Blood and Lymphatic Cancer-Targets and Therapy最新文献

Introduction: Acute myeloid leukemia (AML) prognosis remains challenging due to limited biomarkers integrating tumor microenvironment (TME) dynamics. Neutrophils, key mediators of immune regulation, exhibit dual roles in cancer progression, yet their prognostic significance in AML is poorly defined. This study aimed to construct a neutrophil-related gene signature for AML risk stratification and explore its clinical and immunological implications.

Methods: Utilizing transcriptomic and clinical data from TCGA (The Cancer Genome Atlas), GEO (Gene Expression Omnibus), and OHSU cohorts (n=1537), we identified 148 neutrophil-related genes through literature mining. Prognostic genes were selected via univariate Cox regression and LASSO regression (R packages: survival, glmnet). A 5-gene model (CSF3R, BRAF, FFAR2, CD300A, CD37) was validated across internal (TCGA) and external cohorts (GSE10358, GSE14468, OHSU). Immune profiling, drug sensitivity analysis (GDSC database), and TIDE scoring were performed to assess immunotherapy relevance.

Results: The neutrophil-based model stratified AML patients into high- and low-risk groups with distinct overall survival (OS, p<0.0001 in TCGA). Multivariate Cox analysis confirmed its independence from age, FLT3, and TP53 mutations (HR=2.14, p=0.015). CD37 emerged as the strongest prognostic marker (AUC 5-year=0.680, p=0.0026), correlating with immunosuppressive TME features: elevated myeloid-derived suppressor cells (MDSCs, p<0.01), Treg infiltration (p <0.05), and upregulated immune checkpoints (PD1, CTLA4, LAG3; p<0.001). High CD37 expression predicted immunotherapy responsiveness (TIDE score, p=0.004) and interacted with 146 potential therapeutic agents (eg, BCL2 inhibitors).

Discussion: This study advances a novel 5-gene prognostic model integrating neutrophil biology into AML risk stratification. CD37, a key regulator of immune evasion, serves as a dual biomarker for prognosis and immunotherapy prediction. While validated across multiple cohorts, experimental studies are warranted to unravel CD37's mechanistic role. Our findings highlight the potential of neutrophil-centric biomarkers in guiding personalized AML therapy.

Introduction: Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is the only curative treatment for higher-risk myelodysplastic syndromes (MDS), but optimal timing and donor selection remain controversial.

Methods: We conducted a retrospective analysis of 70 higher-risk MDS patients classified by the revised International Prognostic Scoring System (IPSS-R) undergoing allo-HSCT. Patients were stratified by: 1) the interval from diagnosis to allo-HSCT (early: <6 months vs later: ≥6 months); 2) pre-transplant treatment cycles (fewer: <2 vs more: ≥2); 3) remission status (complete remission [CR] / partial remission [PR] vs non-remission [NR]), and 4) donor type (sibling vs unrelated cord blood [UCB]).

Results: The results showed a significantly higher 3-year overall survival (OS) in the early HSCT group (70% vs 50%, p = 0.05) with lower transplant-related mortality (TRM) (22.7% vs 46.5%, p = 0.0205). Although more pre-transplant treatment cycles were linked to a lower relapse rate (2.3% vs 15.4%, p = 0.0403), they did not significantly affect OS or TRM. Early HSCT emerged as the only significant factor influencing both OS (Hazard Ratio [HR] 2.84, p = 0.01) and TRM (HR 3.21, p = 0.01). While no significant differences were noted between sibling HSCT and unrelated cord blood transplantation (UCBT) for OS and TRM, UCBT demonstrated a lower incidence of chronic graft-versus-host disease (cGVHD) (19.0% vs 52.9%, p = 0.003).

Discussion: Our findings suggest early allo-HSCT may optimize outcomes in higher-risk MDS. In settings where sibling donors are unavailable, UCBT could serve as a potential alternative, though this observation requires validation in prospective multicenter studies to account for inherent selection biases and confounding factors.

Background: Primary central nervous system lymphoma (PCNSL) is a highly aggressive extranodal non-Hodgkin's lymphoma. Moreover, there is currently no specific prognostic model for elderly PCNSL patients.

Methods: This study retrospectively selected patients diagnosed with PCNSL between 1975 and 2016 from the National Cancer Institute Surveillance, Epidemiology, and End Results Database (SEER NCI). The COX model was used to determine the risk factors for overall survival (OS) and disease-specific survival (DSS). The prognostic prediction models for DSS and OS were developed by integrating significant covariates identified through multivariate analysis.

