, Mediterranean diet, moderate-carbohydrate diet, and low glycemic index diet were effective options. Although this study found the ketogenic diet superior, further high-quality and long-term studies are needed to strengthen its credibility.

Individual lifetime benefit from low-dose colchicine in patients with chronic coronary artery disease.

Low-dose colchicine reduces cardiovascular risk in patients with coronary artery disease (CAD), but absolute benefits may vary between individuals. This study aimed to assess the range of individual absolute benefits from low-dose colchicine according to patient risk profile. The European Society of Cardiology (ESC) guideline-recommended SMART-REACH model was combined with the relative treatment effect of low-dose colchicine and applied to patients with CAD from the Low-Dose Colchicine 2 (LoDoCo2) trial and the Utrecht Cardiovascular Cohort-Second Manifestations of ARTerial disease (UCC-SMART) study (n = 10 830). Individual treatment benefits were expressed as 10-year absolute risk reductions (ARRs) for myocardial infarction, stroke, or cardiovascular death (MACE), and MACE-free life-years gained. Predictions were also performed for MACE plus coronary revascularization (MACE+), using a new lifetime model derived in the REduction of Atherothrombosis for Continued Health (REACH) registry. Colchicine was compared with other ESC guideline-recommended intensified (Step 2) prevention strategies, i.e. LDL cholesterol (LDL-c) reduction to 1.4 mmol/L and systolic blood pressure (SBP) reduction to 130 mmHg. The generalizability to other populations was assessed in patients with CAD from REACH North America and Western Europe (n = 25 812). The median 10-year ARR from low-dose colchicine was 4.6% [interquartile range (IQR) 3.6-6.0%] for MACE and 8.6% (IQR 7.6-9.8%) for MACE+. Lifetime benefit was 2.0 (IQR 1.6-2.5) MACE-free years, and 3.4 (IQR 2.6-4.2) MACE+-free life-years gained. For LDL-c and SBP reduction, respectively, the median 10-year ARR for MACE was 3.0% (IQR 1.5-5.1%) and 1.7% (IQR 0.0-5.7%), and the lifetime benefit was 1.2 (IQR 0.6-2.1) and 0.7 (IQR 0.0-2.3) MACE-free life-years gained. Similar results were obtained for MACE+ and in American and European patients from REACH. The absolute benefits of low-dose colchicine vary between individual patients with chronic CAD. They may be expected to be of at least similar magnitude to those of intensified LDL-c and SBP reduction in a majority of patients already on conventional lipid-lowering and blood pressure-lowering therapy.

006 Comparison of alitretinoin vs. psoralen plus ultraviolet A as first-line treatments for chronic severe hand eczema: results from the ALPHA trial

Abstract Severe chronic hand eczema resistant to topical corticosteroid treatment is an important cause of morbidity and occupational disability. There is uncertainty regarding the best treatment approach and currently no treatment pathway is generally accepted by UK dermatologists. The primary aim of the ALPHA trial was to compare alitretinoin and immersion psoralen plus ultraviolet A (PUVA) as a first-line therapy in terms of disease activity at 12 weeks after the planned start of treatment. We conducted a prospective, multicentre, open-label, two-arm parallel group, adaptive randomized controlled trial. The natural logarithm of the Hand Eczema Severity Index (HECSI) + 1 at 12 weeks after the planned start of treatment was chosen as the primary endpoint so the relative effect of treatment could be estimated. In total, 514 participants were required to detect a fold change of 1.3 (5% two-sided significance level, 80% power, 20% attrition). Participants were randomized 1 : 1 by minimization to alitretinoin or immersion PUVA for 12–24 weeks. The intention-to-treat population consisted of 441 participants: 220 (49.9%) allocated to alitretinoin and 221 (50.1%) to immersion PUVA. In total, 212 (96.4%) alitretinoin participants and 196 (88.7%) immersion PUVA participants received at least one dose. There was a statistically significant benefit of alitretinoin compared with immersion PUVA at 12 weeks, with an estimated fold change of 0.66 [95% confidence interval (CI) 0.52–0.82; P &amp;lt; 0.001]. There was no evidence of a difference at 24 or 52 weeks. Of those allocated to alitretinoin and immersion PUVA, 59% and 61%, respectively, were observed to achieve a clear/almost clear assessment during the trial period. Alitretinoin was more cost-effective than immersion PUVA. Limitations include differences in treatment compliance and differential missing data levels. In total, 145 (65.9%) alitretinoin participants and 53 (24.0%) immersion PUVA participants were observed to comply (≥ 80% received and no treatment breaks of &amp;gt; 7 days during first 12 weeks). Thus, twice-weekly attendance for PUVA was not received by most participants. However, this represents standard of care with ALPHA run as a pragmatic trial using standard-of-care settings for the interventions. A further limitation was that assessment of long-term effects of randomized treatments was complicated by permitted use of second-line treatments after the treatment phase; therefore, trial conclusions are for randomized treatments as first-line therapies. We conclude that, as a first-line therapy, patients on alitretinoin showed more rapid improvement and superiority than those treated with immersion PUVA at week 12, but this difference was not observed at later time points. Future studies will need to further address the long-term benefits of treatments given and complex treatment pathways.

