Annals of Hematology最新文献

This meta-analysis aimed to assess the impact of genetic mutations, particularly in the NOTCH2 and TNFAIP3 genes, on the prognostic outcomes of Marginal Zone Lymphoma (MZL) patients. Databases, including PubMed, Embase, and Cochrane Library, were explored up to October 2023. A total of 11 studies encompassing 2,314 records were included. Outcome measures were 5-year overall survival rates (OSR), progression-free survival rates (PFSR), and tumor progression rates (TPR). NOTCH2 and TNFAIP3 mutations were prominently identified across studies. In splenic MZL (SMZL) patients with NOTCH2 mutations, there was a significant decrease in the 5-year OSR (SMD: -11.11, 95% CI: -13.39 to -8.84, P < 0.01) and PFSR (SMD: -23.49, 95% CI: -28.85 to -18.14, P < 0.01). Similarly, TNFAIP3 mutations in SMZL patients demonstrated diminished 5-year OSR (SMD: -14.78, 95% CI: -18.01 to -11.56, P < 0.01) and PFSR (SMD: -21.06, 95% CI: -27.13 to -14.98, P < 0.01). For ocular adnexal MZL (OA-MZL) patients with NOTCH2 mutations, the 5-year OSR significantly declined (SMD: -23.40, 95% CI: -28.87 to -17.93, P < 0.01). Genetic mutations, notably in NOTCH2 and TNFAIP3 genes, have discernable negative implications on the prognosis of MZL patients. Recognizing these genetic markers can guide more personalized therapeutic interventions and inform clinical prognosis.

Refractory Diffuse Large B-cell Lymphoma (DLBCL) presents a major therapeutic challenge due to its resistance to standard treatments. Engineered T-cells, especially Chimeric Antigen Receptor (CAR) T-cells, have shown promise in overcoming drug resistance. This study investigates the effectiveness of WEE1-engineered T-cells in targeting and eliminating refractory DLBCL in vitro. CAR T-cells were created by transducing a 5th-generation CAR construct designed to recognize WEE1, a surface antigen commonly found on refractory DLBCL cells. The cytotoxic effect of engineered T-cells was tested against Rituximab-resistant DLBCL cells (RR-NU-DUL-1). Apoptosis and cell cycle were evaluated using flow cytometry. Quantitative Real-time PCR (RT-PCR) was used to measure the expression of WEE1, BCL2, and CDK2. The results showed a significant increase in target cell lysis, apoptosis, and necrosis, a significant reduction in the percentage of cells in the G2M phase of the cell cycle, as well as a decrease in gene expression level, indicating strong anti-tumor activity. These findings suggest that CAR T-cell therapy holds great promise for treating refractory DLBCL, offering a potential path for clinical application. This in vitro evaluation highlights the potential of WEE1-engineered T-cells as a targeted treatment strategy for refractory DLBCL, emphasizing their clinical applicability and ability to overcome resistance mechanisms in this aggressive lymphoma subtype.

VEXAS syndrome is a complex hemato-inflammatory disorder, driven by somatic mutations in the UBA1 gene within hematopoietic precursor cells. It is characterized by systemic inflammation, rheumatological manifestations, and frequent association with myelodysplastic syndrome (MDS). We present a series of four VEXAS cases, all of which include concomitant MDS, each displaying distinct genetic signatures and clinical features at diagnosis, with a focus on their diagnostic and therapeutic implications. Our findings underscore the importance of extending UBA1 sequencing beyond exon 3 in cases with strong clinical suspicion. Given the rarity of non-canonical variants and the limited gene annotation, germline tissue control should be considered to differentiate somatic from germline mutations. Hematological management, including considerations for transplantation, was primarily guided by the Revised International Prognostic Scoring System (IPSS-R) for MDS due to the absence of a specific risk stratification system for VEXAS or therapy guidelines. A critical point of our discussion is the role of inflammation in the peri-transplant period; in one patient, the combination of disease-modifying antirheumatic drugs (DMARDs) and high-dose corticosteroids before transplant was crucial in controlling inflammation, resulting in a successful hematopoietic stem cell transplantation (HSCT). In contrast, uncontrolled inflammation contributed to the peri-transplant death of another patient. These cases highlight the importance of effective inflammation management in optimizing HSCT outcomes. Additionally, our study emphasizes the urgent need for specific management guidelines for VEXAS syndrome, including a comprehensive risk stratification system and optimal timing for transplantation.

