Estimated pulse wave velocity (ePWV), a simple surrogate of arterial stiffness, predicts cardiovascular events in general and oncology populations, but its relevance in myeloproliferative neoplasms (MPN) is unknown. We evaluated the association of baseline ePWV with major adverse cardiovascular events (MACE) and overall survival (OS) in 664 patients with essential thrombocythaemia (n = 477) or polycythaemia vera (n = 187). Median ePWV was 11.1 m/s (interquartile range [IQR], 9.2-12.9), and 72.1% met criteria for early vascular ageing (≥9.4 m/s). Over a median follow-up of 67.4 months, 58 first MACE (8.7%) and 58 deaths (8.7%) occurred. In multivariable cause-specific Cox models, each 1 m/s higher baseline ePWV was independently associated with MACE (hazard ratio [HR] 1.16, 95% confidence interval [CI] 1.02-1.32; p = 0.025). The adjusted HRs were 1.18 (95% CI 1.00-1.39; p = 0.054) for arterial thrombosis and 0.98 (95% CI 0.74-1.28; p = 0.860) for venous thromboembolism. For OS, ePWV lost significance after adjustment for age (HR 0.92, p = 0.670). Among JAK2-mutated patients, JAK2 V617F variant allele fraction showed a significant correlation with ePWV (ρ = 0.134; p = 0.022). These findings identify ePWV as a scalable marker of vascular ageing associated with cardiovascular risk in MPN, warranting prospective validation.
Essential thrombocythaemia (ET) in adolescents and young adults (AYA, 15-39 years) is a distinct entity with an incompletely defined prognosis. In this multicentre retrospective study, 1728 ET patients from 29 centres across China were stratified into AYA (n = 328) and non-AYA (≥40 years, n = 1400) cohorts. We compared their clinical profiles, genomic landscapes, long-term outcomes and risk factors for progression to post-ET myelofibrosis (MF). AYA patients had fewer cardiovascular risks and lower thrombosis rates, but higher rates of extreme thrombocytosis. Molecularly, AYA patients were enriched for calreticulin (CALR) mutations, whereas Janus kinase 2 (JAK2) predominated in older patients. The burden of non-driver mutations (tet methylcytosine dioxygenase 2 [TET2], DNA methyltransferase 3A [DNMT3A], ASXL transcriptional regulator 1 [ASXL1], SH2‑B adaptor protein 3 [SH2B3]) was lower in AYA patients. Consequently, AYA patients achieved superior long-term outcomes across all key survival endpoints, including overall, myelofibrosis-free and leukaemia-free survival. Analysis of post-ET MF progression risks identified age-specific patterns: CALR mutations are enriched in younger patients and show an age-specific association with MF progression. AYA-ET constitutes a unique clinicomolecular subtype with a favourable prognosis, supporting age-stratified management. The enrichment of CALR mutations and their specific link to MF progression in young patients underscore the urgent need for targeted therapies against CALR-mutant clones.
Complete remission (CR) rates for patients with acute myeloid leukaemia (AML) treated with intensive chemotherapy (IC) have increasingly improved. Yet, relapse remains a concern with a dismal prognosis. In this report, results are presented of a retrospective analysis comparing salvage therapy based on intermediate (I) or high (H)-dose cytarabine (DAC) (n = 203) and venetoclax-azacitidine (VEN-AZA) (n = 114) for patients with AML in first relapse. Patients (median age 60 years, interquartile range [IQR] 48-67) had reached CR1 after a standard 7 + 3 (n = 305) or CPX351 schedule (n = 12). I/HDAC-based and VEN-AZA salvage, respectively, resulted in CR2 in 66.0% and 66.7% of the patients (p = 0.96). Allogeneic haematopoietic stem cell transplantation (allo-HSCT) was performed for 115 patients in CR2 and 18 in failure. Relapse-free survival was 13.2 (IQR 7.0-not reached [NR]) and 13.7 (IQR 7.8-NR) months while overall survival (OS) was 14.5 (IQR 6.2-NR) and 12.3 months (IQR 4.8-NR; p = 0.41) for patients who received I/HDAC-based salvage and VEN-AZA respectively. In multivariable analysis, relapsing patients ≥60 years with low/intermediate-risk cytogenetics and VEN-AZA had a better OS (p = 0.002), while I/HDAC was more efficient for those with poor risk cytogenetics and < 60-year-old (p = 0.002). VEN-AZA salvage therapy thus appears promising compared with conventional I/HDAC-based IC; this question warrants evaluation in randomized studies.