A Bayesian Adaptive Umbrella Trial Design with Robust Information Borrowing for Screening Multiple Combination Therapies

In immuno-oncology, developing combination therapies to overcome resistance to single agent or induce synergistic effects has become a new focus. To accelerate the screening process to identify promising combinations based on objective response rates, we propose a Bayesian adaptive Umbrella Trial design to simultaneously evaluate combinations of an investigational compound with different backbones, where information borrowing across combinations is allowed to increase trial efficiency. A robust borrowing approach is developed to strike a balance between borrowing and not borrowing by accounting for different configurations of homogeneity of treatment effects using Bayesian model averaging. Unlike existing methods that use the response rates to measure the degree of homogeneity by assuming all arms share a common control rate, an advantage of our approach is that it uses relative treatment effects to determine the degree of homogeneity by adjusting for different control effects across combinations. In the proposed design, Bayesian adaptive interim analyses are implemented to drop futile combinations and graduate early efficacious combinations. Simulation studies demonstrate that the proposed design with robust information borrowing outperforms some existing approaches. It improves power when treatment effects are homogeneous and maintains reasonable arm-wise Type I error rates when heterogeneity is present across combinations.

790-P: An Indirect Treatment Comparison of the Cardiovascular Protective Effect of Semaglutide vs. Liraglutide in Subjects with Type 2 Diabetes

Background: In the absence of head-to-head evidence, an indirect treatment comparison (ITC) using individual-level participant data was conducted to provide evidence of the comparative cardiovascular (CV) protective effect of liraglutide vs semaglutide in subjects with type 2 diabetes. Methods: CV outcomes trials (CVOTs) were identified for comparators of interest. LEADER was a randomised controlled trial studying the CV protective effect of liraglutide vs placebo. Similarly, two CVOTs comparing semaglutide with placebo were identified: SUSTAIN 6 and PIONEER 6. Time to first 3-point major adverse CV events (3P-MACE) (adjudicated) was the primary outcome in all trials and was chosen as the primary outcome for the ITC. Potential effect modifiers (baseline indicators of prior CV disease, albumin:creatinine ratio, estimated glomerular filtration rate) were identified in the literature and adjusted for in the ITC. A fixed-effects ITC using individual participant data was conducted in a Bayesian setting. Missing data for potential effect modifiers were imputed using multiple imputation (20 imputations). Comparisons were summarised as cause-specific hazard ratios (HRs). Population-average relative treatment effects between liraglutide and semaglutide were reported for each of the three populations corresponding to the three studies. Results: The ITC showed that the relative risk of semaglutide vs liraglutide for the occurrence of 3P-MACE in the LEADER population favoured semaglutide: HR 0.73 (95% credible interval [CrI]: 0.56;0.94); results also favoured semaglutide in the SUSTAIN 6 (HR 0.76 [95% CrI: 0.59;0.97]) and PIONEER 6 (HR 0.78 [95% CrI: 0.60;1.00]) populations. Conclusion: The results demonstrated a risk reduction of CV events (3P-MACE) for semaglutide vs liraglutide of 22-27% depending on the population studied. These results may have implications for clinical practice. Disclosure B.Chubb: Employee; Novo Nordisk A/S, Stock/Shareholder; Novo Nordisk A/S. M.Bøg: Employee; Lundbeck, Novo Nordisk.

