Annals of Hematology最新文献

Donor cell leukemia (DCL), in which malignancy evolves from donor's stem cells, is an infrequent complication of allogeneic hematopoietic stem cell transplantation. Acute promyelocytic leukemia (APL) derived from donor cell is extremely rare and only four cases have been reported to date. Herein we report a case of donor cell-derived APL developing 32 months after haploidentical peripheral blood stem cell transplantation using posttransplant cyclophosphamide for myelodysplastic syndromes. Donor origin of APL cells was validated by conventional karyotyping, florescence in situ hybridization, and single-nucleotide polymorphisms-based chimerism analysis. Targeted sequencing of both the donor and the recipient demonstrated newly-acquired PML::RARA fusion only in the recipient's cells after transplantation, without additional genetic abnormalities. The telomere length was measured at multiple timepoints before and after transplantation. The analysis revealed markedly shortened telomere length at APL onset, which reflect both stem cell expansion following transplantation and expansion of APL cells. Our first-ever report of telomere dynamics in DCL cases provides evidence for the involvement of telomere attrition in DCL pathogenesis.

The "obesity paradox" suggests that, despite a higher baseline risk for adverse health outcomes, obese patients can experience a lower complication and mortality rate in conditions such as pulmonary embolisms (PE). This study aims to examine the association between obesity and inpatient outcomes of PE patients, utilizing the data from the National Inpatient Sample (NIS) database. We conducted a retrospective study analysis of obese adult PE patients (aged ≥ 18) using the NIS database from 2016 to 2020. Patients were categorized as either obese (body mass index (BMI) ≥ 30) or non-obese, excluding those with cancer diagnosis and age > 75 years to reduce confounding factors. Multivariable logistic regression, adjusted for confounders, compared the inpatient outcomes, including mortality, length of stay, need for mechanical invasive ventilation (MIV), incidence of shock requiring vasopressor use and use of reperfusion therapies. Our results showed obese patients had a lower in-hospital mortality and reduced risk for certain adverse outcomes when compared to non-obese patients. Limitations in our data, such as the lack of imaging confirmation and inability to track certain risk indicators in real time, affected precision in outcome severity classification. Our findings support the existence of an obesity paradox, particularly in PE patients, with obese patients experiencing better inpatient outcomes relative to their non-obese counterparts. This study advances the understanding of obesity's complex role in PE outcomes. However, further research is needed to further elucidate potential protective mechanisms to address our study limitations.

Analyze the clinical phenotype and gene mutations of a family with hereditary FXII deficiency, and preliminarily explore its phenotypic manifestations. The routine coagulation indicators and related coagulation factors were measured.Thromboelastography and thrombin generation tests simulated coagulation and anticoagulation states in vitro and in vivo. PCR direct sequencing was utilized to analyze all exons and flanking sequences of the F12 gene in the proband, confirming suspected mutations through reverse sequencing, and identifying corresponding mutation sites in family members. Using ClustalX-2.1-win to analyze the conservation of the variant, and employing online software to predict the pathogenicity of mutations. The proband exhibited significantly prolonged APTT (169.1 s) and a pronounced decrease in FXII: C to 1.0%. Thromboelastography testing indicated a diminished function of the endogenous coagulation system, while thrombin generation testing revealed a normal ability for thrombin production in the proband. Gene sequencing revealed that the proband harbored a deletion mutation c.303_304delCA in exon 5 and a substitution mutation c.800 + 1G > A in intron 8. All three bioinformatics software indicated that the mutations were pathogenic and could lead to the production of a terminator, potentially altering the structure and function of the protein. The deletion mutation c.303_304delCA and substitution mutation c.800 + 1G > A are associated with a decreased in FXII levels in this family, with the c.800 + 1G > A mutation being the first reported mutation worldwide.

