British Journal of Haematology最新文献

RNA sequencing from 262 patients with paediatric acute myeloid leukaemia (AML) (JPLSG AML-12) was deconvoluted employing adult single-cell RNA-sequencing signatures and Zeng's method, which defined five cellular hierarchy subtypes: primitive, leukaemic stem/progenitor cell (LSPC)-Cycle, ProMono-like, granulocyte-monocyte progenitor (GMP)-like and intermediate. Principal component analysis revealed two main axes that distinguish paediatric from adult AML, with notable LSPC-Cycle and ProMono-like phenotype enrichment. LSPC-Cycle (>25% cycling stem-like cells) had proliferative and quiescent LSPCs, frequent French-American-British (FAB)-M7 and worst prognosis (overall survival odds ratio vs. GMP-like: 11.33). Morphology was related to the primitive (FAB-M0), GMP-like (M2/M4) and ProMono-like (M5) groups. Genomic patterns aligned with hierarchy: CBFA2T3::GLIS2, MYB::GATA1 and MECOM high expression in LSPC-Cycle; CBFB::MYH11, NUP98::NSD1 and NPM1 in the intermediate; and DEK::NUP214 and NUP98::KDM5A were concentrated in the primitive group. bZIP CEBPA and FLT3-ITD mutations clustered in the intermediate and primitive groups. Most of RUNX1::RUNX1T1 clustered in the intermediate group, whereas KMT2A::MLLT3 hierarchy differed with MECOM expression level. Paediatric AML comprised more primitive cells, rarely with mono-like/cDC-like dominance. LSPC-Cycle, FLT3-ITD and NUP98::KDM5A were considered independent prognostic factors in multivariate analysis. Findings indicate the prognostic relevance of cellular hierarchy and the importance of integrating hierarchy-specific molecular profiles for improved risk stratification and treatment formulation.

Acute myeloid leukaemia (AML) is an aggressive disease with poor survival and high relapse rates. Coupled with the complex mutational burden observed, there is an unmet clinical need for more targeted therapies. Epigenetic therapies have shown promise both as monotherapy and in combination strategies and specifically histone lysine demethylase, KDM4A (Lysine demethylase 4), plays a role in the maintenance of AML, with its short hairpin (shRNA) knockdown sufficient to target leukaemia cells while sparing normal haemopoietic cells. In this study, we utilised a novel KDM4 inhibitor based on the structure of IOX-1, the most characterised inhibitor of the 2-oxygenase enzymes to which the KDM4 family belong, to investigate further the role of KDM4A in AML. Our compound induced AML cell death with cell cycle arrest, failure of colony formation and transcriptomic changes in metabolism, transcription control and response to stress. With known roles for KDM4A family members in deoxyribonucleic acid (DNA) damage response repair pathways, inhibition of KDM4A increased accrual of double strand DNA breaks. Hence, we demonstrated KDM4i sensitisation of leukaemia cells to inhibitors of DNA damage pathways such as poly-ADP ribose polymerase (PARP) inhibitor, olaparib, suggesting future clinical evaluation of KDM4A and other key components in DNA damage/response signalling pathways as potential therapeutic vulnerabilities in AML.

Acute myeloid leukaemia (AML) risk stratification relies on cytogenetic and molecular abnormalities defined by European LeukemiaNet (ELN) 2022. Conventional cytogenetic techniques, including chromosomal banding analysis (CBA) and fluorescence in situ hybridization, have limited resolution and may miss cryptic events. Optical genome mapping (OGM) is a genome-wide approach capable of detecting balanced and unbalanced structural variants with high resolution, potentially revealing cryptic abnormalities of diagnostic and prognostic relevance. We retrospectively studied 100 adults with newly diagnosed AML, each showing one to two cytogenetic abnormalities and lacking the World Health Organization 2022-defining rearrangements or baseline ELN adverse karyotypes. OGM was performed to evaluate additional cytogenetic abnormalities and impact on ELN 2022 risk classification. Clinical outcomes were explored descriptively. OGM detected 91.4% of abnormalities identified by CBA and provided additional information in 37% (95% confidence interval: 28%-47%) of patients. Fourteen per cent was reclassified to an unfavourable cytogenetic group, and 7.7% was reclassified to ELN 2022 adverse risk. Cryptic KMT2A and NUP98 lesions were found in 10% of cases, highlighting potential therapeutic targets. Survival analyses suggested a trend towards poorer outcomes in patients reclassified as adverse, though the small sample limits definitive conclusions. In low-complexity AML, OGM provides substantial incremental diagnostic value, detecting cryptic high-risk and targetable abnormalities, supporting its use as a complementary tool.

