Annals of Hematology最新文献

Diffuse large B-cell lymphoma (DLBCL) is a heterogeneous malignancy. Although the R-CHOP regimen has significantly improved the prognosis for most patients, a subset continues to experience poor therapeutic outcomes. Recent studies have highlighted the role of the nervous system in cancer, yet its impact on DLBCL remains unclear. In this study, 21 neuro-related (NR) genes were identified from the Gene Ontology database, and a prognostic risk scoring model for DLBCL was developed and validated across multiple cohorts. The NR-based score effectively stratified patients according to survival outcomes. The high NR score group was characterized by an immunosuppressive microenvironment, activation of pro-proliferative pathways, and increased mutation frequencies of oncogenes such as TP53 and MYC. In contrast, the low NR score group exhibited enriched inflammatory responses and immune activation signals. The key gene TRPV2, associated with favorable prognosis, was found to promote M1-like polarization in monocytes/macrophages and enhance antigen presentation in B cells. This study establishes the NR risk score as a novel prognostic tool for DLBCL and underscores neuro-immune interactions as potential therapeutic targets.

Transplant-associated thrombotic microangiopathy (TA-TMA) is a fatal complication associated with hematopoietic stem cell transplant (HSCT). Endothelial dysfunction and complement activation cause consumptive thrombocytopenia with intravascular hemolysis, resulting in end-organ damage, especially to the kidneys and lungs. There are no U.S. Food and Drug Administration (FDA)-approved agents for TA-TMA, although Eculizumab is the most commonly used agent to treat TA-TMA. Patients who do not respond to Eculizumab have a dismal prognosis, with reported mortality up to 80%. Narsoplimab, a mannan-binding lectin-associated serine protease-2 (MASP-2) inhibitor, has been shown to treat TA-TMA by inhibiting the lectin pathway of the complement cascade. We report the first adult case with successful management of eculizumab-refractory TA-TMA with Narsoplimab. Our patient received a matched unrelated donor (bone marrow) allogenic HSCT and subsequently developed multi-organ damage. He was refractory to numerous treatments, including eculizumab, steroids, rituximab, and plasma exchange. After developing diffuse Alveolar hemorrphage and renal failure, he was initiated on Narsoplimab and later achieved a complete hematological response and became transfusion independent. This case highlights the importance of early recognition of TA-TMA and the need to switch therapy to other complement inhibitors if resistance to Eculizumab is noted.

Background

Few studies have focused on cyclosporine-related adverse events (AEs) in aplastic anemia (AA) patients undergoing immunosuppressive therapy and receive cyclosporine maintenance.

Materials and Methods

We conducted a retrospective study to analyze the relationship between cyclosporine concentrations at different time points and AEs in AA patients who received cyclosporine maintenance. Cutoff values of cyclosporine concentrations for predicting every AE were defined by receiver operating characteristic (ROC) curves respectively.

Results

A total of 382 patients were included. The most common AEs included hypertrichosis (72.3%), gingival hyperplasia (60.5%), hyperuricemia (62.6%), hyperlipidemia (47.0%), and elevated creatinine levels (39.9%). Patients presented with AEs were with higher C0 (trough) and C2 (peak) levels. Most of the values of C0 and C2 were in the ranges of 200–250 μg/L and 700–1000 μg/L, respectively. Patients with C0 higher than 250 μg/L or C2 higher than 1000 μg/L were more likely to develop AEs. Response rate was not associated with cyclosporine concentrations, but C0 levels below 150 μg/L or C2 levels below 500 μg/L showed lower response trend. Based on these findings, we propose a therapeutic range of 150–250 μg/L for C0 and 500–1000 μg/L for C2. This range is intended to balance maintaining therapeutic efficacy with minimizing the risk of adverse events. Then we propose a dose of 4.5–5.5 mg/kg/d for patients under 40 years old and 3.5–4.5 mg/kg/d for those over 40 years old to achieve target concentrations.

Conclusion

In summary, we provide a comprehensive analysis of AEs associated with cyclosporine maintenance in AA patients undergoing IST. We also propose optimal cyclosporine concentration ranges and suggest age-adjusted dosing strategies to ensure both efficacy and safety.

Key Messages.

(1) AA Patients presented with cyclosporine associated AEs were with higher C0 (trough) and C2 (peak) levels.

(2) We recommend the optimal concentration ranges as 150-250 μg/L for C0 and 500-1000 μg/L for C2 for AA patients receive cyclosporine treatment.

