Annals of Hematology最新文献

This case is a rare presentation of severe aplastic anemia in a 31-year-old male with acquired clonality of the X chromosome as the sole cytogenetic abnormality. This abnormality has not been reported to our knowledge, and the significance of this finding remains unclear. Comprehensive diagnostic workup included bone marrow biopsy, cytogenetic analysis, and Next-Generation sequencing, which revealed no tier I/II variants typically associated with clonal hematopoietic disorders. The patient was managed with triple immunosuppressive therapy pending hematopoietic stem cell transplant evaluation and workup. The clinical and genetic findings in this case are noteworthy for possible pre-malignant aberration, highlighting the need for further investigation into isolated chromosomal anomalies in aplastic anemia in the future.

Follicular lymphoma (FL) may undergo histological transformation (HT) into a more aggressive lymphoma. Although rituximab for B-cell non-Hodgkin lymphomas (B-NHL) has greatly improved the overall survival (OS) of patients with transformed FL (tFL), relapse after anthracycline-based chemoimmunotherapy has a poor prognosis. CD19-targeting chimeric antigen receptor-modified T-cell (CAR-T) therapy is a promising treatment for relapsed or refractory (r/r) large B-cell lymphoma (LBCL), including tFL. However, lymphopenia and reduced T-cell fitness caused by bendamustine exposure for treatment of underlying FL may impair the feasibility and reduce the efficacy of CAR-T therapy. Herein, we report the case of a 44-year-old woman with tFL who relapsed following allogeneic hematopoietic stem cell transplantation (allo-HSCT) and received CAR-T therapy. The patient could not initially undergo CAR-T therapy due to lymphopenia caused by bendamustine exposure, but CAR-T therapy became feasible following allo-HSCT. Although CAR-T therapy using T cells harvested from an allo-HSCT recipient may theoretically cause alloreactivity, the patient did not experience graft versus host disease (GVHD) or serious complications specific to CAR-T therapy, such as cytokine release syndrome (CRS) or immune effector cell-associated neurotoxicity syndrome (ICANS), and she has remained in complete response (CR) for >18 months. CAR-T therapy following allo-HSCT for patients with r/r tFL may be a safe and effective treatment option. Allo-HSCT may enhance the efficacy of CAR-T therapy.

Various prognostic models have been proposed to improve the accuracy of prognostic assessment for Myelodysplastic syndromes (MDS). Recently, the Molecular International Prognostic Scoring System (IPSS-M) has been developed. Here, we validated the accuracy of IPSS-M in Chinese MDS patients, and proposed a prognostic model more suitable for Chinese patients. We analyzed the clinical, molecular and cytogenetic data of 798 primary MDS patients, and compared the accuracy of IPSS-R and IPSS-M in predicting overall survival (OS) and acute myeloid leukemia (AML) transformation. Using Cox proportional hazards model, we screened out 14 genes that had significant impacts on OS and AML progression. In our study, 44.86% of individuals were reclassified from IPSS-R to IPSS-M, of whom 64.80% were upstaged and 35.2% were downstaged. IPSS-M showed better performance than IPSS-R in predicting AML transformation (C-index: 0.84 vs. 0.81), but it was similar to IPSS-R in OS (C-index: 0.77 vs. 0.76). By combining age, mutational data and IPSS-R, we developed a new prognostic model more suitable for the Chinese patients (c-index was 0.81 for OS and 0.89 for AML transformation, respectively).

The first-line treatment for chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) has recently undergone major changes, and targeted therapies have ushered in a new era of CLL/SLL treatment. Scientists in different countries have successively analyzed the efficacy of various drugs, but safety studies are relatively insufficient. Therefore, this systematic evaluation and retrospective meta-analysis was conducted to compare the differences in adverse effects and their incidence among first-line treatment regimens for CLL/SLL. We searched the Cochrane Library, PubMed, Web of Science, and Embase databases, with a cutoff date of December 2023. Frequency-based network meta-analysis was performed using STATA 16.0, and the risk of bias was assessed using the Cochrane Risk of Bias Assessment Tool (RoB2.0). Thirty-seven randomized controlled trials involving 15,557 patients were included, and the results showed that, compared with other regimens, zanubrutinib had a lower probability of causing adverse hematologic effects and a lower probability of causing severe anemia (SUCRAs: 79. 6%), all-grade anemia (SUCRAs: 87.2%), severe thrombocytopenia (SUCRAs: 97.0%), all-grade thrombocytopenia (SUCRAs: 90.6%), severe neutropenia (SUCRAs: 91.8%) and all-grade neutropenia (SUCRAs: 86.6%) than the other regimens. The higher rates of adverse reactions seen with each of the other first-line regimens were not concentrated in any single regimen. The second-generation BTK inhibitors may have a lower probability of causing hematologic adverse reactions. However, its adverse effects in other systems are still noteworthy. The cardiovascular toxicity of venetoclax combination regimens should not be overlooked.