Chronic hepatitis C virus (HCV) infection is common among patients with human immunodeficiency virus (HIV)-related non-Hodgkin lymphoma (NHL). Although direct-acting antivirals (DAAs) achieve high sustained virological response (SVR) rates, data on their effects in people with HIV and HCV and affected by NHL remain limited. We conducted a retrospective study of 67 consecutive NHL patients with HIV and HCV (48 diffuse large B-cell lymphoma [DLBCL]) treated at 14 Italian centres (2010-2024). All patients received concomitant anti-retroviral therapy (ART). The median age was 51 years. The majority of patients were male (91%) and people who inject drugs (70%). Most patients (94%) received curative first-line immunochemotherapy (I-CT), mainly rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP). After 2016, 26 patients received DAAs (8 concurrently, 18 after I-CT). DAA toxicity was minimal, and SVR was achieved in all cases. With a median follow-up of 91 months, the 3-year overall survival (OS) was 61%. Patients treated with DAAs had better 5-year OS (81% vs. 48%, p = 0.035), with no difference between those who received DAAs subsequently or concurrently with I-CT. Multivariate analysis identified high age-adjusted International Prognostic Index (aaIPI), HIV score 3-6, female sex and absence of rituximab treatment as independent risk factors for OS, while DAAs had a borderline impact (p = 0.055). In conclusion, DAA therapy during or after I-CT is feasible, safe and highly effective in this high-risk group.
The heterogeneity of multiple myeloma (MM) significantly impacts treatment outcomes. Myeloma risk profile (MRP), introduced by the UK Myeloma Research Alliance, is a novel prognostic model for patients with transplant-ineligible newly diagnosed MM (TIE-NDMM) utilizing easily available clinical parameters. In this study, we evaluated the prognostic value of MRP in TIE-NDMM patients treated with novel agents. We retrospectively analysed the data of 799 evaluable MM patients diagnosed between January 2011 and January 2023, extracted from the Japan Clinical Hematology Research Group-EAST (J-CHARGE)-MM database. Overall survival (OS) differed significantly across the three MRP risk groups (p < 0.01). The MRP risk groups remained independently prognostic when adjusted for treatment period and first-line therapy (medium vs. low: hazard ratio [HR], 1.71; p < 0.01; high vs. low: HR, 2.61; p < 0.01). In subgroup analyses, the MRP classification significantly predicted OS in patients treated with bortezomib-based and lenalidomide-based regimens. However, there was no difference in OS between the MRP risk groups in patients treated with daratumumab-based regimens. MRP is a robust prognostic tool for real-world TIE-NDMM patients treated with novel agents. Further studies are warranted to clarify its prognostic utility in the era of front-line anti-CD38 monoclonal antibody-based therapies.
Bispecific antibodies (BsAbs) targeting B-cell maturation antigen (BCMA) or G protein-coupled receptor, class C, group 5, member D (GPRC5D) represent effective options for relapsed or refractory multiple myeloma (RRMM), yet direct comparative evidence remains limited. We performed a systematic review and meta-analysis of studies evaluating BCMA- or GPRC5D-targeted BsAbs in RRMM. Thirty studies comprising 3218 patients were included. Random-effects models were used to pool efficacy and safety outcomes, followed by meta-regression to identify study-level moderators of response. At the recommended phase 2 dose, BCMA- and GPRC5D-targeted BsAbs showed comparable efficacy, with overall response rates (ORRs) of 65% (95% confidence interval [CI], 60%-70%) and 70% (95% CI, 66%-73%) respectively. Rates of ≥very good partial response and complete response were also similar. Any-grade cytokine release syndrome (CRS) was more frequent with GPRC5D BsAbs (57% vs. 74%, p = 0.006), whereas grade ≥3 CRS and other severe toxicities, including neurotoxicity, infections and haematological adverse events (AEs), were broadly comparable. Meta-regression identified prior penta-drug exposure and higher median lines of therapy as negative moderators of response, with prior BCMA-directed therapy further associated with reduced efficacy in BCMA-targeted cohorts. Overall, BCMA- and GPRC5D-targeted BsAbs demonstrated comparable efficacy. Among the commonly reported non-target specific AEs, the safety profile was broadly comparable. The response appeared to be influenced primarily by treatment history.
