Annals of Hematology最新文献

Congenital sideroblastic anemia (CSA) is a rare genetic disorder caused by defects on heme biosynthesis and mitochondrial energy production. This disease is characterized by the presence of ring sideroblasts in the bone marrow caused by excessive iron accumulation in mitochondria of erythroblasts and by anemia of varying severity. In addition to its clinical variability, CSA is also characterized by genetic heterogeneity which required next-generation sequencing technologies to identify responsible gene. In the present study, whole-exome sequencing followed by Sanger sequencing were performed on a consanguineous family including two patients with congenital sideroblastic anemia. Mitochondrial DNA deletion and copy number were tested respectively by long PCR and QPCR. Subsequent bioinformatic investigations were performed using several programs. WES and Sanger sequencing results revealed a novel pathogenic variant c.579-580insT (p.N194X) in the PUS1 gene. Several bioinformatic tools supported that this variant was disease-causing. This variation leads to an incomplete catalytic site which will be probably non-functional and could disturb heme biosynthesis. In addition, no mtDNA deletion was detected in the two patients whereas mtDNA quantification revealed a decrease of mtDNA copy number in P2 and its increasing in P1. The increase in mtDNA copy number, which is most likely connected to a compensatory mechanism, may be the cause of the moderate phenotypic severity observed in P1 with the same p.N194X variant with P2. In conclusion, we identified a novel truncated pathogenic variant in PUS1 gene in two siblings of consanguineous family with intrafamilial phenotypic variability related to mtDNA copy number.

Carfilzomib, lenalidomide and dexamethasone (KRd) is still a widely used treatment option for patients with relapsed / refractory multiple myeloma (RRMM). However, there is limited real-world evidence. Here we evaluated the efficacy and safety of KRd in patients with RRMM treated following the standard clinical practice of the hospitals in the Catalan region. This was a retrospective, observational study. The objective response rate (ORR) according to IMWG criteria was the primary endpoint. Secondary endpoints included progression-free survival (PFS) and overall survival (OS). The study planned to include at least 100-150 patients. In total 194 patients were included. Median age was 64 years (range: 40-88) and 56% were male. All patients had received bortezomib. Additionally, 89 patients (46%) had received thalidomide and 29 (15%) lenalidomide. The ORR was 73% (95% CI: 66-79), with 72 patients (37%) having ≥ CR. The ORR was influenced by ISS score, number of previous treatments and exposure to lenalidomide. The median PFS was 26 months and 2-years OS rate 70%. The ISS stage and LDH levels were independent prognostic factors of survival. In conclusion, the KRd scheme led to a good effectiveness comparable safety profile to the phase III clinical trial in patients with RRMM.

Multiple myeloma (MM) is a haematological malignancy characterised by high genomic heterogeneity. One of the most common cytogenic abnormalities in MM is the gain of genetic material at the long arm (q) of chromosome 1 (+ 1q). While many mechanisms of resistance have been associated with + 1q alterations (e.g. CD38 downregulation, impairment of complement-dependent cytotoxicity, or induction of immunosuppression), the precise genetic or pathogenetic factors responsible for these alterations are still being investigated. Although interphase fluorescence in situ hybridisation (iFISH) is the gold standard for the detection of + 1q abnormalities used by the majority of diagnostic laboratories worldwide, there are no universally recognised cut-offs for + 1q positivity or a threshold for clinical meaningfulness. Because iFISH alone is insufficient to elucidate the extent of + 1q and other cytogenetic abnormalities in MM, sequencing-based methods could be adopted. The second revision of the international staging system for MM recently recognised + 1q as a high-risk feature. There is increasing evidence that + 1q has a prognostic value and influences the duration of remission, suggesting that patients with MM and + 1q may benefit from tailored therapy. This review comprehensively summarises the most recent biological evidence and clinical data on + 1q abnormalities in MM. However, given the heterogeneous data available, it remains difficult to draw firm conclusions. In clinical practice, +1q alterations should be evaluated along with other cytogenetic abnormalities and other biological and clinical characteristics of the disease. Ongoing and future studies will help the full understanding of the role of + 1q in MM.

