CPX-351 is a standard front-line induction regimen for newly diagnosed acute myeloid leukaemia (AML) with myelodysplasia-related changes (AML-MRC). The 2022 International Consensus Classification (ICC) and World Health Organization (WHO) classifications redefine AML with myelodysplasia-related (AML-MR) to include myelodysplasia-related mutations as well as cytogenetic abnormalities. Clinical outcomes of patients treated with CPX-351 within these refined AML-MR classifications remain unclear. We conducted a retrospective, multicentre study of 235 adults with newly diagnosed AML-MR treated with CPX-351 across seven US academic centres. Patients were stratified by age (younger: <60 vs. older: ≥60 years) and AML-MR subgroup: cytogenetics (AML-MRc), molecular (AML-MRm) and antecedent haematological disorder (AML-AHD). Outcomes included complete remission (CR) and CR with incomplete recovery (CR/CRi), rates of allogeneic haematopoietic stem cell transplant (alloHSCT) and overall survival (OS). The overall CR/CRi rate of CPX-351 was 52%, with no difference by age. AML-MRm had the highest CR/CRi rate (57%). Among CR/CRi responders, 55% underwent alloHSCT (<60 years: 53% vs. ≥60 years: 57%). Median OS was 13.8 months with no significant difference by age. Younger AML-MRm patients had longer median OS compared with older AML-MRm patients (38.0 vs. 19.5 months; p = 0.05). Favourable outcomes in AML-MRm, particularly in younger patients, support molecular classification in guiding therapy and selectively extending CPX-351 use beyond older adults.

Young adults (YAs) undergoing allogeneic haematopoietic stem cell transplantation (HSCT) represent a unique population with distinct medical and psychosocial needs. Optimizing graft-versus-host disease (GvHD) prophylaxis in this population remains critical to improving outcomes. We performed a retrospective analysis of YAs undergoing unrelated donor HSCT using a contemporary Center for International Blood and Marrow Transplant Research (CIBMTR) dataset. GvHD-free, relapse-free survival (GRFS) at 24 months was evaluated across three GvHD prophylaxis strategies: Group A (post-transplant cyclophosphamide [PTCy] + calcineurin inhibitor [CNI] + mycophenolate mofetil [MMF]), Group B (CNI + methotrexate [MTX]/MMF), and Group C (CNI + MTX/MMF + anti-thymocyte globulin [ATG]). A propensity score-matched (PSM) analysis was conducted to adjust for baseline differences. A total of 1387 YA patients were included. In the total cohort, 24-month GRFS was 58.9% (confidence intervals [95% CI], 53-64) in Group A, 32.2% (95% CI, 29-36) in Group B and 44.2% (95% CI, 39-49) in Group C (p < 0.001). On multivariable analysis (MVA), both Group A (hazard ratio [HR] = 0.44; 95% CI, 0.35-0.54) and Group C (HR = 0.79; 95% CI, 0.70-0.90) showed improved GRFS compared to Group B. In the propensity score-matched cohort, GRFS at 24 months remained higher in the PTCy group (58.2%, 95% CI, 52-64) versus the CNI-MTX/MMF ± ATG group (32.9%, 95% CI, 27-39; p < 0.001), with PTCy independently associated with improved GRFS (HR = 0.48; 95% CI, 0.40-0.60; p < 0.001). PTCy-based prophylaxis also reduced non-relapse mortality (NRM), with no significant differences in relapse or overall survival (OS) between groups. In this large, retrospective analysis, PTCy was associated with significantly improved GRFS and reduced NRM in YAs undergoing unrelated donor HSCT. These findings support the use of PTCy-based regimens in this population and warrant prospective evaluation.

To explore the relation between disease characteristics, comorbidities, mutations and overall survival (OS) in chronic myelomonocytic leukaemia (CMML), we collected data from a population-based cohort of 149 consecutive patients. TET2 mutation (TET2) was associated with higher haemoglobin, less leucocytosis and longer OS compared to no TET2 (TET2), despite patients being significantly older. Patients with multihit TET2 had the most favourable outcome (HR 0.55, CI 0.35-0.88, p < 0.05). Multihit TET2 was associated with lower lactate dehydrogenase and less monocytosis, indicating multihit TET2 as a separate disease entity. Autoimmune disease (AID) was present in 33.6% of patients, with no association to any mutations. In multivariable analysis, the number of TET2 was demonstrated to be an independent factor associated with improved OS, and RUNX1, myeloproliferative CMML (CMML-MP), ECOG >0 and transfusion dependence remained significant adverse factors. Internal validation including cross-validation and correction for optimism consistently demonstrated that a prognostic model containing the number of TET2, RUNX1, CMML-MP, ECOG >0 and transfusion dependence showed better calibration, discrimination and overall performance than CPSS-Mol in predicting OS. Importantly, the addition of TET2 mutation status to CPSS-Mol also improved the CPSS-Mol score performance. Taken together, TET2 status, especially multihit TET2, defines a specific CMML phenotype and should be considered in future prognostic scores.