This study aimed to analyze the baseline clinical characteristics, as well as the clinical features and risk factors of early death (ED) in older patients with acute promyelocytic leukemia (APL). A retrospective analysis was conducted on 198 consecutive older patients (age ≥ 50 years) with newly diagnosed APL who received arsenic trioxide alone as induction therapy, with 354 younger patients (age < 50 years) as controls. Ten easily obtainable clinical parameters were selected. Compared with the younger group, the older group had less fever, lower white blood cell (WBC) count, lower levels of albumin, and higher levels of creatinine upon admission. While the younger group had higher levels of aspartate aminotransferase and lower levels of fibrinogen (all P < 0.05). The ED rate was significantly higher in the older group (21.7% vs. 12.4%; P = 0.004). The causes of ED in the older group were bleeding, infection, embolism, differentiation syndrome, and others, in order of incidence. The cumulative incidence of ED due to infection (P = 0.0003) and embolism (P = 0.034) was significantly higher in the older group. For the older patients, independent risk factors for ED were WBC count > 5.9 × 10⁹ /L, albumin < 35.85 g/L, creatinine > 72.9 µmol/L and fibrinogen < 1.137 g/L; independent risk factor for bleeding ED was WBC count > 6.2 × 10⁹ /L; while independent risk factors for infection ED were albumin < 36.55 g/L and fibrinogen < 1.035 g/L. The baseline clinical characteristics, the clinical features and risk factors of ED in older APL patients were all quite different from those in younger patients, so research specifically targeting older patients with APL is very necessary.

Although different types of prognostic indices have been applied in extranodal NK-/T-cell lymphoma (ENKTL), they are based mainly on clinical characteristics before treatment. Moreover, these methods lack early assessment and tumor metabolic parameters. It remains unclear whether changes in the plasma Epstein-Barr virus DNA (EBVDNA) status and SUVmax after two cycles of chemotherapy may predict disease prognosis. We retrospectively analyzed the clinical records of 119 patients with ENKTL. According to the multivariate analysis, limited stage (LS), interim EBVDNA (I-EBVDNA) negativity and a ≥ 50% decrease in the sum of the SUVmax for the target lesion (DSSTL) were significantly associated with complete remission after two cycles of chemotherapy (p = 0.005, p = 0.016 and 0.026, respectively). LS disease, I-EBVDNA negativity and ≥ 50% DSSTL were strongly associated with prolonged PFS (HR = 2.953, 95% CI 1.433-6.009, p = 0.003; HR = 2.479, 95% CI 1.239-4.958, p = 0.01; and HR = 2.048, 95% CI 1.037-4.405, p = 0.039, respectively). Based on these predictors of PFS, a preliminary scoring system was developed. Patients with scores of 1 and 2/3 had poorer survival outcomes than those with a score of 0 (HR = 2.030, 95% CI 0.816-5.048, p = 0.044, and HR = 2.377, 95% CI 1.663-3.396, p = 0.000, respectively). This scoring system also applied well to overall survival (OS) and appeared to be superior to the revised Ann Arbor staging system (p < 0.001, vs. p = 0.205). By assessing the early response to chemotherapy, interim changes in the SUVmax and I-EBVDNA could be used to predict disease prognosis and better stratify patients into subgroups with different prognoses of ENKTL. Further prospective studies are needed to verify these findings.

Hemophilia A (HA) is an X-chromosome-linked recessive genetic disorder. Female carriers may have bleeding symptoms, but rarely have moderate or severe disease. We identified a female patient with moderate HA by pedigree tracking and genetic testing in a HA family involving consanguineous marriage. To investigate the clinical and laboratory data, as well as F8 genetic variant affecting members in her family. We constructed a detailed pedigree diagram and performed coagulation analyses, including factor VIII activity (FVIII:C), FVIII inhibitor, and von Willebrand factor antigen (VWF: Ag) on 20 family members. The genomic DNA of 11 members was screened for intron 1 and intron 22 inversions using long-distance real-time polymerase chain reaction (RT-PCR). Their F8 coding genes were sequenced with an automatic next-generation sequencing. Thirteen HA persons with hemophilia (12 males, one female) and 18 female carriers were identified in the family. VWF: Ag level was normal in all 13 persons with hemophilia and 7 carriers tested. The female HA patient had FVIII:C 1.9 IU/dL and was homozygous for F8:c.1918G > T:p.V640F. Genetic testing is conducive to the diagnosis of hemophilia carriers and persons with hemophilia. F8: c.1918G > T:p.V640F is the pathogenic HA variant in this family. In any hemophilia family, we need to pay more attention to female carriers and patients.

