Annals of Hematology最新文献

Aplastic anemia (AA) is an immune-mediated bone marrow failure syndrome marked by pancytopenia and depletion of hematopoietic stem cells. Although autoreactive T cells and inflammatory cytokines are involved in its pathogenesis, their causal relationships remain unclear. We conducted a bidirectional two-sample Mendelian randomization using large-scale genome-wide association study datasets to explore the causal roles of 731 immune cell traits and 91 inflammatory cytokines in AA. The primary analysis used inverse-variance weighting, with additional sensitivity analyses including MR-Egger regression and MR-PRESSO. Mediation analysis was performed to determine whether cytokines mediate the effects of immune cells on disease risk. We identified 12 immune cell traits conferring protection against aplastic anemia (AA). The strongest protective association was observed for TD CD4 + AC (OR = 0.890, 95% CI: 0.817–0.968, P = 0.007). Conversely, 24 immune cell traits demonstrated positive associations with increased AA risk, with the strongest association found for CD127 − CD8br %T cell (OR = 1.135, 95% CI: 1.032–1.247, P = 0.009). Elevated levels of leukemia inhibitory factor (LIF) and its receptor were associated with reduced AA risk. Mediation analysis indicated partial mediation by LIF of the associations linking dendritic cells, HLA-DR + + monocytes, and AA risk. Sensitivity analyses supported the robustness of these findings. This study established causal relationships between specific immune cell phenotypes, inflammatory cytokines, and AA. Importantly, LIF partially mediated the effects of immune cells on AA, suggesting the LIF-LIFR axis as a potential therapeutic target.

Although nucleophosmin 1 (NPM1) mutation is generally considered a favorable prognostic biomarker in acute myeloid leukemia (AML), its clinical behavior is heterogeneous. A subset of NPM1-mutated patients continues to experience adverse outcomes despite their favorable genotype. We conducted a retrospective analysis of newly diagnosed NPM1-mutated AML patients treated at The First Affiliated Hospital of China Medical University, between June 2015 and June 2025, aiming to identify clinical characteristics and prognostic determinants associated with vascular events. A total of 120 patients fulfilled the inclusion criteria, with a median age of 55 years. The median follow-up was 20.7 months, and the median event-free survival (EFS) was 16.2 months. Forty-seven patients(39.2%) developed major organ vascular events. Compared to those without vascular events, patients who experienced vascular complications more frequently exhibited a CD34⁻/HLA-DR⁻ immunophenotype and harbored concomitant FLT3-ITD/TKD mutations. Notably, of the 37 classified as favorable-risk AML, 10(27%) suffered vascular events. One-year estimated overall survival (OS) was significantly lower in the vascular event group than in the non-event group (48.6% vs. 75.8%, p = 0.008), while the 60-day mortality rate was markedly higher (27.3% vs. 3.0%, p < 0.001). Both a CD34⁻/HLA-DR⁻ immunophenotype and FLT3-ITD/TKD co-mutation were identified as risk factors for vascular events. In summary, patients with NPM1-mutated AML who developed vascular events predominantly exhibited an “APL-like” (acute promyelocytic leukemia-like) phenotype, and FLT3-ITD/TKD co-mutation emerged as an independent predictor of vascular complications in this subgroup.

Immune checkpoint inhibitors (ICIs) may lead to rare but severe hematological adverse events, including pure red cell aplasia (ICI-PRCA). We conducted a nationwide retrospective national case-series and compiled our data with patients from the VigiBase international pharmacovigilance database. We gathered 16 cases of ICI-PRCA Among all the grade ≥ 3 adverse event reported in VigiBase, PRCA was more than two times more reported with ICI compared to all other drugs ROR [IC95%] 2.43 [1.89;3.13]. We identified 15 additional patients in our literature review. Half of the patients were women (52%), median age 63 years (range: 29–90). ICIs were mostly used in melanoma (48%) and lung adenocarcinoma (16%) in metastatic stage (29%). Monoclonal antibody targeting programmed death-1 (PD-1) alone was involved in 61% of cases. The median time from ICI initiation to symptoms onset was 63 days (range: 28–465). Grade ≥3 anemia in found in all cases (100%). Thirteen patients (42%) were treated with corticosteroids as monotherapy with an ORR of 69%. Thirteen patients (42%) required additional therapy. ICI therapy was discontinued in all patients and rechallenge was attempted in 4 patients (13%), with recurrence in one case. ICI-PRCA is a severe and early-onset immune adverse event. Both systemic steroids and cicloporine A seems effective in these immune-related forms. 