This study provides a comprehensive assessment of haematological malignancies among children, adolescents and young adults aged 0-24 years, using data from the Global Burden of Disease 2021 across 204 countries from 1990 to 2021. We found that global incidence and prevalence remained relatively stable, with approximately 150 000 new cases and over one million prevalent cases in 2021, while mortality and disability-adjusted life year (DALY) rates declined markedly. Leukaemia was the leading contributor to incidence, deaths, and DALYs, although decreases were observed across most subtypes. Age- and sex-specific analyses revealed higher burdens in males and a pronounced peak in the <5-year group, with a secondary rise in late adolescence. High-income regions bore higher incidence and DALY burdens but exhibited lower mortality, whereas low-high social-demographic index regions suffered disproportionate lethality and disability. These findings highlight both progress and persisting inequities, underscoring the urgent need for subtype-specific interventions, earlier diagnosis and equitable treatment access to improve outcomes for young patients globally.

This study aimed to investigate the distinct clinical characteristics and molecular features of TP53-mutant acute myeloid leukaemia (AML) patients. We retrospectively analysed 193 TP53-mutant AML patients. Better responses were observed in patients treated with the venetoclax in combination with hypomethylating agent (VEN + HMA) regimen compared to those receiving the '3 + 7' regimens (composite complete remission [CRc], 53.8% vs. 30.2%; p = 0.018). TP53 V272 mutation was associated with a lower relapse rate (0% vs. 35.2%; p = 0.041). The single hit group exhibited superior OS compared to the multi-hit group (the median overall survival [OS]: 14.3 months vs. 10.8 months; p = 0.029). TP53-mutant AML patients with CEBPA bZIP in-frame mutations showed prolonged OS (the median OS: 25.2 months vs. 13.8 months; p = 0.036). Better prognoses were also shown in patients with RUNX1-RUNX1T1 fusion gene (the median OS: 31.1 months vs. 13.7 months; p = 0.002). Multivariate analysis identified three significant prognostic factors for OS: RUNX1-RUNX1T1 fusion gene (hazard ratio [HR] = 0.23, 95% confidence interval [CI], 0.08-0.63; p = 0.005), RUNX1 mutation (HR = 1.84; 95% CI, 1.14-2.96; p = 0.012) and FLT3-ITD mutation (HR = 3.14; 95% CI, 1.80-5.47; p = 0.001). In conclusion, molecular factors matter in influencing the prognosis of TP53-mutant AML patients. Among them, TP53 mutation sites merit particular attention.

Waldenström's macroglobulinaemia (WM) has heterogeneous clinical features and limited standard therapeutic options. Although rituximab-based combinations and Bruton's tyrosine kinase inhibitors have improved outcomes, challenges like incomplete responses and toxicity remain. This prospective, multicentre, phase II study evaluated the efficacy and safety of rituximab, bortezomib, lenalidomide and dexamethasone (R-VRD) induction therapy, followed by lenalidomide maintenance in patients with symptomatic WM. Two-year progression-free survival (PFS) was the primary end-point, and the secondary end-points included overall response rate (ORR), overall survival (OS) and safety. Thirty-eight patients (median age: 66 years) were enrolled. The ORR was 81.6%, and 18.4% of the patients achieved a complete response (CR). The estimated 2-year PFS and OS rates were 57.9% and 94.7%, respectively, after a median follow-up of 38.5 months. Notably, responses deepened during lenalidomide maintenance, and 16 experienced further response improvement during the maintenance phase. The most common adverse events were Grade 3-4 haematological toxicities, particularly neutropenia, but they were manageable. Peripheral neuropathy and rash were generally mild. Patients achieving a CR showed no disease progression within 2 years, emphasizing the deep responses' prognostic value. R-VRD induction, followed by lenalidomide maintenance, demonstrated high efficacy and an acceptable safety profile against symptomatic WM.

A high unmet need for novel, safe and effective therapies exists among older patients with non-Hodgkin lymphoma (NHL). We report safety and efficacy of mosunetuzumab in a subgroup analysis of a phase I/II study, which examined the prognostic impact of age in 218 patients with relapsed/refractory (R/R) B-cell NHL (B-NHL; ≥65 years, n = 102; <65 years, n = 116) from the phase I expansion cohort (NCT02500407) and further evaluated 90 patients with R/R follicular lymphoma (FL; ≥65 years, n = 30; <65 years, n = 60) from the pivotal cohort. The most common adverse event (AE) was cytokine release syndrome, occurring less frequently in older versus younger (33.3% vs. 44.8%) patients with B-NHL. Serious AEs were similar in older versus younger patients (45.1% vs. 46.6%). For patients with R/R FL, overall and complete response rates were numerically higher in older (86.7% and 70.0%, respectively) versus younger (76.7% and 55.0%) patients. Median progression-free survival and time-to-next treatment were 17.9 months and not reached in older patients versus 12.0 and 18.1 months in younger patients. These findings demonstrate mosunetuzumab is effective and well-tolerated across age groups in patients with R/R FL. Additional studies are warranted to further evaluate the safety and efficacy of mosunetuzumab in older patients with B-NHL.

The upper panel illustrates the study design, including recruitment, randomisation, intervention and oral glucose tolerance tests (OGTTs) conducted 2 weeks before and after. The lower panel shows reductions in serum ferritin associated with lower 2-h OGTT glucose and lower glucose area under the curve (AUC). Data from donation (DON) and simulated donation (SIM) groups are shown in red and grey respectively.