Ravulizumab is a second-generation complement component 5 (C5) inhibitor (C5i) approved for the treatment of paroxysmal nocturnal hemoglobinuria (PNH) following positive results from two pivotal trials in patients with PNH originally naive to C5i treatment and eculizumab-experienced patients with PNH. In both trials, after the 26week primary evaluation period, all patients received ravulizumab for up to 6 years. To report ravulizumab treatment outcomes in patients with PNH originally naive to C5i treatment and eculizumab-experienced patients with PNH treated for up to 6 years. Originally C5i-naive (N = 244) and eculizumab-experienced (N = 191) patients with PNH continued ravulizumab treatment for up to 6 years. Major adverse vascular events (MAVEs; including thrombotic events [TEs]) and survival are reported, including a comparison of survival with untreated patients from the International PNH Registry. Laboratory parameters for intravascular hemolysis (IVH) are also described. For up to 6 years (1468.0 patient-years of exposure), ravulizumab provided durable control of terminal complement activity and IVH, resulting in a low incidence of MAVEs (including TEs) reported (MAVE rate: 0.7-1.4 per 100 patient-years) and, compared with untreated patients from the International PNH Registry, reduced the risk of mortality by five-fold. The few breakthrough IVH events reported (N = 122) were commonly associated with complement-amplifying conditions, and only two events (1.8%) were associated with suboptimal inhibition of C5 (i.e. serum free C5 ≥ 0.5 µg/mL). These results support the long-term use of ravulizumab as the first-line treatment of choice for patients with PNH. Trial registration details: NCT01374360; registered: October 29, 2004; NCT02946463; registered: October 27, 2016; NCT03056040; registered: June 05, 2017.

Acute promyelocytic leukemia (APL) is driven by the specific fusion gene PML-RARA produced by chromosomal translocation. Three classic isoforms, L, V, and S, are found in more than 95% of APL patients. However, atypical PML-RARA isoforms are usually associated with uncertain disease progression and treatment prognosis. Recently, we found a novel PML-RARA isoform (named PA) in a patient with atypical clinical characteristics of APL. In order to provide valuable insights for clinical treatment, we constructed the novel PML-RARA isoform zebrafish model for all-trans retinoic acid (ATRA) treatment experiments and comparison with classical isoforms. We found that the effect of PA PML-RARA on the expression of neutrophil-related genes was comparable with classical isoforms and ATRA treatment worked successfully in the zebrafish model. Sequence and structure analysis of the PA protein confirmed its similarity to classical isoforms and the fusion site of PA PML-RARA did not affect the ATRA binding site. As expected, the patient achieved complete remission within two months of treatment with ATRA in combination with arsenic trioxide (ATO) and had a favorable prognosis during the three-year follow-up. Our study highlights the accuracy and efficacy of the PML-RARA zebrafish model in combination with protein structure prediction in support of clinical treatment strategies.

Splenomegaly is a quite common clinical feature of Philadelphia (Ph) negative chronic myeloproliferative neoplasms (MPNs) and its presence may, in some cases, drives treatment decision. Most importantly, palpable splenomegaly is a minor criterion for both pre-fibrotic/early primary myelofibrosis and primary myelofibrosis (PMF) diagnosis, even if clinical assessment by physical examination is poorly reliable and accurate. On the other hand, despite the International Working Group-Myeloproliferative Neoplasms Research and Treatment and European LeukemiaNet guidelines defined spleen response criteria by palpation, they also recognized the highly subjective nature of spleen size assessment by physical examination, and recommended objective confirmation of volume reduction via computed tomography or magnetic resonance imaging (MRI). In particular, spleen volume (SV) reduction of at least 35% via MRI is typically the primary endpoint in PMF and in some polycythemia vera clinical trials. Nevertheless, this technique seems inconvenient in routine clinical practice. To simplify serial monitoring of spleen size by using ultrasonography (US), we retrospectively analyzed medical records of 39 newly diagnosed MPN patients who underwent spleen ultrasonography as well as MRI. The median SV assessed by US was 600 ml (range 200-5000 ml) while median SV evaluated by MRI was 553.1 ml (range 172-5140 ml), revealing a strong linear relationship between methods, with a correlation coefficient of r = 0.96 (95% CI 0.92-0.98, P < 0.0001). Our findings support the role of US into pre-screening assessments for clinical trials and practice, offering a pragmatic solution for evaluating SV in MPN patients and ultimately improving patient care and clinical decision-making in this complex disease landscape.

Sickle cell disease (SCD) is an inherited hematologic disease caused by sickle hemoglobin as the predominant RBC hemoglobin or by sickle hemoglobin in combination with other abnormal β-hemoglobin variants like HbC, HbD and others. Sickling of erythrocytes under deoxygenated conditions is the basis of inflammatory and thrombotic cascades which result in multiple serious complications, leading to early morbidity and mortality. While HLA-matched allogeneic bone marrow transplantation is potentially curative, it has considerable limitations due to potential severe toxicities. Despite slow progress towards novel therapeutic strategies for SCD and hydroxyurea being the sole medication that is shown to reduce vaso-occlusive events and mortality for almost 20 years, several pharmacological agents targeting different mechanisms have been examined in clinical trials and recently US- US-FDA-approved, including L-glutamine and crizanlizumab. Voxelotor was previously US-FDA-approved but has been voluntarily withdrawn from the market as the overall benefit did not outweigh the risks. Gene therapies based on CRISPR-Cas9 and lentiviral vectors have been very recently approved. However, excessive costs are a barrier to widespread use. Nonetheless, there is still a large area of unmet needs for patients with SCD, and further research towards better care is warranted.