This clinical study evaluates the bioequivalence of recombinant factor VIII with Fc fusion protein (rFVIII-Fc) developed by AryoGen Pharmed Company compared to the reference product, Elocta^® by Sobi Co., in severe haemophilia A patients. Fc-fused recombinant factor VIII represents a significant advancement in haemophilia A treatment, offering extended half-life and reduced infusion frequency, thus improving patients' adherence to treatment and quality of life. In a randomized, double-blind, single-dose crossover trial, 50 Iranian patients were assigned to treatment groups in a 1:1 ratio. Subjects received both the test and the reference product with a 7-day washout period between treatments. Pharmacokinetic assessments were conducted over five days post-administration to evaluate the primary outcome, the dose-normalized area under the curve (DNAUC). The results established bioequivalence between rFVIII-Fc (AryoGen Pharmed Company) and Elocta^®, based on the DNAUC as the primary outcome, in which the ratio of test and reference products was calculated to be 108.56 (90% confidence interval 104.88 to 112.37), falling within the pre-defined equivalence margin of 80-125%. Secondary outcomes, including area under the curve (AUC_inf), maximum concentration (C_max), and half-life, further supported bioequivalence. Safety profiles were comparable, with adverse events mainly related to haemophilia A rather than the intervention. In conclusion, the rFVIII-Fc product is bioequivalent to Elocta^® with a similar safety profile, offering an effective alternative for severe haemophilia A patients. This trial was registered in ClinicalTrials.gov (NCT06137092).

Four multi-species conserved sequences (MCSs) are important enhancers which affect α-globin expression. Deletions of MCS can cause α-thalassemia. So far, duplication of MCS has never been reported to account for thalassemia. In this study, an unusual transfusion-dependent case of hemoglobin H disease was identified by whole-genome sequencing, optical genome mapping and longer PCR with special primers, which was caused by a familial 96,620-bp inverted duplication (from MCS-R1 to MCS-R4), inserted between chr16:199348 and 199349 (GRCh37/hg19) within MCSs. The duplication segment included an inverted repeat sequence from chr16:102712 to176193 and one direct repeat sequence from chr16:176208 to 199348. The associated α-thalassemia trait was confirmed to result from disrupted topological chromatin domains using ATAC-seq and the dual‑luciferase reporter assay system. This case presents a new mechanism of α-thalassemia, and may aid our understanding of the effects of enhancers on gene expression and the differential contribution of the four enhancer elements in the human a-globin locus.

Peripheral nervous system involvement in lymphoproliferative diseases, often due to direct nerve infiltration (neurolymphomatosis, NL), is mostly seen in aggressive B-cell lymphoma. We report the case of an 88-year-old man with stage IVA DLBCL, who achieved the first complete response after six R-miniCHOP21 cycles. One year post-treatment, he developed severe neurological symptoms, and PET-CT revealed widespread relapse with extensive neural involvement. Treatment with tafasitamab and lenalidomide led to a complete morpho-metabolic remission and full neurological recovery, with minimal side effects. This case underscores for the very first time the efficacy and tolerability of this regimen in treating NL, highlighting its potential for frail patients unfit for more intensive therapies.

