Annals of Hematology最新文献

There is increasing evidence that points to ubiquity of clonal haematopoiesis of indeterminate potential (CHIP) especially with rising age. CHIP has been associated with a multitude of inflammatory, cardiovascular and malignant conditions. In this review article, we evaluate the current literature on CHIP and clinical associations with cardiovascular and haematological diseases. We also discuss high risk features of CHIP that predispose to haematological malignancies, as well as further zoom in on the association between clonal haematopoiesis and therapy-related myeloid neoplasm (tMN). CHIP increases risk of atherosclerotic cardiovascular disease and other cardiovascular conditions such as heart failure, arrhythmias and valvular disease. Hematopoietic clones with mutations in TP53 and spliceosome gene U2AF1 in particularly have repeatedly been shown to increase risk for AML. Other factors such as increased clonal size i.e. variant allele fraction (VAF), clonal complexity have also been shown to increase risk for haematological malignancy. In this comprehensive review, we consolidate the most recent advancements in the understanding of clonal haematopoiesis of indeterminate potential (CHIP) and its associations with cardiovascular and haematological disease. This review is also one of the first to focus on potential biochemical markers routinely utilized in clinical practice that may suggest a more sinister progression of CHIP. We hope to provide physicians with a nuanced perspective on the evolving landscape of CHIP, and offering valuable insights into its clinical implications and potential prognostic indicators.

In classic Hodgkin-lymphoma (cHL), only a few cases recur, and only a limited fraction of patients is primary-refractory to standard-polychemotherapy. Underlying genomic features of unfavorable clinical courses remain sparsely characterized. Here, we investigated the genomic characteristics of primary-refractory/relapsed cHL in contrast with responders. Therefore, ultra-deep next-generation panel-sequencing was performed on a total of 59 FFPE-samples (20 responders, 26 relapsed (rHL: 11 initial-diagnosis, 15 relapse) and 13 primary-refractory (prHL: 8 initial-diagnosis, 5 progression) from 44 cHL-patients applying a hybrid-capture approach. We compared samples associated with distinct disease courses concerning their oncogenic drivers, mutational signatures, and perturbed pathways. Compared to responders, mutations in genes such as PMS2, PDGFRB, KAT6A, EPHB1, and HGF were detected more frequently in prHL/rHL. Additionally, we observed that in rHL or prHL, BARD1-mutations occur, whereas ETV1, NF1, and MET-mutations were eliminated through clonal selection. A significant enrichment of non-synonymous variants was detected in prHL compared to responders and a significant selection process in favor of NOTCH-pathway mutations driving rHL or prHL was observed. However, our analysis revealed a negative selection process for non-synonymous variants affecting the hippo-pathway. This study delineates distinct mutational signatures between responders and rHL/prHL, whilst illustrating longitudinal dynamics in mutational profiles using paired samples. Further, several exploitable therapeutic vulnerabilities for rHL and prHL were identified.

Monitoring anemia recovery is crucial for clinical intervention. Morphological assessment of red blood cells (RBCs) with peripheral blood smears (PBSs) provides additional information beyond routine blood tests. However, the PBS test is labor-intensive, reliant on manual analysis, and susceptible to variability in expert interpretations. Here we introduce a deep semi-supervised learning method, RBCMatch, to classify RBCs during anemia recovery. Using an acute hemolytic anemic mouse model, PBS images at four different time points during anemia recovery were acquired and segmented into 10,091 single RBC images, with only 5% annotated and used in model training. By employing the semi-supervised strategy Fixmatch, RBCMatch achieved an impressive average classification accuracy of 91.2% on the validation dataset and 87.5% on a held-out dataset, demonstrating its superior accuracy and robustness compared to supervised learning methods, especially when labeled samples are scarce. To characterize the anemia recovery process, principal components (PCs) of RBC embeddings were extracted and visualized. Our results indicated that RBC embeddings quantified the state of anemia recovery, and the second PC had a strong correlation with RBC count and hemoglobin concentration, demonstrating the model's ability to accurately depict RBC morphological changes during anemia recovery. Thus, this study provides a valuable tool for the automatic classification of RBCs and offers novel insights into the assessment of anemia recovery, with the potential to aid in clinical decision-making and prognosis analysis in the future.

Background: Patients with fever of unknown origin (FUO) can sometimes be accompanied by haemophagocytic lymphohistiocytosis (HLH), a life-threatening disease. The prognostic model and specific markers for the early prognosis and the optimized treatment regimen are of considerable research interest.