An optimal sequential design in ethical allocation with an adaptive interim analysis

The present article provides a distribution-free test procedure for comparing the effectiveness of two competing treatments A and B, say, in a clinical trial. Here, the relative treatment effect is measured by the functional θ = P ( X < Y ) , where X and Y are respectively the response variables corresponding to two treatments, A and B. The treatment comparison is done through a testing of hypothesis regarding θ under a patient-benefit oriented two-stage response-adaptive design with an interim analysis in which an optimal sequential sampling scheme with equal randomisation is adopted in stage 1 and a response-adaptive randomisation is employed in stage 2 with the objective of allocating more patients to more promising treatment. The performance of the proposed procedure is compared with that of various other competitive procedures.

Multi-state network meta-analysis of progression and survival data.

Multiple randomized controlled trials, each comparing a subset of competing interventions, can be synthesized by means of a network meta-analysis to estimate relative treatment effects between all interventions in the evidence base. Here we focus on estimating relative treatment effects for time-to-event outcomes. Cancer treatment effectiveness is frequently quantified by analyzing overall survival (OS) and progression-free survival (PFS). We introduce a method for the joint network meta-analysis of PFS and OS that is based on a time-inhomogeneous tri-state (stable, progression, and death) Markov model where time-varying transition rates and relative treatment effects are modeled with parametric survival functions or fractional polynomials. The data needed to run these analyses can be extracted directly from published survival curves. We demonstrate use by applying the methodology to a network of trials for the treatment of non-small-cell lung cancer. The proposed approach allows the joint synthesis of OS and PFS, relaxes the proportional hazards assumption, extends to a network of more than two treatments, and simplifies the parameterization of decision and cost-effectiveness analyses.

Comparative effectiveness of psychological interventions for treating the psychological consequences of sexual abuse in children and adolescents: a network meta-analysis.

Comparative effectiveness of psychological interventions for treating the psychological consequences of sexual abuse in children and adolescents: a network meta-analysis.

Reliability of major bleeding events in UK routine data versus clinical trial adjudicated follow-up data

ObjectiveTo assess how reliable UK routine data are for ascertaining major bleeding events compared with adjudicated follow-up.MethodsThe ASCEND (A Study of Cardiovascular Events iN Diabetes) primary prevention trial randomised 15...

Comparative efficacy of zanubrutinib (ZANU) versus rituximab (RTX) in relapsed marginal zone lymphoma (MZL): Matching-adjusted indirect comparison (MAIC).