Experience using olverembatinib as maintenance therapy in patients with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph⁺ ALL) after allogeneic hematopoietic cell transplantation (allo-HCT) is limited. We retrospectively collected data from 26 patients with Ph⁺ ALL who received only olverembatinib as maintenance therapy after allo-HCT. Olverembatinib was administered as prophylaxis in 18 patients (69.2%), and preemptively in 8 patients (30.8%). The median time of olverembatinib initiation after transplantation was 2.5 months (range, 1-7.3). The median starting dose of olverembatinib was 35 mg qod (range, 15-40). The median duration of olverembatinib treatment was 12.5 months (range, 6-23). Olverembatinib maintenance treatment was discontinued in 8 patients (8/26,30%), seven stopped the drug for a long-lasting BCR-ABL1 negativity and 1 for recurrent fever associated with the drug. BCR-ABL1 turned positive in 3 patients in 2, 3 and 6 months after discontinuation. During olverembatinib treatment, three patients developed grade ≥ 3 hematologic side effects, which resolved with dose interruption or dose reduction. The median follow-up time after allo-HCT were 17.75 months (range 7-31). The hematologic relapse rate was 7.7% (2/26), with no event in the preemptive group. The 3-year probability of overall survival and relapse free survival after allo-HCT was 91.7% and 79.1%, respectively. Only one patient in prophylaxis group died of central central nervous system (CNS) relapse. Thus, our data suggest that olverembatinib is effective and safe as maintenance treatment in patients with Ph⁺ ALL who underwent allo-HSCT. The main adverse effect was hematologic toxicity, which was tolerated.

There is a limited information available on the clinical characteristics, treatment patterns and outcomes on older patients diagnosed with Acute Myeloid Leukemia (AML) in Latin-America. This multicenter retrospective study analyzed 269 patients over 60 years of age diagnosed with AML in Colombia, using data from RENEHOC-PETHEMA registry, from 2009 to 2023. The median age at diagnosis was 70 years (Range:60-98), 55% were men, 61% had an ECOG < 2, and 75.5% had de novo AML. FLT3-ITD or NPM1 mutations were performed in 23.4% and 15.6% patients, and detected in 14.3% and 16.7% of cases, respectively. Treatment included intensive chemotherapy (IC) (36.8%), Low-Intensity Regimen Based on Low-Dose Cytarabine (LDAC-based) (12.6%), hypomethylating agents (HMAs, with/without venetoclax) (35.3%), and supportive care (15.2%). The overall survival (OS) rate was 35.2% at 1 year and 5.6% at 5 years (13.7% for IC, 9.4% for LDAC-based, and 0% for other treatments); with median OS of 8.2 months (10.6 months after IC, 8.8 months after non-IC, 8.9 months after azacitidine/decitabine, 8.2 months after azacitidine-venetoclax, and 1.9 months with supportive care). Only 1.5% of patients underwent a transplant in the first line. The Leukemia-free survival (LFS) rate was 45.8% at 1-year and 13.7% at 5-years (22.4% for IC, 9.4% and 0% for other treatments); with median LFS of 9.5 months (17.3 months after IC, 7.4 months after LDAC-based, and 10.8 months after HMA). This study provides new insights into the management of patients in Colombia, highlighting the need for a highly individualized approach in treating AML in elderly patients.

