Lancet Haematology最新文献

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

The increasing use of immunotherapeutic approaches, cellular therapies, and targeted agents is rapidly and profoundly changing the treatment paradigms of haematological malignancies. These novel therapies are increasingly incorporated into earlier lines of treatment. Some are administered for a fixed duration, often with curative intent, whereas others are administered chronically for disease control. The associated acute, mid-term, and long-term toxic effects can differ markedly from conventional cytotoxic chemotherapy and radiotherapy. Accumulating clinical experience and data enable identification of class-specific effects and development of consensus-based guidelines for toxicity management. In this third paper in the Series on adverse event reporting, we build on our emerging understanding of toxicity profiles of novel treatments to propose an actionable framework for improved assessment, reporting, and critical appraisal of treatment tolerability. We discuss recent insights regarding second cancers and the relevance of infectious complications, explore tolerability aspects of time-limited treatments, and suggest approaches to address gaps in tolerability assessment.

Incorporating patient-generated data into drug development is crucial for assessing the tolerability of treatments, particularly in patients with haematological malignancies, some of whom receive high-intensity, short-duration treatments and others who endure chronic therapies for months to years at a time. With increasing use of novel therapies such as oral targeted agents and immunotherapy, including chimeric antigen receptor T-cell therapy and bispecific antibodies across different haematological malignancies, new types of toxicity assessment techniques that harness patient-generated data, including patient-reported outcomes (PROs) are required to fully evaluate short-term and long-term side-effects. In this second paper in this Series, we describe progress in PRO implementation in clinical trials and outline future directions for use of patient-generated data, including PRO implementation in early-phase trials, novel PRO-based endpoints in haematology trials, and updated PRO measures that reflect treatment advances across haematological malignancies.