Results: A total of 135 FUO/HLH patients were enrolled and classified according to the 60-day outcomes following diagnosis. 79 patients (including 5 patients lost in follow-up) enrolled from 2007 to 2015 served as the derivation cohort, and 56 patients from 2016 to 2023 served as the validation cohort. In the derivation cohort, 27 patients (27/74, 36.5%) survived within 60 days and multivariate analyses showed that age > 67 years (P = 0.003), baseline PLT < 42 × 10^9/L (P = 0.012) and LDH > 1505 U/L (P = 0.002) were associated with a higher mortality rate in HLH patients. The external validation proved the reliability of the prediction model. In derivation cohort, the median alteration of PLT (△PLT) were + 78 × 10^9/L and - 17 × 10^9/L in the survival and non-survival groups, respectively (P < 0.001). The median △LDH was - 197.5U/L in the survival group, while in the non-survival group was + 119U/L (P < 0.001).

Conclusions: Age, baseline LDH and PLT levels may predict early mortality in secondary HLH patients and identify patients in critical conditions. △LDH and △PLT levels were of high value to monitor the efficacy of therapeutic regimen and the disease progression in HLH patients.

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a highly aggressive and rare hematologic malignancy characterized by poor response to multiagent chemotherapy and dismal survival outcomes of 8-16 months. Tagraxofusp, the first-in-class CD123-directed antineoplastic agent, has emerged as a highly effective therapy and is the only FDA approved drug for BPDCN. Nonetheless, significant treatment-related toxicities with tagraxofusp such as hepatotoxicity and capillary leak syndrome are unfortunately not uncommon and can be prohibitive for older or unfit patients. The success of venetoclax (VEN) with a hypomethylating agent (HMA) has recently been described in the literature however, clinical outcomes are limited to case reports and small case series. To confirm these findings, we performed a multicenter, retrospective cohort study utilizing the TriNetX Networks database to compare survival outcomes between BPDCN patients (≥60 years-of-age) who received VEN + HMA versus tagraxofusp. In total, 32 and 39 patients received VEN + HMA and tagraxofusp, respectively, between February 1, 2019 and September 1, 2024. Median follow-up time was 7.4 and 9.3 months in the VEN + HMA and tagraxofusp cohorts, respectively. Overall survival (OS) between VEN + HMA and tagraxofusp-treated patients was comparable at 12-months (41.2% vs. 53%; HR 1.15; 95% CI, 0.53-2.48; P = 0.73). In a subgroup analysis of older adult patients (≥75 years-of-age), OS at 12-months (38.1% vs. 56.5%; HR 1.20; 95% CI, 0.47-3.04; P = 0.71) was not significantly different. In conclusion, this large-scale, retrospective database analysis suggests that VEN + HMA is an effective therapeutic alternative to tagraxofusp in older patients for the management of BPDCN. Future studies are needed to prospectively validate these findings.

Pure red cell aplasia (PRCA) is a rare hematological disorder characterized by erythroid hypoplasia and maturation arrest in the bone marrow. We present a case of acquired PRCA secondary to smoldering multiple myeloma (SMM), initially presenting as severe anemia requiring multiple blood transfusions. This case highlights the diagnostic dilemma at presentation as well as the therapeutic challenges in treating PRCA secondary to SMM. Here we discuss the appropriate workup and identify a potential option for managing these patients with subcutaenous daratumumab.