(3) We propose a dose of 4.5-5.5 mg/kg/d for patients under 40 years old and 3.5-4.5 mg/kg/d for those over 40 years old to achieve target concentrations.

Plitidepsin (P) is a marine-derived anticancer compound isolated from the tunicate Aplidium albicans. P plus low-dose dexamethasone (LD-DXM) was evaluated versus LD-DXM alone in patients with relapsed/refractory multiple myeloma (r/r MM) in the randomized phase III ADMYRE trial. In absence of a randomized study with P + LD-DXM vs. POM + LD-DXM, a direct matched comparison between P + LD-DXM (ADMYRE data) and pomalidomide (POM) + LD-DXM as an External Control Arm (ECA) was conducted using individual patient-level data from several contemporary POM + LD-DXM trials with a similar design. A first analysis (ECA1) showed that P + LD-DXM was non-inferior to POM + LD-DXM in terms of median overall survival (OS): 11.8 vs. 13.9 months; HR = 1.009 (95%CI, 0.812–1.254; p = 0.9336). Safety profile showed a lower rate of grade ≥ 3 hematological treatment-related adverse events (TRAEs) (neutropenia 2.5% vs. 37.1%; thrombocytopenia 2.5% vs. 13.2%) and infections (8.1% vs. 18.7%) for P + LD-DXM, and a higher rate of grade ≥ 1 gastrointestinal TRAEs (52.8% vs. 27.4%), grade ≥ 3 blood creatine phosphokinase (14.3% vs. 0%) and grade ≥ 3 myalgia (5.6% vs. 0%). A second analysis (ECA2) compared POM + LD-DXM with the LD-DXM alone arm included in ADMYRE and showed a treatment effect in OS (HR = 0.762; 95%CI, 0.566–1.026) similar to that observed in ADMYRE (HR = 0.797, 95%CI, 0.596–1.067). Safety profile of POM + LD-DXM was associated to a higher rate of TRAEs, as expected for a combination. In conclusion, P + LD-DXM can be an alternative therapeutic option in r/r MM as this comparison shows that P + LD-DXM is non-inferior in OS to POM + LD-DXM with an advantageous safety profile in terms of hematological and infection events.

The survival of Langerhans cell histiocytosis (LCH) in high-income countries is favorable, with rates of over 95%. However, there are few studies from resource-limited countries. Thus, this study aimed to examine survival risk factors and outcomes of LCH patients in Thailand. A retrospective review was conducted on LCH patients aged < 15 years at Songklanagarind Hospital over 40-year period. Cox regression analysis was utilized to identify risk factors. The overall (OS) and event-free survival (EFS) rates were calculated using the Kaplan-Meier method. A total of 68 patients were included with a median age of 2.1 years. Of these, 27 (39.7%) had single-system (SS)-LCH, 17 (25.0%) had no risk organ (RO-) multisystem (MS)-LCH, and 24 (35.3%) had risk organ (RO+) MS-LCH. The 5-year EFS of patients with SS-, RO-, and RO + MS-LCH were 95.2%, 58.4%, and 44.1%, respectively (p < 0.01). MS-LCH patients had a higher reactivation rate compared to those with SS-LCH (50.0% vs. 4.3%, p = 0.02, respectively). Age < 1 year was an independent risk factor for inferior survival (HR 13.79, 95% CI: 1.5-123.4, p = 0.02). The OS and reactivation rates of LCH patients treated with our national protocol are comparable to those of high-income countries. The infant was associated with inferior survival.

Women with chronic lymphocytic leukemia (CLL) face unique challenges when it comes to contraception. CLL predominantly affects older adults, with an age-adjusted incidence of approximately 4.7 new cases per 100,000 people per year and a median age at diagnosis of 70 years (Hallek and Al-Sawaf Am J Hematol 96(12):1679–1705, 2021). Although only about 9% of patients are diagnosed before age of 45, those who are of reproductive potential must carefully balance cancer treatment, fertility preservation, and effective contraception. In contemporary practice, most patients are treated with continuous Bruton’s tyrosine kinase (BTK) inhibitors or fixed-duration BCL2 inhibitor–based regimens, while chemoimmunotherapy is reserved for selected cases. These targeted approaches have variable profiles of cytopenias, bleeding and drug–drug interactions and can compromise ovarian reserve and carry teratogenic risks. This necessitates the need for tailored contraceptive counseling within a multidisciplinary oncofertility framework (Oktay et al J Clin Oncol 36(19):1994–2001, 2018).