e19526 Background: ZANU is a Bruton tyrosine kinase inhibitor that has been evaluated for relapsed/refractory MZL in two phase 2, single-arm (MAGNOLIA, n=66, NCT03846427; BGB-3111-AU-003, n=20, NCT02343120). At 28 and 35 months of study follow-up in MAGNOLIA and BGB-3111-AU-003, respectively, median progression-free survival (PFS) and overall survival (OS) were not reached. Here, we conducted an unanchored MAIC to estimate relative treatment effects of ZANU vs RTX, a commonly used treatment for patients with relapsed MZL. Note the comparison was restricted to the relapsed population because RTX refractory patients would not be retreated with RTX. Methods: The MAIC was performed using pooled individual patient-level data from MAGNOLIA and BGB-3111-AU-003. Study level-data of RTX in relapsed patients were used from CHRONOS-3 (Özcan et al., Ann Oncol 2021) which was identified as the most suitable comparator study via a systematic literature review. A logistic propensity score model was used to estimate weights for patients in ZANU trials such that their weighted mean baseline characteristics matched those of CHRONOS-3. The following characteristics were identified as key prognostic factors and included in the base case propensity score model: prior lines of therapy, MZL subtype, relapse after prior therapy, and age. Sensitivity analyses incorporating additional characteristics were not possible owing to a lack of reporting from CHRONOS-3, but the impact of each covariate in the base model was explored via a leave-one-out analysis. Comparisons were conducted for OS, PFS, and objective response rate (ORR) by independent review committee using weighted statistical models, with relative treatment effects presented as hazard ratios (HRs), odds ratios (ORs), and 95% CIs. Results: After applying weights estimated from the base case propensity score model, the effective sample size (ESS) for ZANU was 39. ZANU reduced the risk of progression (HR 0.29; 95% CI 0.13–0.65) and had a higher probability of response (OR 5.09; 95% CI: 1.84–14.08) when compared with RTX (Table). OS was comparable for ZANU and RTX, which is consistent with the survival expectancy for indolent lymphomas. The leave-one-out analysis showed that removing any of the characteristics from the propensity score model yielded comparable results. Conclusions: MAIC results suggest ZANU is associated with improved PFS and ORR compared with RTX in relapsed MZL. [Table: see text]

A matching-adjusted indirect treatment comparison of elranatamab in patients with triple-class exposed relapsed/refractory multiple myeloma: Comparisons with belantamab mafodotin, selinexor plus dexamethasone, and real-world physician’s choice of treatment.

e20038 Background: Elranatamab, a bispecific antibody targeting B-cell maturation antigen on multiple myeloma (MM) cells and CD3 on T cells, is being evaluated as a monotherapy in the MagnetisMM-3 trial (MM3; NCT04649359) in patients with triple-class exposed (TCE) relapsed/refractory MM. While there is no standard of care for TCE MM, belantamab mafodotin (belamaf) and selinexor plus dexamethasone (sel-dex) are treatment options. LocoMMotion is a prospective, non-interventional study investigating real-world physician’s choice of treatment (PCT) in patients with TCE MM. In the absence of head-to-head trials, unanchored matching-adjusted indirect comparisons (MAIC) were conducted to compare the relative efficacy across comparators. Methods: Individual patient-level data were obtained for elranatamab from MM-3 (data cut Oct 2022). Aggregated data for belamaf, sel-dex, and PCT were obtained from DREAMM-2 (NCT03525678), STORM (NCT02336815), and LocoMMotion (NCT04035226). Unanchored MAICs were conducted to compare the relative treatment effect on objective response rate (ORR) accounting for potential different distributions of prognostic variables (PVs) and effect modifiers (EMs). In the base case, PVs identified via logistic regressions based on MM-3 data were adjusted. In sensitivity analyses, PVs/EMs identified from the literature were added. Relative treatment effects were measured by rate differences and odds ratios. Results: After MAIC adjustments, the selected PVs/EMs were balanced in each comparison. The table presents the results from the naïve comparison with no MAIC adjustment plus the MAIC base case. The ORR of elranatamab was statistically higher than belamaf, sel-dex, and PCT in LocoMMotion. Results were consistent across all sensitivity analyses. Conclusions: Elranatamab had a significantly higher ORR than belamaf, sel-dex, and real-world PCT in LocoMMotion for patients with TCE MM, demonstrating its clear clinical benefit for this population. [Table: see text]

Matching‐adjusted indirect comparison (MAIC) of zanubrutinib (ZANU) versus ibrutinib (IBRU) in relapsed/refractory marginal zone lymphoma (R/R MZL)

