Lancet Haematology最新文献

Background: Avatrombopag is an oral thrombopoietin receptor agonist (TPO-RA), taken with food without any specific restrictions, approved for the treatment of adults with chronic immune thrombocytopenia (ITP) who have had an insufficient response to a previous treatment. The aim of this study was to assess the efficacy, safety, tolerability, and pharmacokinetic and pharmacodynamic profile of avatrombopag for children and adolescents with persistent and chronic primary ITP.

Methods: AVA-PED-301 is a global, multicentre, randomised, double-blind, placebo-controlled, parallel-group, phase 3b study. Children and adolescents aged ≥1 to <18 years with a confirmed diagnosis of primary ITP for at least 6 months and an insufficient response to a previous treatment were randomly assigned (3:1) to avatrombopag (aged ≥6 years: 20 mg oral tablet once daily; aged ≥1 to <6 years: 10 mg oral suspension once daily) or matching placebo. Doses were titrated to maintain a platelet count of 50-150 × 10⁹ cells per L. The core-phase (12-week double-blind treatment period) full analysis set included all randomly assigned patients; efficacy analysis was performed based on randomised study drug. The safety analysis set included all patients who received at least one dose of study drug in each study phase. The primary endpoint was durable platelet response (proportion of patients with at least six out of eight weekly platelet counts ≥50 × 10⁹ cells per L during the last 8 weeks of the 12-week treatment period in the absence of rescue therapy); the alternative primary endpoint was platelet response (proportion of patients with at least two consecutive platelet assessments ≥50 × 10⁹ cells per L over the 12-week treatment period in the absence of rescue therapy). The trial core phase is complete and was registered with ClinicalTrials.gov (NCT04516967).

Findings: Between March 2, 2021, and Aug 2, 2023, 83 children were screened, with 75 randomly assigned to avatrombopag (n=54; 24 [44%] female; 48 [89%] White) or placebo (n=21; 12 [57%] female; 15 [71%] White). 15 (28%) patients in the avatrombopag group met the primary endpoint of durable platelet response versus no (0%) patients in the placebo group (difference in response rate 28% [95% CI 16-40]; p=0·0077); 44 (81%) patients in the avatrombopag group met the alternative primary endpoint of platelet response versus no (0%) patients in the placebo group (difference in response rate 81% [71-92]; p<0·0001). The most common adverse events across treatment groups were petechiae (n=20), epistaxis (n=16), and headache (n=14). Serious adverse events were reported in five (9%) patients in the avatrombopag group and one (5%) patient in the placebo group. No deaths, thromboembolic events, or grade 3 or higher bleeding events were reported.

Interpretation: Avatrombopag is an effective oral treatment for children and a

Background: Bexmarilimab blocks Clever-1 on macrophages to enhance antigen presentation and T cell activation. Because Clever-1 is expressed by myeloid leukaemia cells, bexmarilimab may combat leukaemia and influence the tumour microenvironment to augment the effectiveness of standard-of-care therapy in patients with myelodysplastic syndrome and acute myeloid leukaemia. The aim of this study was to determine the safety of bexmarilimab in combination with standard-of-care treatment in myelodysplastic syndrome and acute myeloid leukaemia and to identify the recommended dose for expansion of bexmarilimab in combination with standard of care.

Methods: The phase 1 dose-escalation part of this multicentre, single-arm, phase 1/2 study was done at six centres in Finland and the USA. Patients aged 18 years or older (Eastern Cooperative Oncology Group performance status of 2 or less) with myelodysplastic syndrome (2016 WHO) with a Revised International Prognostic Scoring System (IPPS-R) score of 3·5 or more for USA (3·0 for the European Union), chronic myelomonocytic leukaemia (2016 WHO) with 10-19% marrow blasts, myelodysplastic syndrome or chronic myelomonocytic leukaemia with no response to or disease progression during hypomethylating agent treatment, or relapsed or refractory acute myeloid leukaemia were treated with escalating doses of bexmarilimab (1·0 mg/kg, 3·0 mg/kg, and 6·0 mg/kg, intravenous, once weekly, 28-day cycle) in combination with azacitidine, administered as per label. Here we report the phase 1 part of the study, for which the primary outcome was safety (the incidence and frequency of dose limiting toxicities and the frequency and severity of adverse events) as well as the determination of the maximum tolerated dose and recommended expansion dose for the phase 2 part using a Bayesian optimal interval design. All patients receiving at least one dose of bexmarilimab were included in safety analyses, and those with a post-baseline activity assessment were included in activity analyses. This trial is registered with ClinicalTrials.gov (NCT05428969) and EudraCT (2021-002104-12) databases. Phase 2 of the study is ongoing in patients with myelodysplastic syndrome with no response to hypomethylating agent.

Findings: Between June 2, 2022, and Dec 7, 2023, 33 patients (14 with myelodysplastic syndrome, 19 with relapsed or refractory acute myeloid leukaemia) were enrolled in phase 1; no patients with chronic myelomonocytic leukaemia were identified. 19 (58%) patients were male and 14 (42%) were female, and 24 (73%) patients were non-Hispanic ethnicity, and eight (24%) were White. Median follow-up time for all patients was 6·2 months (IQR 3·5-10·7). The maximum tolerated dose was not reached, and the recommended expansion dose for phase 2 was established as 6·0 mg/kg in patients with myelodysplastic syndrome with no response to hypomethylating agents. There were no dose-limiting to

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.