The Smart Start trial demonstrated the combination of ibrutinib, rituximab, and lenalidomide resulted in impressive efficacy in newly diagnosed non-GCB diffuse large B-cell lymphoma (DLBCL). However, ibrutinib was associated with increased unexpected toxicity in elderly patients. Zanubrutinib and orelabrutinib have better target selectivity. This single-center, real-world, off-label study retrospectively included patients with newly diagnosed DLBCL who received SMART regimen (rituximab, lenalidomide plus BTK inhibitor) between January 2021 and June 2024. The outcomes included objective response rate (ORR), progression-free survival (PFS), overall survival (OS), and safety. A total of 84 patients were analyzed for efficacy with a median follow-up of 13.5 (range, 2.5–42.2) months. The OR2 regimen (orelabrutinib, rituximab and lenalidomide) was administered to 60.7% (51/84) patients, and ZR2 regimen (zanubrutinib, rituximab and lenalidomide) to 39.3% (33/84) patients. The median PFS was 32.4 months, with PFS rates of 85.3% at 1-year, and 63.3% at 2-year. Median OS was not reached, with the estimated 1-, 2- and 3-year OS rates of 93.4%, 85.1%, and 84.7%, respectively. Fifty-one (60.7%) patients reported grade ≥ 3 adverse events, with the most common being neutropenia (54.8%). This real-world data support SMART regimen as a potential treatment option for DLBCL patients, with promising efficacy and acceptable safety.

KIT mutations are well-established as poor prognostic markers in core binding factor AML (CBF AML). However, data on KIT mutation in CBF-negative (CBF-neg) AML remains scarce. This retrospective study aimed to characterize the clinical features and outcomes of patients with KIT mutant (KIT mut)/CBF-neg AML. We conducted a retrospective study in our single center and identified non-M3 de novo AML with KIT mutations by next-generation sequencing (NGS) from January 2018 to June 2024. Core binding factor (CBF) AML or patients with underlying systemic mastocytosis were excluded. The clinical data of KIT mut/CBF-neg AML was collected and analyzed. 45 patients were enrolled in the cohort, including 3 patients with secondary AML. The median variant allele frequency (VAF) of KIT mutation was 41.2% and the most frequent comuations were CEBPA (27/45, 60%), WT1 (12/45, 26.7%) and NRAS (11/45, 24.4%). After a median follow-up of 48 months, the median event-free survival (EFS) and overall survival (OS) of the cohort was 15.3 months and 24.1 months, respectively. Patients with KIT exon 17 mutations tended to harbor an inferior EFS and OS. In conclusion, KIT mutant/CBF-neg AML was a complex subgroup with dismal prognosis and NIT might bring benefits for those patients.

Elderly people are facing an increasing burden of non-Hodgkin lymphoma. However, accurate information on the NHL burden among elderly people remains limited. On the basis of the Global Burden of Diseases 2021, we described the global burden of non-Hodgkin lymphoma in people aged ≥ 65 years and estimated the effects of age, period, and birth cohort on disease burden. The estimated number of prevalent cases among people aged ≥ 65 years was 1,147,321 worldwide in 2021. The age-standardized prevalence rate was 148.21 per 100,000 population. There were 306,296 new cases and 158,813 deaths. The age-standardized rates of incidence and mortality were 59.20 and 21.46 per 100,000 population, respectively. The disease burden was greater in men than in women, and it varied across regions. High-sociodemographic index countries recorded the highest age-standardized incidence and mortality rates, while low-sociodemographic index countries exhibited relatively low incidence rate but high mortality rate. From 1990 to 2021, the incidence and prevalence tended to increase, whereas mortality and disability-adjusted life years tended to decrease. Age effects tended to increase overall mortality risk with increasing age. Period effects showed improvements in mortality after 2004, and cohort effects revealed progressively lower mortality risks in successive birth years after 1922. It is estimated that the age-standardized incidence rate will be relatively stable, whereas the age-standardized mortality rate is expected to decline rapidly by 2035. A focus on elderly men and the implementation of region-specific improvements in clinical diagnosis and treatment are needed.

Human immunodeficiency virus (HIV) is a rare cause of thrombotic microangiopathies (TMA), that can present either with normal ADAMTS13 activity (referred as HIV-related TMA) or suppressed ADAMTS13 activity (referred as HIV-related acquired thrombotic thrombocytopenic purpura, aTTP). The distinct characteristics and management of these two conditions is poorly known, given their rarity and often overlapping features. Here, we report the case of a 46-year-old female patient with TTP who received a diagnosis of HIV infection at her ADAMTS13 relapse and obtained complete remission only with antiretroviral therapy (ART). Moreover, we summarize the existing evidence in the literature about clinical presentation, outcomes and treatment of HIV-related aTTP/TMA.

