Annals of Hematology最新文献

Eosinophilia associated with PCM1::JAK2 fusion and classic Philadelphia (Ph)-negative myeloproliferative neoplasms (MPN) are both clonal disorders caused by a dysregulation of the JAK2 signaling pathway. The myeloid neoplasm with t(8;9)(p22;p24.1) and PCM1::JAK2 rearrangement is now formally included among the myeloid/lymphoid neoplasms with eosinophilia (M/LN-eo) and tyrosine kinase fusion genes. To date, no data on genetic predisposition to M/LN-eo with PCM1::JAK2 rearrangement are known, while it is well recognized that a subset of classic Ph-negative MPN segregates within families, suggesting a role for germline predisposition in disease etiology. Here we report the first pedigree with a case of classic Ph-negative MPN and a case of M/LN-eo with PCM1::JAK2. Our patient carried two acquired molecular abnormalities involving JAK2 gene (PCM1::JAK2 fusion and JAK2 H531Y) along with a germline mutation (BLM Y736fs*5, variant allele frequency VAF 41.7%), whereas his sister had the canonical JAK2 V617F driver mutation. This particular pedigree could arise the hypothesis of a genetic predisposition to acquire different JAK2 molecular abnormalities as a maladaptive somatic genetic rescue of an underlying germline predisposition, namely the germline BLM Y736fs*5 mutation.

Chimeric Antigen Receptor (CAR) T-cell therapy is an established treatment for relapsed or refractory large B-cell lymphoma (rr LBCL). While clinical efficacy is well documented, data on health-related quality of life (HRQoL) remain limited. This study assessed HRQoL in rr LBCL patients with long-term remission after CAR T-cell therapy versus high-dose chemotherapy with autologous stem cell transplantation (HD-ASCT). Twenty-eight consecutive rr LBCL patients in sustained remission were analyzed, with 15 receiving CAR T-cell therapy (tisagenlecleucel) and 13 undergoing HD-ASCT between 2019 and 2023. HRQoL was assessed using EQ-5D-5 L and PROMIS-29 questionnaires at 12 months and at a median of 36.8 months (range 15.7-57.2 months) post cellular therapy. Groups were compared for differences in HRQoL indices and domain scores. Median age was 63.5 (range 23-73) years. Twelve months post-treatment, CAR T-cell recipients reported significantly higher HRQoL scores than HD-ASCT patients (EQ-5D-5 L index value: 0.89 ± 0.11 vs. 0.72 ± 0.21; p = 0.015). Consistently, PROMIS-29 revealed clinically meaningful advantages in the CAR T-cell cohort across all seven categories. At later follow-up, EQ-5D-5 L index values converged (index-value 0.82 ± 0.22 vs. 0.7 ± 0.25; p = 0.2), whereas PROMIS-29 still indicated sustained benefit in five domains among CAR T-cell recipients. CAR T-cell therapy was associated with superior HRQoL in the first year compared to HD-ASCT. Although some differences diminished over time, CAR T-cell patients continued to experience better outcomes in several domains. These findings highlight clinical relevance of patient-reported outcome in rr LBCL, particularly in longitudinal surveys, and underscore the value of integrating patient-centered metrics into therapeutic decisions-making.

Background: Adding daratumumab to initial therapy in randomized controlled trials (RCTs) for newly diagnosed multiple myeloma (MM) enhances deep remission and prolongs progression-free survival (PFS). Given the differences between trial-eligible and real-world patients, and healthcare access variability in developing countries, real-world data are essential to complement RCT evidence.

Methods: We analyzed 761 newly diagnosed MM patients treated with (n = 177) or without (n = 584) daratumumab as first-line therapy from 2017 to 2023 across southern China. Propensity score matching (PSM) generated cohorts of 158 and 278 patients, respectively, matched for stage, cytogenetic abnormalities, and regimen type. Responses were evaluated per International Myeloma Working Group criteria, and measurable residual disease (MRD) was assessed via next-generation multiparameter flow cytometry.