Introduction: ZANU is a Bruton tyrosine kinase inhibitor (BTKi) that has been evaluated for the treatment of R/R MZL in two phase 2, single-arm trials (MAGNOLIA, n = 66, NCT03846427; BGB-3111-AU-003, n = 20, NCT02343120). At 28 and 35 months of study follow-up in MAGNOLIA and BGB-3111-AU-003, respectively, median progression-free survival (PFS) and overall survival (OS) were not reached. IBRU, a first-generation BTKi, has also been evaluated for R/R MZL in a phase 2, single-arm trial (PCYC-1121, n = 60 [Noy et al. Blood 2017; Noy et al. Blood Adv 2020]). Here, we conducted an unanchored MAIC to estimate the comparative efficacy of ZANU versus IBRU in R/R MZL. Methods: The MAIC utilized study-level data from PCYC-1121 and pooled individual patient-level data from MAGNOLIA and BGB-3111-AU-003. A logistic propensity score model (PSM) was used to estimate weights for patients in the ZANU trials so that weighted mean baseline characteristics matched those in PCYC-1121. Number of prior lines of therapy, MZL subtype, response to prior therapy, and age were identified as key prognostic factors and included in the base case PSM. A sensitivity analysis was conducted including additional characteristics (B symptoms, time since last therapy, prior anti-CD20 therapy, bulky disease [>5 cm], and lactate dehydrogenase above normal). Comparisons were conducted for OS, PFS, and objective response rate (ORR) by independent review committee using weighted statistical models with relative treatment effects presented as hazard ratios (HRs), odds ratios (ORs), and 95% confidence intervals (CIs). Results: After applying weights estimated from the base case PSM, the effective sample size (ESS) for ZANU was 68 (Table). Compared with IBRU, ZANU significantly reduced the risk of progression (HR 0.38; 95% CI: 0.21, 0.69; p = 0.001) and was associated with a higher ORR (OR 2.37; 95% CI: 1.13, 4.96; p = 0.022). OS was comparable for ZANU and IBRU, which is consistent with expected survival for indolent lymphomas. The sensitivity analysis accounting for additional prognostic factors suggested the 2 treatments were comparable across all outcomes, owing in part to the low ESS (24) for ZANU associated with the expanded model. A leave-one-out analysis showed improved PFS (HR 0.33–0.45) for ZANU when excluding B symptoms, time since last therapy, or bulky disease from the expanded model. Conclusions: This MAIC demonstrated ORR and PFS benefits for ZANU versus IBRU in R/R MZL. Encore Abstract - previously submitted to ASCO 2023 and EHA 2023 The research was funded by: BeiGene Keywords: Indolent non-Hodgkin lymphoma, Molecular Targeted Therapies Conflicts of interests pertinent to the abstract. C. Thieblemont Honoraria: AbbVie, Bayer, Celgene, Gilead Sciences, Incyte, Janssen, Novartis, and Roche Research funding: Roche Educational grants: AbbVie, Janssen-Cilag, Kite/Gilead, Novartis, and Roche S. Keeping Employment or leadership position: PRECISIONheor Research funding: BeiGene I. Zhang Employment or leadership position: PRECISIONheor Research funding: BeiGene K. Yang Employment or leadership position: BeiGene Stock ownership: BeiGene Research funding: BeiGene Educational grants: BeiGene B. Tang Employment or leadership position: BeiGene Stock ownership: BeiGene Other remuneration: BeiGene L. Mohseninejad Employment or leadership position: BeiGene Consultant or advisory role: BeiGene Research funding: BeiGene

EFFICACY OF FRONT‐LINE IMMUNOCHEMOTHERAPY FOR TRANSPLANT‐INELIGIBLE MANTLE CELL LYMPHOMA: A NETWORK META‐ANALYSIS OF RANDOMIZED CONTROLLED TRIALS