Large B-cell lymphoma (LBCL) frequently affects very elderly patients, and treatment decisions for those aged ≥ 80 years are complicated by heterogeneity in frailty. Evidence focusing specifically on prognostic factors in this age group treated with rituximab-containing chemotherapy remains limited. In this study, we retrospectively analyzed 137 patients aged ≥ 80 years with LBCL who received rituximab-based chemotherapy at our institution to identify prognostic factors. The median age was 83 years. Of 137 patients, 51 (37.2%) were > 85 years, and 92 (67.0%) were classified as high-risk by the elderly prognostic index. Cell of origin was determined in 109 patients (79.6%) using the Hans classifier: 46 (33.6%) were germinal center B-cell (GCB) subtype and 63 (46.0%) non-GCB. Median serum albumin at diagnosis was 3.50 g/dL (range, 1.70–4.80). First-line therapies included R-CHOP in 93 patients (67.9%), R-THP-COP in 30 (21.9%), Pola-R-CHP in 4 (2.9%), DA-EPOCH-R in 3 (3.2%), and rituximab monotherapy in 7 (5.1%). The 2-year overall survival (OS) and progression-free survival (PFS) rates were 58.1% and 48.1%, respectively. Multivariate analysis identified four independent adverse prognostic factors for both OS and PFS: age ≥ 85 years (OS HR 2.25, PFS HR 2.11), serum serum albumin < 3.5 g/dL (OS HR 2.25, PFS HR 2.46), non-GCB (OS HR 2.20, PFS HR 2.21) and EPI-high-risk (OS HR 2.83, PFS HR 1.81). In LBCL patients aged ≥ 80 years treated with rituximab-containing chemotherapy, low serum albumin and non-GCB subtype are independent adverse prognostic factors. These accessible indicators should inform treatment eligibility decisions in very elderly patients.

To investigate possible role of IGF1R/PI3K/Akt/mTOR signal pathway related genes in the pathogenesis of ITP. Akt/mTOR Total Protein 11-plex Magnetic Bead Kit was used for measurement of related genes of IGF1R/PI3K/Akt/mTOR signal pathway in ITP patients and healthy controls. Genome-wide patterns of DNA methylation and gene expression with IGF1R/PI3K/Akt/mTOR signal pathway were determined in ITP and controls respectively. Elevated protein levels of IGF1R was found in ITP patients compared to healthy controls [Median Fluorescence Intensity (inter-quartile range, IQR), 2551.0 (941.1-4213.0) vs 786.50(276.0-2555.0), P<0.05], the level of p70S6K in ITP patients with active disease was significantly higher [801.0(609.5-1012.0)] than that in healthy controls [652.3(531.8-776.6), P<0.05]. Further study by Genome-wide patterns of DNA methylation showed that differentially methylated regions (DMRs) of IRS1, TSC2 and RPS6KA1 were found in ITP patients. Moreover, methylation variable position of IGF1R was also found in ITP patients. Abnormal elevated expression of IGF1R may play a role through abnormal methylation of IGF1R/PI3K/Akt/mTOR signal pathway in the pathogenesis of ITP.

Acute Myeloid Leukemia (AML) remains challenging to treat, especially in cases with mutations in the BCL-6 co-repressor (BCOR), which are associated with poor prognosis and chemo-resistance. In this study, we reveal a synthetic lethal interaction between BCOR and dihydroorotate dehydrogenase (DHODH). We demonstrate that BCOR-deficient cells have a heightened sensitivity to DHODH inhibitors such as brequinar and leflunomide, that are already in clinical use. We confirm that DHODH inhibition selectively induces cell death in BCOR-mutant cells in multiple cellular models, in malignant and non-malignant cells, through chemical and genetic manipulation. Interestingly, we find that the dependency on DHODH does not stem from its role in de novo pyrimidine biosynthesis disruption. Rather, DHODH’s role in the electron transport chain, essential for mitigating reactive oxygen species, may be the physiological vulnerability that pushes BCOR-mutant cells toward cell death when DHODH is inhibited. DHODH inhibitors could be repurposed as targeted therapies for BCOR-mutant tumors, offering a promising strategy for precision medicine in AML and other cancers.