Plasma free hemoglobin (PFH) is a direct biomarker for hemolysis that has been associated with clinical complications such as pulmonary hypertension and death in patients with sickle cell disease (SCD). We sought to characterize the relationship between PFH and more clinically available hemolytic markers including lactate dehydrogenase (LDH), aspartate aminotransferase (AST), bilirubin, reticulocyte percentage and to derive a composite hemolysis score derived from principal component analysis (PCA) of these biomarkers. In 68 adult patients (median age 31 years old, IQR 25-39) with HbSS or HbSβ⁰-thalassemia enrolled in the IMPROVE II study, median PFH was elevated at 21.9 mg/dL (IQR 9.9-44.9 mg/dL) at steady state. Using Pearson correlation analysis, PFH had a stronger relationship to LDH (R = 0.699), AST (R = 0.587), and total bilirubin (R = 0.475), compared to reticulocyte count (R = 0.316). The hemolysis score was significantly associated with PFH (R = 0.677). When compared with other laboratory measures, PFH correlated with hemoglobin (R= -0.275) and HbS (R = 0.277), but did not correlate with white blood cell count (WBC) or HbF. The hemolysis score was significantly associated with WBC (R = 0.307), hemoglobin (R = -0.393), HbF (R=- 0.424), and HbS (R = 0.423). This study confirms that the conventional hemolytic biomarkers LDH, AST, bilirubin, and reticulocyte percentage correlate with PFH. Additionally, the hemolysis score is a valid tool to measure hemolysis and that it may be a marker of global hemolysis as opposed to PFH, which quantifies intravascular hemolysis. Further studies will be needed to elucidate the role of PFH and intravascular hemolysis in the development of clinical complications of sickle cell disease. Statements and Funding Declarations: The research leading to these results received funding from the National Heart, Lung, and Blood Institute (NHLBI) R01 HL142671 Grant under J.G. J.G. has also served as a consultant for CSL Behring, Novartis, and Novo Nordisk synteract DSMB and is supported by NHLBI RO1HL159116, R01 HL142671, R01 ES030717, UG1 HL138645, UH3 HL143192, U01HL167036, and the Doris Duke Charitable Foundation Advancing Cures grant. S.C. has served as a consultant for Pfizer and is supported by the NHLBI 5K23HL151884 grant. A.L. is supported by the NHLBI 5T32HL129974-05. C.J.M is supported by the NHLBI 5T32HL129974-05. P.S., and S.M. declare no conflicts and/or funding.

Acute promyelocytic leukemia (APL) is typically associated with bleeding, whereas thromboembolism (TE) is a less common cause of early death (ED) and frequently underestimated complication. To investigate the clinical characteristics and predictive risk factors for TE, we conducted this retrospective study. Our study included 306 patients diagnosed with APL at the Second Hospital of Shanxi Medical University between May 2012 and May 2023. Among them, 16(5.2%) patients (11 males and 5 females, with a median age of 58 years) experienced TE, including 13 cases of arterial TE (10 cerebral infarctions and three myocardial infarctions), one case of combined arterial and venous TE, and two cases of venous TE. Multivariate logistic regression analysis revealed age (OR 1.08, 95% CI 1.03-1.13, p = 0.001), smoking (3.26, 1.01-10.49, p = 0.048), alkaline phosphatase (ALP) > 125U/L (10.8, 2.26-51.46, p = 0.021), and serum creatinine (SCr) > 62µmol/L (7.09, 1.35-37.35, p = 0.003) as independent risk factors for TE in newly diagnosed APL patients. A nomogram incorporating the four aforementioned predictive factors demonstrated high accuracy and clinical applicability. With a median follow-up of 6.6 years (range: 0.6-11.8 years), the overall survival (OS) rate for all patients was 86.2%. When excluding patients who succumbed to ED, the OS rate increased to 96.2%. Importantly, there was no statistically significant difference in OS rates between non-ED patients with and without TE (p = 0.405). Our findings underscore that age, smoking, ALP, and SCr are four independent risk factors for TE in APL. Furthermore, TE primarily affects early survival but not OS rates in APL patients.

Acute myeloid leukemia (AML) commonly affects the elderly with a poor prognosis. Body water composition analysis provides a new perspective for biomedical research. This study aims to develop and validate a simple nomogram for predicting overall survival (OS) in AML survivors. A total of 291patients were enrolled and randomly divided into a training cohort and an internal validation cohort. The median duration of follow-up was 32.2 months.The LASSO regression was used to screen predictors of survival in the training cohort, and the multivariate Cox model was used to establish a nomogram. The discrimination and calibration of the nomogram were evaluated using the C-index, area under the time-dependent receiver operating characteristic curve (time-dependent AUC), and calibration plots. The net benefits of the nomogram at different threshold probabilities were quantified. Five predictors of AML survival were identified: Age, Extracellular water/Intracellular water (ECW/ICW) ratio, European Leukemia Net Risk, Sarcopenia, and WBC. The nomogram showed good performance in both the training cohort (C-index 0.755, 95% CI 0.728-0.782) and the internal validation cohort (C-index 0.773, 95% CI 0.729 to 0.817). The AUC values for the training cohort were 0.866, 0.849, 0.818, and 0.779 at 12, 24, 36, and 48 months, respectively; the AUC values for the internal validation cohort were 0.799, 0.779, 0.797, and 0.786 at 12, 24, 36, and 48 months, respectively. The calibration curves of the nomogram showed acceptable consistency, and the decision curve analysis indicated higher net benefit in clinical practice. In this study, we developed and validated an easily applicable model to predict OS in AML patients.