Background: In the past 20 years, there have been significant advances in the prognosis of mantle cell lymphoma (MCL) patients because of the introduction of rituximab. However, there is still no cure, and the relapse is inevitable. The earlier MCL patients progress after the first-line therapy, the worse the prognosis, especially for those who progress within 6 months after first-line therapy. There is no standard first-line immunochemotherapy regimen for transplant-ineligible patients with MCL currently, and the efficacy of various treatment remains unclear. Methods: Network meta-analysis (NMA) can compare the relative treatment effects of multiple interventions by synthesizing evidence from a network of randomized controlled trials (RCTs), which can be very useful for the choice of clinical treatment plans. We conducted a Bayesian NMA of all eligible randomized controlled trials. Pairwise comparisons and ranking of different first-line treatment options were performed. Results: nine studies were included in the NMA, involving a total of 2,897 MCL patients. The BR-Ibrutinib+R regimen showed the best progression-free survival (PFS), with a surface under the cumulative ranking curve (SUCRA) of 0.89 (Figure 1a) and probability of being the best treatment (PbBT) of 69%, followed by the BR+R regimen (SUCRA 0.76, PbBT 11%) and the BVR regimen (SUCRA 0.64, PbBT 13%). The VR-CAP regimen was the most potential intervention to improve overall survival (OS), with a SUCRA of 0.89 (Figure 1b) and PbBT of 63%, followed by the BR regimen (SUCRA 0.74, PbBT 22%) and the R-CHOP regimen (SUCRA 0.65, PbBT 1%). Compared with the R-CHOP regimen, the BR regimen achieved a better PFS (hazard ratio [HR] 0.45 [95% credible interval 0.2–0.96]). The BR-Ibrutinib+R regimen (HR 0.14 [0.02–0.99]), BR+R regimen (HR 0.19 [0.034–0.99]), and BR regimen (HR 0.19 [0.08–1.03]) were superior to CHOP regimen with better PFS. The R-FC regimen (HR 2.27 [1.01–5.21]) or FC regimen (HR 3.17 [1.15–8.71]) was inferior to the VR-CAP regimen with a worse OS. The research was funded by: This work was supported by Achievement Transformation Project (No. CGZH21001), 1.3.5 Project for Disciplines of Excellence, West China Hospital, Sichuan University (No. ZYJC21007), Translational Research Grant of NCRCH (No. 2021WWB03), Chengdu Science and Technology Program (No. 2022-YF05-01443-SN, 2022-YF05-01444-SN), Key Research and Development Program of Sichuan Province (No. 2023YFS0031, 2023YFS0306), National Natural Science Foundation of China (No. 82204490), and National Key Research and Development Program of China (No. 2022YFC2502600, 2022YFC2502603). Keywords: Aggressive B-cell non-Hodgkin lymphoma, Chemotherapy, Immunotherapy No conflicts of interests pertinent to the abstract.

Matching-adjusted indirect comparison (MAIC) of zanubrutinib (ZANU) versus ibrutinib (IBRU) in relapsed/refractory marginal zone lymphoma (R/R MZL).

e19527 Background: ZANU is a Bruton tyrosine kinase inhibitor (BTKi) that has been evaluated for the treatment of R/R MZL in two phase 2, single-arm trials (MAGNOLIA, n=66, NCT03846427; BGB-3111-AU-003, n=20, NCT02343120). At 28 and 35 months of study follow-up in MAGNOLIA and BGB-3111-AU-003, respectively, median progression-free survival (PFS) and overall survival (OS) were not reached. IBRU, a first-generation BTKi, has also been evaluated for R/R MZL in a phase 2, single-arm trial (PCYC-1121, n=60 [Noy et al., Blood 2017; Noy et al., Blood Adv 2020]). Here, we conducted an unanchored MAIC to estimate the comparative efficacy of ZANU vs IBRU in R/R MZL. Methods: The MAIC utilized study-level data from PCYC-1121 and pooled individual patient-level data from MAGNOLIA and BGB-3111-AU-003. A logistic propensity score model was used to estimate weights for patients in the ZANU trials so that weighted mean baseline characteristics matched those in PCYC-1121. The following characteristics were identified as key prognostic factors and included in the base case propensity score model: number of prior lines of therapy, MZL subtype, response to prior therapy, and age. A sensitivity analysis was conducted including additional characteristics (B symptoms, time since last therapy, prior anti-CD20 therapy, bulky disease [&gt;5cm], and lactate dehydrogenase above normal). Comparisons were conducted for OS, PFS, and objective response rate (ORR) by independent review committee using weighted statistical models with relative treatment effects presented as hazard ratios (HRs), odds ratios (ORs), and 95% CIs. Results: After applying weights estimated from the base case propensity score model, the effective sample size (ESS) for ZANU was 68 (Table). Compared with IBRU, ZANU reduced the risk of progression (HR 0.38; 95% CI 0.21–0.69) and was associated with a higher ORR (OR 2.37; 95% CI: 1.13–4.96). OS was comparable for ZANU and IBRU, which is consistent with expectations for indolent lymphomas. The sensitivity analysis accounting for additional prognostic factors suggested the two treatments were comparable across all outcomes, owing in part to the low ESS (24) for ZANU associated with the expanded model. A leave-one-out analysis showed improved PFS (HR 0.33–0.45) for ZANU when excluding B symptoms, time since last therapy, or bulky disease from the expanded model. Conclusions: This MAIC demonstrated ORR and PFS benefits for ZANU vs IBRU in R/R MZL. [Table: see text]

