EClinicalMedicine最新文献

Background: For chronic lymphocytic leukaemia (CLL) and intermediate risk factors (unmutated IGHV and/or 11q deletion and/or complex karyotype; no TP53 alteration), the best first-line treatment is unclear. We compared an MRD-guided, fixed-duration ibrutinib-venetoclax (IV) regimen to fludarabine-cyclophosphamide-rituximab (FCR) in this population.

Methods: The ERADIC randomised, phase 2 trial (NCT04010968), conducted at 35 French hospitals, recruited previously untreated, fit adults with intermediate-risk CLL. Randomisation was 1:1 to: 6x4-weekly cycles of FCR (Months 1-6); or ibrutinib 420 mg/day from Month 1 plus venetoclax (ramp-up to 400 mg/day from Month 4) for a duration depending on the bone marrow measurable residual disease level at Month 9 (if undetectable at a threshold of <0·01% [BM uMRD4] to Month 15; otherwise to Month 27). Primary outcome was the BM uMRD4 rate at Month 27, by assessment oligocentrally (intent-to-treat, worst-case scenario method).

Findings: Between 27 September 2019 and 31 January 2021, 120 patients were enrolled (73% male). At Month 27, the BM uMRD4 rate was 37% (22/59; 95% confidence interval [CI] 25, 51) with IV versus 13% (8/61; 95% CI 6, 24) with FCR. The high amount of missing BM MRD data, along with imbalance in missing data between arms, meant that no confirmatory statistics were performed. Best rate of BM uMRD4 plus peripheral blood uMRD5 was 47% (22/47) with IV versus 19% (8/43) with FCR (p = 0·0090). With median 43 months' follow-up, progression-free survival was longer with IV versus FCR (estimated hazard ratio 0·35, 95% CI 0·16, 0·80, p = 0·012). By Month 27, six deaths had occurred (FCR: acute myeloid leukaemia, septic shock, myelodysplastic syndrome; IV: 2 sudden deaths, COVID-19). By the time of follow-up, the most common serious grade 3/4 events were infections and haematological toxicities with FCR, and infections and cardiovascular/metabolic toxicities with IV.

Interpretation: Due to the high amount of missing BM MRD data at Month 27, the primary outcome statistical analysis was not deemed feasible. The outcomes reported are secondary and exploratory, and were not been powered for in the study design. A patient profile suitable for an MRD-guided, fixed-duration IV regimen requires consideration of potential toxicities.

Funding: Abbvie and Janssen France.

Background: Obesity increases the risk of developing chronic kidney disease and progression to kidney failure (KF) and precludes kidney transplantation (KT). Challenges exist in people with KF losing weight to access KT, therefore understanding patients' and clinicians lived experiences of obesity management is crucial to improving equitable access to KT. This review aimed to synthesise qualitative and quantitative evidence to better understand patients' and clinicians' experiences of obesity management in KF prior to transplantation.

Methods: This mixed-methods systematic review followed the integrated methodological framework by the Joanna Briggs Institute. MEDLINE, Embase, and Web of Sciences were searched from 1st January 1980 to 16th April 2025 for studies investigating patients' and clinicians' perspectives on obesity management in KF. Qualitative, quantitative and mixed methods studies published in English in which patients or clinicians reported on their experiences of obesity management in kidney failure were included. Two investigators independently screened studies, extracted data, and assessed the risk of bias. Summary data were extracted from published reports and quantitative data underwent transformation into 'qualitised' data, Qualitative findings and qualitised survey results were analysed inductively using thematic synthesis. The study was registered with PROSPERO, CRD42024510237. The Mixed Methods Appraisal Tool version 2018 was used to evaluate the quality of selected studies.

Findings: Of 6525 records identified, 5203 remained after de-duplication and 7 studies met inclusion criteria with a total of 738 participants The overall quality of the studies was low and only one study scored highly on the quality assessment. Four main themes were constructed 1) Hungry and exhausted: The impact of dialysis on eating behaviour and activity (six studies [n = 339]) 2) Weight stigma-lack of support, trust and open communication (five studies [n = 212]) 3) Lack of resources as a barrier for weight loss (six studies [n = 339]) 4) Who gets a transplant? Moving beyond BMI to improve equity in transplantation (four studies [n = 631]).

Interpretation: Significant barriers to accessing and delivering obesity management were identified. When interpreting the results it should be appreciated that the overall quality of the studies was low. and clinician perspectives were limited to dietitians, nephrologists and transplant surgeons. To address these barriers, targeted strategies are recommended, such as enhanced training for health professional on obesity and communication about weight and weight stigma. There is an urgent paradigm shift needed to ensure equitable access to obesity management for people with obesity and KF.