Calreticulin (CALR) mutations are detected in around 20% of patients with primary and post-essential thrombocythemia myelofibrosis (MF). Regardless of driver mutations, patients with splenomegaly and symptoms are generally treated with JAK2-inhibitors, most commonly ruxolitinib. Recently, new therapies specifically targeting the CALR mutant clone have entered clinical investigation. To collect information on efficacy and safety of ruxolitinib in CALR-mutated patients, we report a sub-analysis of the "RUX-MF" (NCT06516406) study, comprising 135 CALR-mutated and 786 JAK2-mutated ruxolitinib-treated patients. Compared to JAK2-mutated patients, CALR-mutated patients started ruxolitinib with a more severe disease (higher peripheral blast counts, lower hemoglobin levels and worse marrow fibrosis) and after a longer median time from diagnosis (2.6 versus 0.7 years, p < 0.001). At 6 months, spleen responses were numerically inferior in CALR-mutated patients, who also had significantly lower rates of symptom responses (56.1% versus 66.7%, p = 0.04).

Epcoritamab, a bispecific T-cell engager (BiTE) antibody targeting CD3 and CD20, has shown significant efficacy in treating refractory diffuse large B-cell lymphoma (DLBCL). However, its use can lead to severe side effects, such as tumor flare. Here, we report the case of an 84-year-old male with relapsed DLBCL who developed fatal unilateral pleural effusion following Epcoritamab treatment. Initially, the patient showed a favorable response, but later developed significant pleural effusion with elevated interleukin-6 (IL-6) levels, indicating a severe inflammatory response. This suggests that Epcoritamab directly affected the pleural lesions and caused a local cytokine release syndrome (L-CRS). Despite aggressive management, including Tocilizumab and Dexamethasone, the patient's condition worsened, leading to his death. This case underscores the importance of regular lab tests and imaging follow-ups to monitor and manage severe inflammatory reactions based on tumor location. Comprehensive monitoring protocols are needed to mitigate risks associated with novel immunotherapies. To our knowledge, this is the first reported case of fatal unilateral pleural effusion in a patient with relapsed DLBCL following Epcoritamab treatment.

Classic Hodgkin lymphoma (CHL) histologically consists of Hodgkin Reed-Sternberg (HRS) cells and the tumor microenvironment (TME), but the relationship between TME characteristics and clinical features of CHL remains unclear. We aimed to investigate the effects of the TME structure on the outcomes of patients with CHL. We performed a high-throughput analysis of HRS cells and their topological relationship with the reactive immune cells in the TME. After multiplexed immunofluorescence labeling against CD4, CD8, CD30, CD68, CD163, PD-1, and PD-L1, visual images were analyzed. Phenotypes were assigned to all reactive cells, such as CD4⁺ and CD8⁺ T-cells and macrophages. Since the densities of PD1⁺/CD4⁺ T-cells, CD8⁺ T-cells, and PD-L1⁺ macrophages were significantly higher in the area < 60 μm than in the area < 120 μm from each HRS cell in 45 tissue samples from 34 patients with CHL, we further analyzed the TME-component cells by focusing on the 60 μm radius in the initial samples. TMEs containing > 15 CD8⁺ T-cells were associated with a significantly better 3-year progression-free survival than those with ≤ 15 CD8⁺ T-cells (100% vs. 53%, p = 0.006). In comparison with TMEs containing ≤ 15 CD8⁺ T-cells, TMEs containing > 15 CD8⁺ T-cells had significantly more PD-L1^- macrophages (mean 3 vs. 1 cell, p = 0.015) and fewer PD-1⁺/CD4⁺ T-cells (mean 16 vs. 28 cells, p = 0.036). Epstein-Barr virus positivity in HRS cells was significantly associated with a higher number of macrophages in the 60 μm radius area. In conclusion, the TME structure in patients with CHL can differ, enabling precision therapies.