Lancet Haematology最新文献

Background: Machine-learning models directly predicting iron biomarkers after blood donation could help to manage donation-associated iron deficiency and avoid low haemoglobin deferrals. No such models have been externally validated internationally. Our aim was to develop and externally validate machine-learning models predicting returning blood donors' haemoglobin and ferritin.

Methods: We developed machine-learning models using retrospective blood donation data. The training cohort included 2425 repeat donors (2007-09 US-based RISE study); external validation used 2014-23 cohorts from the USA, South Africa, and the Netherlands. Models predicted donors' ferritin and haemoglobin at return donations by use of variables that are commonly measured by blood collectors (time until donors return, donation history, demographics, and baseline iron biomarkers). Models were selected via cross-validation and externally validated in donors aged at least 15 years in two contexts: those with baseline ferritin and haemoglobin measured (haemoglobin and ferritin) and those with only baseline haemoglobin measured (haemoglobin only). Model performance was assessed by use of root-mean-square percentage error (RMSPE).

Findings: When predicting return haemoglobin in the RISE cohort, model performance was similar in the haemoglobin and ferritin dataset (n=2625 donation visits, RMSPE=6·78) and haemoglobin only dataset (n=3488 donation visits, RMSPE=6·78). In the external datasets, containing 11 000 to 514 000 donations, RMSPE never increased more than 8%. When predicting return ferritin in RISE, performance was better in the haemoglobin and ferritin dataset (RMSPE=14·9) than in the haemoglobin only dataset (RMSPE=27·4). In external validation, RMSPE never increased more than 0·4% and 28% in the haemoglobin-only datasets and the haemoglobin and ferritin datasets, respectively.

Interpretation: Machine-learning models predicting haemoglobin and ferritin at return donations generalised well across diverse settings and could enable individualised approaches to manage iron deficiency while maintaining a sufficient blood supply.

Funding: The Association for the Advancement of Blood and Biotherapies.

Translation: For the Dutch translation of the abstract see Supplementary Materials section.

As the therapeutic landscape in haematological malignancies has evolved from traditional chemotherapies to novel biological, targeted, and cellular therapies, adverse event profiles have accordingly shifted with emerging and newly described chronic, cumulative, and delayed symptomatic adverse events. The current standard of toxicity reporting in clinical trials, centred on maximum-grade adverse events, is wholly inadequate for characterising the tolerability of therapies in the modern era. As such, the science of adverse event measurement, analysis, and reporting in clinical trials needs to evolve with our ever-growing repertoire of therapeutics to facilitate more comprehensive and accurate toxicity assessment for treatment decision making. In this first paper in the Adverse Event Reporting Series, a follow-up of a 2018 Lancet Haematology Commission, we review advances in the reporting of newly described adverse events and toxicity domains in haematological malignancies, emerging clinical trial designs to more accurately identify optimal dosing strategies through enhanced adverse event measurement, and novel analytic and visualisation tools to facilitate interpretation of trial adverse event data.

Background: The factor B inhibitor iptacopan improved 24-week outcomes in adult patients with paroxysmal nocturnal haemoglobinuria in the phase 3 APPLY-PNH and APPOINT-PNH trials; the trial extension periods assessed clinical activity and safety up to 48 weeks. Here, we report the final 48-week data from APPLY-PNH and APPOINT-PNH.

Methods: In both APPLY-PNH and APPOINT-PNH trials, patients were aged 18 years or older, with paroxysmal nocturnal haemoglobinuria (red and white blood cell population sizes ≥10%) and without laboratory evidence of bone marrow failure. In APPLY-PNH (an open-label, randomised, phase 3 trial conducted in 39 centres [38 hospitals, one outpatient research clinic] from 12 countries or regions), patients with haemoglobin concentration lower than 10 g/dL on anti-C5 treatment (stable eculizumab or ravulizumab regimen for ≥6 months) were randomly assigned (8:5) via interactive response technology to either receive oral iptacopan 200 mg twice daily (iptacopan group) or to continue their individual intravenous eculizumab or ravulizumab regimen for 24 weeks (anti-C5 group). Randomisation was stratified by type of anti-C5 and receipt of red blood cell (RBC) transfusions in the preceding 6 months. In APPOINT-PNH (an open-label, single-arm, phase 3 trial conducted in 12 hospitals from eight countries), complement inhibitor-naive patients with paroxysmal nocturnal haemoglobinuria and with haemoglobin concentration lower than 10 g/dL and lactate dehydrogenase (LDH) concentration higher than 1·5 times the upper limit of normal received iptacopan 200 mg twice daily for 24 weeks. Both trials had 24-week extension periods in which all patients received iptacopan monotherapy. Primary endpoints were the proportion of patients with an increase from baseline in haemoglobin concentration of 2 g/dL or higher (APPLY-PNH and APPOINT-PNH) and haemoglobin concentration 12 g/dL or higher (APPLY-PNH) between weeks 18 and 24, all in the absence of RBC transfusions between weeks 2 and 24; results for these primary endpoints have been reported previously. We report final activity and safety data at the completion of both trials (week 48). Prespecified endpoints at week 48 included percentage of patients with a haemoglobin increase from baseline of 2 g/dL or higher or haemoglobin 12 g/dL or higher (including post-transfusion data). Efficacy data were analysed per the intention-to-treat principle, and safety was analysed according to the treatment that patients received. APPLY-PNH and APPOINT-PNH are registered with ClinicalTrials.gov, NCT04558918 and NCT04820530, respectively.

Findings: In APPLY-PNH, between Jan 25, 2021, and April 8, 2022, 62 patients (43 [69%] female, 19 [31%] male; 48 [77%] White, 12 [19%] Asian, two [3%] Black) were randomly assigned to the iptacopan group and 35 patients (24 [69%] female, 11 [31%] male; 26 [74%] White, seven [20%] Asian, two [6%] Black) to the anti-C5 g