Results: A total of 3,554 patients with PCNSL were included in this retrospective study based on inclusion and exclusion criteria. Significant differences exist in clinical profiles between elderly (≥60 years) and younger (<60 years) patients with PCNSL. The results showed that the age at diagnosis, pathological subtype, whether or not they have undergone surgical treatment, and whether or not they have received chemotherapy are independent risk factors for DSS, among elderly PCNSL patients. In addition to the risk factors, etc for DSS, human immunodeficiency virus (HIV) infection was also an independent risk factor for OS. Based on this, we developed nomograms to estimate OS and DSS for 1, 2, and 3 years.

Conclusion: This study found differences in baseline data between elderly PCNSL patients and younger PCNSL patients. Surgery and chemotherapy are associated with better OS and DSS. However, in the long run, radiotherapy is not beneficial to OS and DSS of elderly PCNSL patients.

This podcast episode reviews recent advances in the treatment of IDH1-mutant acute myeloid leukemia (AML), focusing on the mechanisms, efficacy, and safety profiles of approved IDH1 inhibitors. The purpose is to present expert insights and clinical data from key trials that underscore the clinical benefits of these targeted therapies. Through discussion of key findings from pivotal clinical trial studies, including data supporting the use of these agents in both newly diagnosed and relapsed or refractory (R/R) settings, the episode highlights significant outcomes such as increased overall response and prolonged duration of remission in patients treated with IDH1 inhibitors. The analysis examines critical factors including treatment sequencing, combination regimens, and toxicity management, particularly the monitoring and mitigation of differentiation syndrome and QT interval prolongation. Emphasis is placed on the clinical rationale for individualized therapy selection and the importance of repeat mutation testing at diagnosis and relapse to guide treatment decisions. The results obtained from these clinical trials provide evidence that integrating oral targeted agents into the management of relapsed or refractory AML improves patient outcomes, especially for older or unfit patients who cannot undergo intensive chemotherapy. In conclusion, the episode demonstrates that the evolving use of IDH1 inhibitors, supported by rigorous clinical evidence, represents a promising advance in AML treatment by offering more precise, effective, and tolerable therapeutic options.

Acute myeloid leukemia (AML) is a heterogeneous malignancy characterized by diverse genetic mutations, including IDH1 and IDH2, which are present in approximately 15-20% of cases. Recent clinical practice guidelines, including the 2025 NCCN guidelines, emphasize the importance of comprehensive mutational profiling at diagnosis and at relapse to guide targeted treatment strategies for patients with refractory or relapsed (R/R) AML. IDH1-mutations, which occur in 5-7% of AML cases, result in the production of the oncometabolite 2-hydroxyglutarate (2-HG), disrupting cellular differentiation. IDH1-inhibitors, such as ivosidenib and olutasidenib, block this aberrant metabolic pathway, allowing for differentiation and apoptosis of leukemia cells. Given the rarity of these mutations, comprehensive molecular testing remains essential to optimize therapeutic decision-making.

Leukemia remains a major health challenge in Africa, where limited access to advanced diagnostic technologies often leads to delayed diagnosis and suboptimal treatment outcomes. This review explores the role of WHO-supported laboratory innovations in advancing leukemia diagnosis across the continent. It examines key technologies such as molecular diagnostics, flow cytometry, and cytogenetics, highlighting how these innovations have enhanced the accuracy and speed of leukemia detection in resource-limited settings. By facilitating early and precise diagnoses, these technologies are improving patient management and treatment outcomes. Despite the promising advancements, significant barriers to widespread implementation persist, including high costs, inadequate infrastructure, and a shortage of trained personnel. WHO's efforts to address these challenges through regional collaborations, technical assistance, and capacity-building initiatives are pivotal in overcoming these obstacles. The establishment of specialized diagnostic centers and the integration of advanced technologies into national healthcare systems are key strategies to expand access and improve leukemia care in Africa.

In the first episode of the AML Expert Series, titled Unveiling the Mysteries of Molecular Testing in AML: A Guide for Oncologists, experts from Yale Cancer Center and MD Anderson Cancer Center describe the evolving landscape of molecular diagnostics in acute myeloid leukemia (AML). The discussion traces the shift from morphology- and immunophenotype-based classification to genomics-driven stratification, catalyzed by advancements in next-generation sequencing (NGS). Discussants emphasize the clinical importance of identifying key genetic mutations-such as FLT3, IDH1/2, TP53, NPM1, KMT2A, and NUP98-to inform prognosis and guide use of targeted therapies. They review the sensitivity and applications of testing modalities including Sanger sequencing, NGS, PCR, and capillary electrophoresis, and highlight how combining DNA and RNA analyses enhances detection of both mutations and gene fusions. Practical insights are offered on assay selection, test interpretation, and turnaround times, noting that while NGS is generally adequate for most targets, single-gene PCR may be needed for urgent decision-making. The episode concludes by underscoring the need for oncologists to partner with pathologists and review test coverage data to ensure appropriate molecular profiling. These insights support the integration of precise molecular diagnostics into routine AML management, enhancing personalized therapy and improving clinical outcomes.