Heterogeneity of Treatment Effects of Hydrocortisone by Risk of Bronchopulmonary Dysplasia or Death Among Extremely Preterm Infants in the National Institute of Child Health and Human Development Neonatal Research Network Trial

Extremely preterm infants who develop bronchopulmonary dysplasia (BPD) are at a higher risk for adverse pulmonary and neurodevelopmental outcomes. In the National Institute of Child Health and Human Development Neonatal Research Network (NICHD NRN) Hydrocortisone Trial, hydrocortisone neither reduced rates of BPD or death nor increased rates of neurodevelopmental impairment (NDI) or death. To determine whether estimated risk for grades 2 to 3 BPD or death is associated with the effect of hydrocortisone on the composite outcomes of (1) grades 2 to 3 BPD or death and (2) moderate or severe NDI or death. This secondary post hoc analysis used data from the NICHD NRN Hydrocortisone Trial, which was a double-masked, placebo-controlled, randomized clinical trial conducted in 19 US academic centers. The NICHD HRN Hydrocortisone Trial enrolled infants born at a gestational age of less than 30 weeks who received mechanical ventilation for at least 7 days, including at the time of enrollment, and who were aged 14 to 28 postnatal days. Infants were enrolled between August 22, 2011, and February 4, 2018, with follow-up between 22 and 26 months of corrected age completed on March 29, 2020. Data were analyzed from September 13, 2021, to March 25, 2023. Infants were randomized to 10 days of hydrocortisone or placebo treatment. Infants' baseline risk of grades 2 to 3 BPD or death was estimated using the NICHD Neonatal BPD Outcome Estimator. Differences in absolute and relative treatment effects by baseline risk were evaluated using interaction terms in models fitted to the efficacy outcome of grades 2 to 3 BPD or death and the safety outcome of moderate or severe NDI or death by follow-up. Among the 799 infants included in the analysis (421 boys [52.7%]), the mean (SD) gestational age was 24.9 (1.5) weeks, and the mean (SD) birth weight was 715 (167) g. The mean estimated baseline risk for grades 2 to 3 BPD or death was 54% (range, 18%-84%) in the study population. The interaction between treatment group and baseline risk was not statistically significant on a relative or absolute scale for grades 2 to 3 BPD or death; the size of the effect ranged from a relative risk of 1.13 (95% CI, 0.82-1.55) in quartile 1 to 0.94 (95% CI, 0.81-1.09) in quartile 4. Similarly, the interaction between treatment group and baseline risk was not significant on a relative or absolute scale for moderate or severe NDI or death; the size of the effect ranged from a relative risk of 1.04 (95% CI, 0.80-1.36) in quartile 1 to 0.99 (95% CI, 0.80-1.22) in quartile 4. In this secondary analysis of a randomized clinical trial, the effect of hydrocortisone vs placebo was not appreciably modified by baseline risk for grades 2 to 3 BPD or death. ClinicalTrials.gov Identifier: NCT01353313.