Bleeding assessment tools (BATs) are used by trained medical personnel for screening bleeding disorders on a one-to-one basis with patients; hence, they are time-consuming and limited in use for large-population screening. The aims of the study were to develop, validate, and demonstrate a Thai BAT mobile application (mBAT) for self-screening of bleeding disorders. mBAT was developed and validated using the paper-based Thai version of pediatric bleeding questionnaire (TPBQ). Then, mBAT was applied to 916 subjects from communities and hematology clinics. Those with scores of ≥3 consented to further investigation of bleeding disorders. mBAT was developed for Thai children using simple sentences, a video introduction, pictures, and auto-calculation. It showed a high correlation with the TPBQ: r = 0.96 and 0.97 in the PBQ and ISTH scoring systems, respectively (P<0.01). A score ≥3 was considered abnormal. The mBAT was applied to 916 subjects, with a mean (range) age of 10.5 (0.07-18.0) years. Most subjects (97.3%) were from the community, and the rest (2.7%) were from hematology clinics. The results showed 41 subjects had abnormal scores, and 35 (16 from the community and 19 from clinics) consented to diagnostic investigation. Eleven subjects (31.4%) were found to have bleeding disorders, including four with VWD, two each with hemophilia A and thrombocytopenia, and one each with factor VII deficiency, platelet dysfunction, and MYH9-related disorder. Thus, the prevalence rates of bleeding disorders in the subjects whose scores ≥3 from community and hematology clinics were 6.25% and 52.6%, respectively. In conclusions, the mBAT had a high correlation with the TPBQ. As a self-screening tool, it could enhance the diagnosis of bleeding disorders.

Recognizing and diagnosing lymphoma in patients with fever of unknown origin (FUO) can be challenging, and misdiagnosis is not uncommon. To improve understanding of the clinical characteristics of lymphoma patients presenting with FUO who were misdiagnosed with autoimmune diseases. A retrospective, observational study of 140 consecutive patients with FUO and lymphoma presenting to a tertiary center between January 2017 and December 2023. Patients were divided into those who were correctly diagnosed and those misdiagnosed as connective tissue diseases (CTD) and the clinical features compared. Of 140 lymphoma patients with FUO, 21 patients (15.0%) were misdiagnosed as CTD. The median time between symptom onset and diagnosis was significantly longer in the misdiagnosed group than in the non-misdiagnosed group (11.0 (IQR 6.0, 22.5) months vs. 4.0 (2.5, 9.0) months; p = 0.001). The misdiagnosed group had significantly less lymph node and bone marrow involvement and more skin rashes than the non-misdiagnosed group (47.6% vs. 70.6%, p = 0.039; 23.8% vs. 47.9%, p = 0.040; 47.6% vs. 25.2%, p = 0.036), as well as significantly lower ESR (p = 0.026) and hsCRP (p = 0.049). The misdiagnosed group had higher frequency of ANA/ANCA (57.1% vs. 27.7%; p = 0.008) and anti-phospholipid antibody (42.9% vs. 6.1%; p = 0.008) positivity. The distribution of lymphoma subtypes was different between groups (p = 0.058). Lymphoma patients with an atypical presentation and FUO suggesting inflammatory systemic disease are easily misdiagnosed. Autoantibody positivity is not rare in lymphoma patients with an atypical presentation and FUO, so close follow-up and repeated histopathological examination may be helpful to establishing a correct diagnosis.

Severe acute graft-versus-host disease (GVHD) can occur during allogeneic hematopoietic stem cell transplantation (allo-HSCT), causing considerable morbidity and mortality. Although several biomarkers have been reported for predicting acute GVHD, they are often difficult to measure in routine clinical practice. Recently, three-dimensional computed tomography (3D-CT) has been used to quantify the detailed bronchial structure, which might correlate with acute GVHD. We retrospectively evaluated 55 patients who underwent their first allo-HSCT at our hospital between 2016 and 2020. Using 3D-CT analysis, the airway inner luminal area (Ai), wall area (WA), and wall thickness (WT) were measured at each third- to fifth-generation bronchus. Values were adjusted according to body surface area (BSA). Ratios of values at neutrophil engraftment to those of pre-conditioning were assessed. In the cohort, Ai/BSA narrowed, WA/BSA enlarged, and WT/BSA thickened during neutrophil engraftment compared with pre-conditioning. The cumulative incidence of grade II-IV acute GVHD after allo-HSCT was 24%. The ratio of WA/BSA at neutrophil engraftment to that of pre-conditioning in fourth-generation bronchi (WA4/BSA) was significantly lower in patients with grade II-IV acute GVHD compared with those with grade 0-I (0.99 vs. 1.08, P < 0.01). The ratio of WA4/BSA of < 0.955 was significantly associated with the incidence of grade II-IV acute GVHD (< 0.955; 60% vs. ≥ 0.955; 16%, P < 0.01). This is the first study to demonstrate that 3D-CT analyses could quantify changes in bronchial structure during neutrophil engraftment after allo-HSCT; these changes might correlate with the incidence of severe acute GVHD.