Feline McDonough sarcoma (FMS)-like tyrosine kinase 3 internal tandem duplication (FLT3-ITD) mutations are clinically important in acute myeloid leukaemia (AML). We developed and validated a machine learning model using routine laboratory tests to estimate the probability of FLT3-ITD mutations in newly diagnosed AML to prioritise rapid molecular testing. Consecutive patients treated at Ruijin Hospital during 2021-2024 were included. Those diagnosed in 2021-2023 comprised the training cohort, and those in 2024 formed the internal temporal validation cohort, and the BeatAML2 cohort served as external validation. Following Boruta feature selection, seven machine learning algorithms were evaluated via area under the receiver operating characteristic curve (AUC). The optimal model was interpreted using SHapley Additive exPlanations (SHAP) and deployed as a web-based calculator. Overall, 514 patients were included (training, n = 254; validation, n = 84; external validation, n = 176). Boruta algorithm selected five candidate features, and a simple four-feature model was constructed. Gradient boosting machine (GBM) performed best, with AUCs of 0.847, 0.772 and 0.760 in the training, internal validation and external validation cohorts respectively. SHAP analysis showed absolute blast count contributed most to the model. The GBM model may help identify patients with newly diagnosed AML who should be prioritised for rapid molecular testing for FLT3-ITD mutations.
We report the results of an open-label, single-centre phase 4 clinical trial evaluating haploidentical haematopoietic stem cell transplantation (Haplo-HSCT) in patients with transfusion-dependent thalassaemia (TDT). A total of 134 patients with TDT were enrolled; the median age was 8.7 years (interquartile range [IQR], 6.0-11.7 years; range, 3-20 years). All patients received a uniform conditioning regimen consisting of busulfan, cyclophosphamide, fludarabine and anti-thymocyte globulin (ATG). Graft-versus-host disease (GVHD) prophylaxis included methotrexate (MTX), mycophenolate mofetil (MMF) and tacrolimus. The primary end-point was 2-year overall survival (OS). Median follow-up is 23.4 months (IQR: 11.5-38.7; range: 6.1-81.5). The 2-year OS, event-free survival (EFS) and graft-versus-host disease-free, relapse-free survival (GRFS) rates were 93.4%, 92.6% and 77.5% respectively. The cumulative incidence rates of aGVHD, grade 2-4 aGVHD and grade 3-4 aGVHD were 47.8%, 30.9% and 12.5% respectively. Donor-specific antibodies (DSAs) and male-recipient/female-donor pairing were associated with inferior OS (p = 0.021; p = 0.010) and EFS (p = 0.040; p = 0.020). Hepatomegaly (≥5 cm) was associated with inferior OS (p = 0.037). Collectively, these findings support Haplo-HSCT as a key curative option for TDT patients in the absence of fully matched donors.
After adjusting for confounders, the ibrutinib cohort had significantly better overall survival (adjusted hazard ratio, 0.39; 95% confidence interval, 0.23-0.68; p = 0.0008) than the allogeneic haematopoietic stem cell transplantation (alloHSCT) cohort. Our large, retrospective analysis suggests that ibrutinib treatment may offer improved overall survival and progression-free survival compared to alloHSCT in patients with relapsed/refractory del(17p) chronic lymphocytic leukaemia/small lymphocytic lymphoma.