Funding: National Institute for Health and Care Research.

Background: To investigate the efficacy and safety of adding tislelizumab to neoadjuvant chemotherapy with nab-paclitaxel and carboplatin (TP) followed by adjuvant tislelizumab for early TNBC to explore the optimal neoadjuvant chemotherapy backbone and courses.

Methods: The cTRIO study (ChiCTR2100041675) is a multicenter, prospective, open-label phase II trial across 8 sites in China, evaluating the efficacy and safety of neoadjuvant tislelizumab plus TP followed by adjuvant tislelizumab in patients with early triple-negative breast cancer (TNBC). We included women aged ≥18 years with histologically confirmed early TNBC defined by estrogen receptor immunohistochemistry (IHC) with T1 N1-3 or T2-4 N0-3 stage. Participants received six cycles of neoadjuvant tislelizumab (200 mg on day 1) plus nab-paclitaxel and carboplatin (TP; 125 mg/m² on days 1 and 8), definitive surgery 3-6 weeks after completion of neoadjuvant therapy, followed by adjuvant tislelizumab every 3 weeks for 1 year. The primary endpoint was pathologic complete response (pCR).

Findings: Sixty-two patients were enrolled from March 2021 to October 2022, including 44 cases with programmed cell death ligand 1 (PD-L1) positive and 9 cases at N3. At final analysis, 35/62 patients had achieved pathologic complete response (pCR, 56%; 95% confidence interval [CI], 43%-69%), with 33% (3/9) of N3 cases achieving pCR. The 3-year EFS and OS rates were 82.2% (95% CI, 70.2%-89.7%) and 87.7% (95% CI, 75.6%-94.0%), respectively. The incidence rates of grade ≥3 treatment-related adverse events (TRAEs) and grade ≥3 immune-related adverse events (irAEs) were 53% (33/62) and 5% (3/62), respectively. Patients with a higher PD-L1 combined positive score were less likely to experience relapse (P = 0.0090).

Interpretation: Despite being a de-escalating and anthracycline-free neoadjuvant treatment approach, the triplet combination therapy showed promising efficacy and safety, signifying a crucial step toward the optimization of chemoimmunotherapy for early TNBC.

Funding: This study was supported by BeOne Medicines, Ltd.

Background: Pharmacogenetics (PGx) aims to revolutionize healthcare by individualizing drug doses and medication choices. However, clinical uptake will require positive evaluation evidence of both clinical utility and cost-effectiveness. We have recently demonstrated the clinical utility of this approach, using a panel-based PGx-guided treatment of patients from various indications recruited in seven countries (PREPARE study).

Methods: Here, we provide economic evidence from a multinational cost-utility analysis of PGx-guided treatment in 6930 patients participating in the PREPARE study. The study was conducted from March 2017 to June 2020. We used the national healthcare system's perspective in each participating country, including only direct medical costs that budget holders cover. A Visual Analog Scale was used to measure utility and the quality of life was estimated by averaging the Visual Analog Scale scores of participants over four specific time points in the study, namely baseline visit (day 1), week 4, week 12, and 18 months from the baseline visit.

Findings: Our analysis showed that the PGx-guided treatment is marginally cost-effective at the threshold of €11,000 QALYs. Cost drivers were hospitalization and ADRs costs, accounting for most of the resources used in both groups (46% and 37.5% in the PGx-guided group versus 49% and 48% in the control group, respectively), as a result of the average duration of hospitalization [1.51 days (95% CI: 1.23-1.82) for the PGx-guided group and 2.37 days (95% CI: 1.95-2.89) for the control group, resulting in a mean difference of 0.86 days (95% CI: 0.37-1.44). The difference in QALYs gained was 0.00178 (95% CI: 0.00176-0.00180). The ICER was €12,020 (95% CI: €10,957-€13,356) per QALY on average (SD: €116). When comparing cost and effectiveness of actionable PGx-guided versus actionable control patients, the total cost for the PGx-guided group was €491 (95% CI: €384-€613), versus €767 (95% CI: €583-€982) in the control group, with an incremental cost difference of €276 (95% CI: €62-€511), favoring the PGx-guided group. Also, the difference in effectiveness was 0.007 QALYs (95% CI: -0.021 to 0.033). Lastly, the difference in the mean total cost was estimated to be €21.4 (95% CI: €19.5-€23.8), while without considering the PGx test cost, indicative of a pre-emptive genetic testing approach, the PGx-guided treatment becomes a cost-saving option, with an estimated savings of approximately €103.6 (€124-€21.4) per patient.