While second primary malignancies (SPMs) in Western patients with chronic lymphocytic leukaemia (CLL) are well documented, data from Asian populations remain limited. This nationwide, retrospective cohort study assessed SPM risk in 2702 CLL patients diagnosed in Taiwan between 1991 and 2020 using the Taiwan Cancer Registry. Standardized incidence ratios (SIRs), absolute excess risks and cumulative incidences were calculated relative to the general population, stratified by sex, age, latency and treatment. The overall SPM risk was elevated (SIR, 1.14, 95% confidence interval [CI], 1.00-1.29), with a 5-year cumulative incidence of 6.53%. Notably increased risks were observed for epithelial skin cancer (SIR, 2.55; 95% CI, 1.60-3.86) and urinary bladder cancer (SIR, 1.99; 95% CI, 1.06-3.41). A lower risk of breast cancer was detected among younger women (SIR, 0.29; 95% CI, 0.06-0.85). SPM risk was highest within 5 years of CLL diagnosis (SIR, 2.72; 95% CI, 2.27-3.22) and then decreased thereafter (SIR, 0.67; 95% CI, 0.56-0.81). These findings reveal a distinct SPM risk profile among Asian CLL patients, particularly the excess risk of bladder cancer, underscoring the importance of tailored surveillance strategies for this population.

Venetoclax (VEN)-based therapies have improved the treatment of acute myeloid leukaemia (AML); however, the emergence of resistance remains a major limitation. Mutations in protein tyrosine phosphatase (PTP) non-receptor type 11 (PTPN11) and FMS like tyrosine kinase 3 with internal tandem duplication (FLT3-ITD) are common in resistant patients and are linked to activation of mitogen-activated protein kinase (MAPK) signalling and increased expression of anti-apoptotic proteins such as myeloid cell leukaemia 1 (MCL-1) and b-cell lymphoma-extra large (BCL(x)L). Murine Ba/F3 cells with different FLT3-ITD variants were lentiviral transduced to express either wild-type PTPN11 (Src-homology 2 containing PTP) or the activating PTPN11-E76K mutation. Cells were treated with VEN, the MCL-1 inhibitor S63845 and the mitogen-activated protein kinase (MEK) inhibitor trametinib (TRA), alone or in combination. Additionally, primary AML samples were examined for drug sensitivity and protein expression profiles. Cells expressing PTPN11-E76K showed marked resistance to VEN, coinciding with sustained extracellular signal-regulated kinase activation and elevated MCL-1 and BCL(x)L levels. Combining VEN with MCL-1 inhibition significantly increased apoptosis. Co-treatment with TRA provided substantial synergistic benefits while yielding a more modest benefit in PTPN11-E76K-mutant cells. Both PTPN11 and FLT3 mutations confer resistance in AML, making them key factors in identifying high-risk patients. The presented results highlight the role of MAPK-driven MCL-1 and BCL(x)L expression, which mediates VEN resistance. While dual inhibition of B-cell lymphoma 2 and MCL-1 is already effective, additional MEK inhibition may further improve outcomes in PTPN11-mutated AML.

There is an urgent need to improve transfusion services in the National Health Service. Current transfusion practice remains largely paper-based, labour-intensive and error-prone, contributing to rising adverse events. Inappropriate blood use is common, measures for the avoidance of transfusion are underutilised and both blood wastage and shortages are at unacceptable levels. There have been many national initiatives to improve transfusion practice over the last 25 years, but the implementation of their recommendations has been poor, as evidenced by the disturbing results of the annual national audits of compliance with the National Institute for Health and Care Excellence Quality Standards for Blood Transfusion. This article discusses these issues and argues for investment in the transfusion workforce, a modernised digital infrastructure and greater oversight of transfusion practice. It is now time to renew efforts to modernise transfusion practice to standards of safety, efficiency and clinical effectiveness, which our patients should reasonably expect.

Iron deficiency anaemia (IDA) is associated with adverse pregnancy outcomes globally. Women with inherited bleeding disorders are at increased risk, with scarce data on rates of IDA screening and correction during pregnancy. The impact of correction on outcomes is unclear. To assess the frequency of IDA screening, the frequency of IDA in pregnancies with and without bleeding disorders and the impact of correction on outcomes. This retrospective population-based cohort study includes all hospitalized pregnancies using the Alberta Pregnancy Birth Cohort. IDA was defined as haemoglobin <110 g/L in first/third trimester, <105 g/L in second trimester and ferritin <30 μg/L. Logistic regression was performed to assess the association between IDA, corrected IDA and pregnancy outcomes. 36 500/207 355 (18%) pregnancies and 14/58 (24%) pregnancies in the bleeding disorder subgroup had anaemia. Only one of three pregnancies with anaemia had a concurrent ferritin test, and over 80% demonstrated IDA. Ferritin screening was performed in 60% of the overall cohort and 79% in bleeding disorders. Young maternal age, multiparity, lower socioeconomic status and mothers from African and Asian countries significantly predict IDA. Despite the increased risk for adverse outcomes, only 43 (8%) first-trimester and 96 (9%) third-trimester IDA were corrected. IDA screening and correction remained suboptimal among pregnant women. Updated screening guidelines may promote better identification and outcomes.

In this prospective, multicentre clinical trial, we evaluated zanubrutinib combined with lenalidomide, temozolomide and rituximab monoclonal antibody ± methotrexate (RLZT ± MTX) as first-line treatment for primary central nervous system lymphoma. RLZT ± MTX demonstrated good efficacy and safety, especially for elderly patients who cannot undergo intensive chemotherapy.