A comparison index in mortar repair treatments by microbiologically induced carbonate precipitation and its evaluation by a non-destructive technique

Cracks in cement-based materials are a common issue to be solved in construction and civil engineering. Although in the last 20 years microbiologically induced carbonate precipitation (MICP) has been investigated successfully to recover and improve the physical properties of cracked concrete, the assessment of the effectiveness of treatments is a very important challenge to solve. In this article, a non-destructive methodology is reported to monitor the progress of crack sealing and calcium carbonate (calcite) deposition during MICP. An ureolytic bacteria was applied to treat mortar specimens for 30 wk, in which the effectiveness of calcite precipitation was evaluated. For this, two-dimensional X-ray tomography was used to characterize the calcite filling progress, showing that the MICP treatment had a higher CaCO3 filling effect when compared to control. It was estimated that MICP activity allowed to fill mortar holes with CaCO3 by 18–27%, after 8 wk. As a comparison indicator during repair treatments of cement-based materials using microorganisms that perform MICP, a Relative Treatment Effect (RTE) index was proposed. It is concluded that X-ray tomography can be used as an effective non-destructive technique to track the progress of MICP during calcite deposition and crack repair. HIGHLIGHTS An experimental study was carried out to monitor progression of mortar healing by ureolytic bacteria by non-destructive methods. X-ray tomography technology was feasible to monitor mortar healing in real time. Relative effect (RTE) is proposed as a comparison index in the repair treatments of cement-based materials by Microbiologically Induced Carbonate Precipitation (MICP).

Effect of Canagliflozin on Heart Failure Hospitalization in Diabetes According to Baseline Heart Failure Risk

BackgroundIn the CANVAS (Canagliflozin Cardiovascular Assessment Study) program, canagliflozin reduced the risk of heart failure (HF) hospitalization among individuals with type 2 diabetes mellitus (T2DM). ObjectivesThe purpose of this study was to evaluate heterogeneity in absolute and relative treatment effects of canagliflozin on HF hospitalization according to baseline HF risk as assessed by diabetes-specific HF risk scores (WATCH-DM [Weight (body mass index), Age, hyperTension, Creatinine, HDL-C, Diabetes control (fasting plasma glucose) and QRS Duration, MI and CABG] and TRS-HFDM [TIMI Risk Score for HF in Diabetes]). MethodsParticipants in the CANVAS trial were categorized into low, medium, and high risk for HF using the WATCH-DM score (for participants without prevalent HF) and the TRS-HFDM score (for all participants). The outcome of interest was time to first HF hospitalization. The treatment effect of canagliflozin vs placebo for HF hospitalization was compared across risk strata. ResultsAmong 10,137 participants with available HF data, 1,446 (14.3%) had HF at baseline. Among participants without baseline HF, WATCH-DM risk category did not modify the treatment effect of canagliflozin (vs placebo) on HF hospitalization (P interaction = 0.56). However, the absolute and relative risk reduction with canagliflozin was numerically greater in the high-risk group (cumulative incidence, canagliflozin vs placebo: 8.1% vs 12.7%; HR: 0.62 [95% CI: 0.37-0.93]; P = 0.03; number needed to treat: 22) than in the low- and intermediate-risk groups. When overall study participants were categorized according to the TRS-HFDM score, a statistically significant difference in the treatment effect of canagliflozin across risk strata was observed (P interaction = 0.04). Canagliflozin significantly reduced the risk of HF hospitalization by 39% in the high-risk group (HR: 0.61 [95% CI: 0.48-0.78]; P < 0.001; number needed to treat: 20) but not in the intermediate- or low-risk groups. ConclusionsAmong participants with T2DM, the WATCH-DM and TRS-HFDM can reliably identify those at high risk for HF hospitalization and most likely to benefit from canagliflozin.