The aim of this study was to investigate the prognostic value of baseline PET/CT parameters alone and combined with clinical features in Extranodal Natural killer/T-cell lymphoma (ENKTL) patients treated with P-GEMOX regimen (pegaspargase, gemcitabine and oxaliplatin). A total of 97 patients were retrospectively evaluated. The relationships between baseline PETCT metabolic parameters and survival were tested using Cox regression analysis and receiver operating characteristic(ROC) curve analysis was employed to evaluate the optimal cut-off value of these parameters. Kaplan-Meier curves with log-rank tests were used for survival analysis. At a median follow-up of 49 months, the 3-year PFS and OS were 62.9% and 70.1%. SUVmean, SUVmax, and SUVpeak were related to both PFS and OS in univariate analysis(P < 0.05 for all). Further multivariate analysis including PET/CT parameters and clinical parameters revealed that SUVmean was an independent prognostic factor and seemed to be slightly superior to SUVmax and SUVpeak. The low SUVmean was significantly associated with a better prognosis (3-year OS 85.1% vs.65.0%, P = 0.014; 3-year PFS 76.8% vs.62.1%, P = 0.032). SUVmean was able to further separate patients with a low-risk PINK/PINKE of < 2(n = 85, 79, separately) into two subgroups with significantly different outcomes. Moreover, the metabolic-parameter-contained m-PINK/PINKE model was constructed and showed superior predictive performance in the whole cohort. Conclusions. SUVmean was an independent prognostic factor in patients with ENKTL treated with P-GEMOX chemotherapy. Adding SUVmean to the PINK or PINKE model could improve the predictive value and further distinguish patients with poor outcomes.

Reactivation of fetal hemoglobin (Hb F, α2γ2) has been demonstrated to be a therapeutic strategy for patients with β-hemoglobinopathies. MicroRNAs (miRNAs) are small noncoding RNAs that regulate gene expression by silencing RNA. Both coding and non-coding RNAs can compete for the same miRNAs, acting as competing endogenous RNAs (ceRNAs). However, the role of ceRNAs in β-thalassemia major (β-TM) and their impact on γ-globin expression remains poorly understood. In this study, we conducted transcriptome sequencing to collect circularRNA (circRNA), miRNA, and mRNAs from β-TM patients and healthy individuals. Through bioinformatics analysis, we constructed a GATA2‑associated ceRNA network, emphasizing the hsa_circ_0005245_hsa-miR-425-3p_GATA2 pathway. Validation using qRT-PCR analysis in β-TM samples, RNA immunoprecipitation, and dual-luciferase reporter assays confirmed this pathway. Furthermore, overexpression of hsa_circ_0005245, hsa-miR-425-3p, and GATA2 in HUDEP-2 cells individually resulted in elevated γ-globin levels. Our findings identify a novel hsa_circ_0005245_hsa-miR-425-3p_GATA2 pathway that regulates γ-globin expression, providing potential insights for the clinical management of β-TM patients.

Chronic eosinophilic leukemia (CEL) is a rare myeloproliferative neoplasm. Diagnosis of CEL is often challenging, notably because of the lack of recurrent and specific molecular event. We report here a case of CEL occurring in a 49-year-old man who presented a persistent hypereosinophilia (HE) associated with anemia and thrombopenia. Karyotyping showed a translocation t(5;12)(q31;p13). Targeted RNA Sequencing identified a novel ETV6::RAPGEF6 fusion gene, confirmed by RT-PCR. Despite several lines of treatment, the patient died after 16 months of duration with transformation to acute myeloid leukemia (AML).Contrary to myeloid/lymphoid neoplasms with eosinophilia and tyrosine kinase gene fusions (MLN-TK), where fusion genes are both class defining and involve tyrosine kinase genes as the 3' partner, fusion genes are exceedingly rare in non-MLN-TK myeloid malignancies with HE. The most reported fusion gene is ETV6::ACSL6, in rare cases. Previously, overexpression of IL3 (interleukin 3) has been described in myeloid neoplasms with ETV6::ACSL6 (previously named ACS2). In our case of CEL with the ETV6::RAPGEF6 fusion, we also demonstrated overexpression of IL3, which could potentially result from the proximity of the IL3 gene to RAPGEF6, similar to what is observed with ACSL6 and IL3. The use of RNA sequencing in routine diagnosis of CEL could provide evidence for clonal event such as gene fusion, improving diagnosis as well as prognosis and therapeutic approaches.