To clarify the biological roles of the putative target thrombospondin-1 (THBS1) and the impact of the traditional Chinese medicine monomer Lycorine on acute myeloid leukemia (AML) cells. The AML cell lines HL-60 and THP-1 were used in vitro to assess the effects of lycorine on cell growth and apoptosis. Network pharmacology and Gene Expression Omnibus (GEO) database analysis were used to predict potential lycorine targets in AML. Clinical samples were used to validate the target THBS1’s expression. The binding affinity between lycorine and THBS1 was examined using molecular docking. Lastly, THBS1 overexpression in AML cells confirmed its function. In a dose-dependent way, lycorine induced apoptosis and markedly suppressed the growth of AML cell lines. THBS1 is a common target of lycorine in AML, and its expression is dramatically downregulated in AML, according to network pharmacology, GEO database analysis, and confirmation using clinical samples. Lycorine’s ability to bind to THBS1 and increase its expression levels in AML cells was validated by molecular docking. In AML cells, THBS1 overexpression mirrored the effects of lycorine by preventing cell division and triggering apoptosis. Lycorine inhibits the growth of AML cells and triggers apoptosis by targeting and upregulating the expression of THBS1. Therefore, it has antileukemic actions. One of the main targets for anti-AML treatment is THBS1.

The incidence of paediatric blastic plasmacytoid dendritic cell neoplasm (BPDCN) is extremely low, and little is known about the disease. This study aims to investigate its clinical course and optimal management. We retrospectively analysed the clinical manifestations, laboratory findings, treatment responses, and survival outcomes of 18 paediatric patients with BPDCN treated at our hospital. In this cohort, the male-to-female ratio was 2.6, and the median age of onset was 12 years. Bone marrow involvement was observed in 88.9% of patients (16/18), making it the most commonly affected site, followed by the skin (13/18) and lymph nodes (13/18). Central nervous system infiltration occurred in the youngest patient (Case 13), who experienced relapse after matched sibling donor haematopoietic stem cell transplantation (MSD-HSCT). Immunohistochemical and flow cytometry analyses revealed a distinct immunophenotype, with high expression of CD4 (94.4%), CD56 (100%), CD123 (100%), CD304 (100%), and HLA-DR (100%), and no expression of myeloperoxidase and CD19. In terms of the initial response, 14 patients received acute lymphoblastic leukaemia (ALL)-like regimens, all of whom achieved complete remission (CR) after induction chemotherapy. All 18 patients proceeded to HSCT post-chemotherapy, including 15 haploidentical and 3 MSD transplants. The 4-year overall survival (OS) and event-free survival (EFS) rates for the entire cohort were 94.4% ± 5.4% (95% CI, 83.8%–100.0%) and 87.7% ± 8.2% (95% CI, 71.6%–100.0%), respectively. Paediatric patients with BPDCN who receive allogeneic HSCT—particularly haploidentical HSCT—during CR following ALL-like induction chemotherapy appear to have favorable outcomes in this limited cohort.

Polycythemia vera (PV) and Essential thrombcythemia (ET) are myeloproliferative neoplasms (MPNs) that can progress to secondary myelofibrosis, a complication associated with increased mortality. Circulating CD34-positive cells at diagnosis can be used to distinguish primary myelofibrosis from other MPNs with a threshold of 10/µL. In this study, we evaluate the interest of serial CD34-positive cell quantifications during the follow-up of MPNs. We retrospectively include 180 patients with MPN (90 ET, 55 PV and 35 myelofibrosis) with at least two measurements of circulating CD34-positive cells. CD34-positive cell count showed an AUC of 0.901 for the diagnosis of post-ET/PV myelofibrosis, with a sensitivity of 54.8%, a specificity of 99.5%, a PPV of 89.5% and a NPV of 96.3% for the threshold of 15 cells/µL. The decreased sensibility could be explained by an impact of cytoreductive treatments. Then we focused on primary and secondary myelofibrosis (MF) and found that patients achieving partial or complete response (per IWG-MRT criteria) had lower CD34-positive cell levels. Finally, CD34-positive cell levels had a prognostic impact on overall survival in MF, a count ≥ 100/µL is predictive of a higher risk of death (HR = 2.9 [1.5–5.9]), independently of DIPSS classification. In conclusion, monitoring of circulating CD34-positive cells is valuable for evaluating both disease progression and prognosis in MPN patients.