Results: The daratumumab group demonstrated significantly higher rates of ≥ very good partial response (85.0% vs. 61.3%; P < 0.001) and MRD negativity (73.0% vs. 51.9%; P = 0.024) at the end of induction. Additionally, 3-year PFS (75.6% vs. 55.0%, hazard ratio [HR] 0.49, 95% confidence interval [95% CI] 0.36-0.66, P < 0.001) and overall survival (OS) rates (78.3% vs. 74.4%; HR 0.56 [95% CI 0.36-0.86], P = 0.008) were superior in the daratumumab group, and these results remained consistent after PSM. Daratumumab improved PFS in patients with gain/amp(1q21) but not in those with del17p or t(4;14). Survival benefit was also observed in the addition of daratumumab to bortezomib/lenalidomide/dexamethasone combined treatment subgroup.

Conclusion: In real-world settings, daratumumab-based first-line therapy improved the depth of response, PFS, and OS, though not all patients benefited.

Follicular lymphoma (FL) is the most common indolent non-Hodgkin lymphoma (NHL) in Western countries, with 65 beign the average age at diagnosis [1]. First-line treatment regimens combining Bendamustine (B) with Rituximab (R) or Obinutuzumab (G) have shown favorable outcomes in pivotal trials [2-4]. Their efficacy and safety in patients aged 70 or older, who often receive reduced doses, remain unclear. This retrospective study evaluated the impact of reduced Bendamustine Delivered Dose Intensity [DDI, calculated as the total amount of Bendamustine (mg/m²) administered divided by the time taken to complete the regimen, with imputation for missed cycles] on outcomes and toxicities in FL patients (grade 1-3a) aged 70 or older treated with B-R or B-G between January 2014 and December 2023 at our center. Patients were categorized in reduced intensity (Low-DDI) and full intensity (High-DDI), based on the median DDI of the cohort. Efficacy was evaluated in the low DDI vs. high DDI setting, while toxicity outcomes were evaluated in the elderly (age ≥ 70 < 75 years) vs. very elderly (age ≥ 75yrs) population. Primary outcomes included progression-free survival (PFS) and overall survival (OS). Secondary outcomes included response rates, Progression of disease at 24 months (POD24) and toxicities. Among 139 FL patients, 39 met inclusion criteria (median follow-up: 73 months). Median OS was 31.5 vs. 65.0 months (p 0.238) and median PFS was 20.5 vs. 28.0 months (p = 0.081) for low- (n = 20) and high-DDI (n = 19), respectively. ORR was 78.9% vs. 100% (p = 0.105); CRR was 36.8% vs. 72.2% (p = 0.067). POD24 rates were similar (29.4% vs. 22.2%, p = 0.711). Patients were significantly older in the low-DDI group; other baseline features were comparable. Toxicity analysis showed no significant difference in grade ≥ 3 hematologic (p = 0.399) or non-hematologic (p = 0.920) events, or rate of hospitalization (p = 0.378) between elderly and very elderly. Secondary primary malignancies (SPM) occurred in 13 patients (34.2%), with no difference between groups. These findings support the feasibility of bendamustine dose reduction in elderly FL patients, showing no significant compromise in efficacy or increased toxicity. However, larger prospective studies are needed to confirm optimal dosing strategies in this population.