This study aims to investigate the clinical characterization and molecular pathogenic basis of hereditary protein C (PC) deficiency in two independent Chinese families, and conduct in vitro expression studies on the newly discovered p.Trp444Arg mutation. The PC activity (PC: A) was tested using the chromogenic substrate, and PC antigen (PC: Ag) was detected via enzyme-linked immunosorbent assay (ELISA). To identify the mutation sites, nine exons of the PROC gene were amplified by PCR, and the products were directly sequenced. The conservation and pathogenicity of the mutations, as well as changes in the spatial structure of PC proteins before and after mutations, were analyzed using ClustalX-2.1-win, online bioinformatics software, and PyMOL. The function of the mutant proteins was detected using the thrombin generation assay (TGA). Recombinant PC was ectopically expressed in HEK293T cells, with mRNA levels quantified by RT-qPCR. The recombinant protein was further characterized using Western blotting, ELISA, and immunofluorescence microscopy. Proband A and B, aged 39 and 63 respectively, are both diagnosed with deep vein thrombosis (DVT) in both lower limbs and pulmonary embolism (PE). Two missense mutations, p.Arg440Cys and p.Trp444Arg, were identified in the probands. Bioinformatics and protein modeling analyses revealed that the two mutations probably affected the normal function of PC. The thrombin generation assay revealed impaired thrombin generation capacity in both probands, with proband B showing more severe impairment. In vitro expression experiments demonstrated that p.Trp444Arg do not significantly affect mRNA expression levels of PC protein compared to wild-type, but result in lower PC: Ag content and protein expression in the supernatant and higher levels in the lysate. These two mutations may be the causes of reduced PC in two independent Chinese families. Notably, this is the first reported instance of the p.Trp444Arg mutation.

Dasatinib, a second-generation tyrosine kinase inhibitor, has been reported to have immunomodulatory effects. Epstein-Barr virus (EBV)-associated lymphoproliferative disorders (EBV-LPD) occur in immunocompromised patients, such as those receiving methotrexate or other immunosuppressive drugs or after allogenic transplantation. EBV-LPD is also reported to be a rare side effect in patients receiving long-term dasatinib or imatinib. The present report describes a 60-year-old woman with Philadelphia chromosome-positive acute lymphoblastic leukemia who was treated with dasatinib and prednisolone for induction of remission. Fever, enlargement of the tonsils, multiple cervical lymphadenopathies and a splenic mass emerged after 1 month of treatment. Histopathological analysis of tonsil biopsy specimens showed diffuse proliferation of CD20-positive atypical cells with large, irregular nuclei. Some of these cells were positive for EBV-encoded small RNA, and her peripheral blood was positive for EBV-DNA (4.9 Log IU/mL), leading to a diagnosis of EBV-LPD. After discontinuation of dasatinib, her high fever and cervical lymphadenopathies disappeared without recurrence. The subsequently removed splenic mass was largely composed of non-neoplastic cytotoxic T cells resulting from a reaction to EBV-infected B cells. EBV-LPD should be included in the differential diagnosis of patients who develop lymphadenopathy during dasatinib treatment, regardless of its duration.

ETV6::LYN fusion gene is recognized as one of the genetic alterations responsible for myeloid/lymphoid neoplasms with eosinophilia and tyrosine kinase gene fusions (MLN-TK) according to the 2022 WHO classification. However, the clinical features and pathogenesis of MLN-TK with ETV6::LYN are not well defined because of the rarity of the disease. Here, we report an MLN-TK patient with ETV6::LYN that manifested as myeloproliferative neoplasms (MPN) with eosinophilia, myelofibrosis, and T-lymphoblastic lymphoma (T-LBL), which eventually led to acute myeloid leukemia. Targeted RNA sequencing of both lymph node specimens diagnosed with T-LBL and bone marrow specimens diagnosed with MPN specimens detected an identical ETV6::LYN fusion gene. Whole exome sequencing (WES) detected several identical missense and nonsense mutations in both specimens. Detected mutations were not found to be relevant to pathogenesis of T-LBL and MPN in previous reports and were considered variants of uncertain significance. Based on the WES results, ETV6::LYN fusion gene was considered the driver gene essential for the pathogenesis of MPN-TK with ETV6::LYN.