Background: Multiple myeloma (MM) is a haematological malignancy, driven by complex interactions between tumor and immune cells. Nevertheless, the overall pattern of immune cells and MM pathogenesis within the bone marrow tumor microenvironment (BM-TME) remains underexplored.

Methods and results: Firstly, we performed Mendelian Randomization analysis for 731 immunocyte phenotypes and MM, identifying 21 immune traits significantly associated with increased MM risk (OR>1, P_FDR<0.05). Flow cytometry analysis confirmed that the MFI of CD14 (p<0.01) and HLA-DR (p<0.05) on CD14⁺ monocytes was significantly elevated in early-stage MM. Secondly, we analyzed monocytes gene characteristics in the MM BM-TME via scRNA-seq, identifying 1,447 differentially expressed genes (moDEGs) (p<0.05). Subsequently, based on 482 prognostic moDEGs, we developed and validated an optimal model, termed the Monocyte-related Gene Prognostic Signature (MGPS), by integrating 101 predictive models generated from 10 machine learning algorithms across multiple transcriptome sequencing datasets. MGPS was found to be an independent prognostic factor for MM (HR 2.72, 95% CI: 1.84-4.0, p<0.001), and the MGPS-based nomogram exhibits robust and reliable predictive performances. Next, MM patients with the low MGPS score exhibiting significantly better overall survival (OS) than the high MGPS score (p<0.0001). Finally, we evaluated the predictive value of MGPS for treatment response and explored its molecular mechanisms. Results indicated that low-risk patients are more likely to benefit from immunotherapy, while a high MGPS score reflects cellular functional impairment.

Conclusion: Our findings reveal a complex interplay between immune cells and MM. Through multi-omics analyses and machine learning algorithms, we established a robust monocyte-related prognostic signature. By identifying high-risk patients, MGPS may help refine treatment strategies, such as intensifying immunomodulatory therapies, potentially improving survival and immunotherapy outcomes for MM patients.

Purpose: Elranatamab is a BCMAxCD3 bispecific antibody approved for the treatment of relapsed/refractory multiple myeloma (RRMM). The registrational Phase 2 MagnetisMM-3 (NCT04649359) trial was single-armed; the aim of this indirect comparison was to contextualize the efficacy of the most recent 28.4-month follow-up data cut from this trial, allowing for more mature data, with real-world data serving as an external control.

Patients and methods: We conducted a retrospective cohort study to indirectly compare the efficacy observed in the elranatamab arm of MagnetisMM-3 Cohort A (BCMA-naïve; N=123) from the March 26, 2024 data cut with COTA, a US-based oncology electronic health record database, as an external control. All MM patients with triple-class refractory disease who initiated a new line of therapy (representing real-world physician's choice) between November 2015 and August 2023 in the COTA database were included. MagnetisMM-3 inclusion (eg, ≥18 years, measurable disease within 90 days of the index, Eastern Cooperative Oncology Group [ECOG] ≤ 2) and exclusion criteria (eg, plasma cell leukemia, smoldering MM) were applied to obtain comparable patient populations across sources. The elranatamab cohort was compared with the physician's choice cohort on progression-free survival (PFS), overall survival (OS), and duration of response (DOR) using Cox proportional hazard models implementing inverse probability of treatment weighting to adjust for any remaining imbalances on confounding variables.

Results: N=123 patients treated with elranatamab were compared with 577 patients treated with real-world physicians' choice of therapy. Compared with physician's choice, elranatamab significantly improved PFS (HR = 0.38 [0.22, 0.65], p<0.05), OS (HR = 0.58 [0.35, 0.96], p<0.05), and DOR (HR = 0.16 [0.07, 0.34], p<0.05).

Conclusion: In this comparison of patients from the MagnetisMM-3 trial and real-world patients who resemble those from the trial, patients treated with elranatamab exhibited significantly better clinical outcomes compared with treatments currently used in real-world clinical practice.

T-cell engagers (TCEs) are engineered to bind both the CD3 subunit on T-cells and specific antigens on tumor cells, triggering T-cell activation and tumor cell lysis. TCEs targeting B-cell maturation antigen (BCMA) and G-protein-coupled receptor, class C, group 5, member D (GPRC5D) have demonstrated significant clinical activity in heavily pretreated patients with relapsed/refractory multiple myeloma (RRMM). As a monotherapy, TCEs have had overall response rates (ORRs) of over 60%, with deep and durable hematological responses. Common toxicities include cytokine release syndrome (CRS), infections, and on-target off-tumor effects. Ongoing research looks to enhance the efficacy and tolerability of TCEs for the next generation of products to play an even bigger role in treating patients with MM.