In a previous preliminary study, radiomic features from the largest and the hottest lesion in baseline ¹⁸F-FDG PET/CT (bPET/CT) of classical Hodgkin's Lymphoma (cHL) predicted early response-to-treatment and prognosis. Aim of this large retrospectively-validated study is to evaluate the predictive role of two-lesions radiomics in comparison with other clinical and conventional PET/CT models. cHL patients with bPET/CT between 2010 and 2020 were retrospectively included and randomized into training-validation sets. Target lesions were: Lesion_A, with largest axial diameter (D_max); Lesion_B, with highest SUV_max. Total-metabolic-tumor-volume (TMTV) was calculated and 212 radiomic features were extracted. PET/CT features were harmonized using ComBat across two scanners. Outcomes were progression-free-survival (PFS) and Deauville Score at interim PET/CT (DS). For each outcome, three predictive models and their combinations were trained and validated: - radiomic model "R"; - conventional PET/CT model "P"; - clinical model "C". 197 patients were included (training = 118; validation = 79): 38/197 (19%) patients had adverse events and 42/193 (22%) had DS ≥ 4. In the training phase, only one radiomic feature was selected for PFS prediction in model "R" (Lesion_B F_cm.corr, C-index 66.9%). Best "C" model combined stage and IPS (C-index 74.8%), while optimal "P" model combined TMTV and D_max (C-index 63.3%). After internal validation, "C", "C + R", "R + P" and "C + R + P" significantly predicted PFS. The best validated model was "C + R" (C-index 66.3%). No model was validated for DS prediction. In this large retrospectively-validated study, a combination of baseline ¹⁸F-FDG PET/CT two-lesions radiomics and other conventional models showed an added prognostic power in patients with cHL. As single models, conventional clinical parameters maintain their prognostic power, while radiomics or conventional PET/CT alone seem to be sub-optimal to predict survival.

Polycythemia vera (PV) is characterized by clonal hematopoietic stem or progenitor cells with constitutively active somatic mutation(s) in the Janus kinase 2 gene. Phlebotomy (Phl) and aspirin are often used alone for low-risk PV patients. However, data from the Low-PV study demonstrated that Phl and aspirin may not be adequate for patients. Therapeutic intervention with disease-modifying treatment appears to be beneficial for patients with PV regardless of the risk category. Ropeginterferon alfa-2b (ropeg) is a novel interferon-based therapy with favorable dosing schedules. A higher starting-dose (250 µg) regimen with simpler dose titrations was found to have a potent disease-modifying effect with respect to inducing a molecular response. PARADIGM-PV is a randomized, phase 4 study with the primary goal of assessing the efficacy of ropeg at this dosing regimen in alleviating Phl-dependence in both low- and high-risk patients with PV. The secondary endpoints include complete hematologic response, molecular response, symptom improvement, maintenance of median hematocrit (Hct) values < 45% without disease progression, and safety. Patients will be randomized equally to receive either ropeg every two weeks or to continue their current treatment with Phl or other cytoreductive agents (e.g., hydroxyurea, other interferons, or ruxolitinib) as applicable. All patients will receive Phl if their Hct values are elevated to ≥45% according to the National Comprehensive Cancer Network guidelines. The study will enroll approximately 70 patients internationally, including patients in the US. This study will provide new efficacy data, measured as the ability of ropeg to reduce Phl eligibility and modify the disease.