Interpretation: These data suggest that panel-based PGx testing is cost-effective, which, together with the clinically beneficial outcomes already demonstrated in the PREPARE study, provides additional evidence of the need to implement PGx into clinical practice.

Funding: European Union Horizon 2020.

Background: Effective time-limited therapies remain an unmet need in chronic lymphocytic leukaemia (CLL). We evaluated a novel regimen combining ibrutinib with intermittent fludarabine, cyclophosphamide, and rituximab (FCR) in patients with CLL.

Methods: This single-arm, multicentre, phase 2 trial was conducted at three centres in China. Eligible participants were adults (aged 18-65 years) with previously untreated CLL requiring therapy according to the International Workshop on Chronic Lymphocytic Leukaemia criteria. The regimen consisted of ibrutinib (420 mg daily) combined with three cycles of FCR administered on days 1-3 of cycles 1, 5, and 9. After the completion of induction therapy, among patients who had achieved complete remission (CR) with undetectable minimal residual disease (uMRD): those without TP53 deletion or mutation could discontinue treatment; those with TP53 deletion or mutation continued maintenance therapy for 6 months before discontinuing treatment; all other patients continued ibrutinib until they achieved CR-uMRD, followed by an additional 6 months of treatment. The primary endpoint was CR rate at best response. This trial is registered with ClinicalTrials.gov, NCT03980002.

Findings: Between June 1, 2019, and July 30, 2023, 50 patients were enrolled with a median follow-up of 55 months (IQR 40-65). The median age of participants was 57 years (IQR 48-62), and 36 (72%) were male. Among 47 patients with available IGHV data, 18 (38%) had unmutated IGHV. TP53 deletion/mutation were present in four (8%) patients. The CR rate, the primary outcome, was 70% (35/50) at best response. 18 patients (36%) achieved CR with undetectable MRD in both bone marrow and peripheral blood, discontinuing treatment post-induction. Four deaths occurred; one due to Richter's transformation, two from COVID-19, and one from cerebral infarction. Grade 3/4 neutropenia occurred in 13 (26%) patients, leucopenia in 11 (22%) patients, and lymphocytopenia in 12 (24%) patients. No therapy-related cases of myelodysplastic syndrome or acute myeloid leukaemia were observed.

Interpretation: This regimen achieved deep remissions with manageable toxicity. Whilst acknowledging study limitations and that pathway inhibitors are the current standard of care, these findings provide proof-of-principle that this regimen could be a feasible, time-limited treatment option for CLL. Particularly in resource-limited healthcare systems where continuous novel agents are less accessible. Future studies should explore long-term durability beyond 5 years and validate MRD thresholds for treatment cessation.

Funding: National Nature Science Foundation of China, the Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences, and Beijing Xisike Clinical Oncology Research Foundation.

Background: Two chikungunya vaccines, Ixchiq and Vimkunya are licensed. In April 2025, Brazil is the first endemic country to license Ixchiq, but optimal age groups for vaccination remain unclear. Our aim is to model the public health impact of age-specific chikungunya outbreak response immunisation strategies in Brazil and infer broader implications for vaccine use case scenarios in outbreak prone regions.

Methods: We developed an age-structured transmission dynamic model calibrated with state-level Brazilian surveillance data for 2022 and long-term average annual force of infections. We simulated outbreak response immunisation strategies targeting ages 1-11, 12-17, 18-59, and ≥60 years for Ixchiq and Vimkunya across 11 out of 27 states in Brazil. We assessed vaccine impact by symptomatic cases, deaths, and disability-adjusted life years (DALYs) averted and number needed to vaccinate (NNV) based on vaccine protection against disease only and against both disease and infection.

Findings: Ixchiq and Vimkunya showed similar vaccine impact. Across strategies, vaccinating children 1-11 years yielded the lowest NNV for both vaccines, whereas vaccinating adults 18-59 years achieved the greatest absolute reduction in symptomatic cases, averting 62.5% (95% Uncertainty Intervals [UI]: 54.2-84.1) of total symptomatic cases with Vimkunya and 66.2% (58.2-86.0) with Ixchiq, under disease and infection blocking mechanism. Vaccinating adults 18-59 years with Ixchiq or Vimkunya yielded similar efficiency, with NNVs to avert a DALY of 339 (39-3412) and 361 (40-3777) respectively, under disease and infection-blocking mechanism.

Interpretation: Under current licensure, vaccinating adolescents aged 12-17 years first, followed by 18-59 years are efficient strategies, with similar NNVs for both Ixchiq and Vimkunya. If eligibility expands to younger populations, vaccinating 1-11-year age group will have relatively higher efficiency.

Funding: International Vaccine Institute and Japan Agency for Medical Research and Development.