Non-deletional α-thalassemia variants, particularly hemoglobin Constant Spring (Hb CS) and hemoglobin Pakse, are prevalent in northeastern Thailand and neighboring regions. Homozygous Hb CS and compound heterozygous Hb CS/Hb Pakse can present with a wide clinical spectrum. In this study, 49 patients with these α-globin variants-with or without co-inheritance of beta-thalassemia-were evaluated. Genotypes included homozygous Hb CS (n = 27), homozygous Hb CS with Hb E (n = 8), compound heterozygous Hb CS/Hb Pakse (n = 10), compound heterozygous Hb CS/Hb Pakse with Hb E (n = 3), and homozygous Hb Pakse (n = 1). Fetal anemia with hydrops fetalis occurred in 25 patients; 21 underwent intrauterine transfusions (IUTs), resulting in favorable postnatal outcomes in most cases. Two patients with homozygous Hb CS died from complications of severe anemia and prematurity. Early neonatal jaundice occurred in 27 patients, most requiring phototherapy. Direct hyperbilirubinemia was observed in 10 patients; most recovered with supportive care and transfusion, though one died from progressive cholestasis. Twenty four patients required 1-2 postnatal transfusions, with only two requiring later transfusion. Four patients with childhood anemia were initially misdiagnosed with iron deficiency anemia before confirmation of α-thalassemia variants. After the first few months of life, patients typically exhibit mild hypochromic microcytic anemia, elevated red cell distribution width, and reticulocytosis, with basophilic stippling more prominent in Hb CS. During follow-up (3-160 months, median 66), no patients developed hepatosplenomegaly, iron overload, or gallstones. These α-thalassemia variants may cause severe fetal anemia requiring IUT but generally evolve into transfusion-independent mild anemia. Early detection and targeted intervention can improve outcomes in high-prevalence regions.

The mutation of the plant homeodomain finger protein 6 gene (PHF6^MUT) in patients with myeloid neoplasms (MNs) is rare and appears to play a role in prognosis, though this is still under debate. We conducted a retrospective analysis of a cohort of 313 patients diagnosed with MNs. We also performed a systematic review (SR) of the literature to evaluate the prognostic role of PHF6 gene status in MNs. We identified 15 patients with PHF6^MUT. In the multivariate analysis, PHF6^MUT was associated with higher mortality compared to PHF6^{wild - type} (hazard ratio [HR] = 1.02; 95% confidence interval [CI], 1.00-1.05; P = 0.075), with no apparent impact from other co-mutations. In the multilevel logistic model by MN subtype, the presence of PHF6^MUT (independent of variant allele frequency > 20%) was shown to have a positive coefficient (adverse prognosis) in acute myeloid leukemia; in the remainder of MNs, the effect was not significant. PHF6^MUT had a marginal and significant effect compared to PHF6^{wild - type} cases (HR = 1.02; 95% CI, 1.00-1.05; P = 0.039). There were no significant differences in time to blast transformation or time to next treatment depending on PHF6 gene status. According to the results of most studies published to date (SR), PHF6^MUT has a prognostic role in MNs; our results are consistent in terms of clinical outcomes, but these marginal effects should be interpreted with caution in the context of existing prognostic models given the limitations of the small sample size.

High molecular weight kininogen (HK) deficiency is a rare autosomal recessive disorder caused by mutations in the KNG1 gene. This study reports a 66-year-old male Chinese patient who presented with significantly prolonged activated partial thromboplastin time (aPTT) and microcytic hypochromic anemia. Whole-exome sequencing revealed a homozygous nonsense mutation in exon 6 of the KNG1 gene (c.718 C > T, p.Arg240*) in the proband. This mutation results from a cytosine-to-thymine substitution, generating a premature termination codon that leads to truncated HK protein translation and loss of function. Additionally, genetic testing identified a concurrent heterozygous α-thalassemia --^SEAdeletion in the proband, located at 16p13.3 and encompassing the HBA2 and HBA1 genes. Pedigree analysis indicated that both the proband and his sister were homozygous for the KNG1 mutation and exhibited prolonged aPTT, whereas their children and some descendants were heterozygous carriers with normal coagulation function. Within the same family, all heterozygous carriers of the α-thalassemia --^SEAdeletion presented with microcytic hypochromic anemia. This study represents the first documented case of co-occurrence of a homozygous KNG1 p.Arg240* mutation and the --^SEAdeletion α-thalassemia.