Annals of Hematology最新文献

This study aimed to initially characterize the effects of GANT61, a Hedgehog (Hh) signaling pathway inhibitor, on the biological behaviors of ALK-positive anaplastic large cell lymphoma (ALK + ALCL) cell lines and explore its underlying mechanisms. Cell proliferation was determined by CCK-8 assays. Cell cycle distribution and apoptotic rates were assessed by flow cytometry. Differential gene analysis and pathway enrichment studies were conducted using datasets from the GEO database with R packages. Protein expression levels of apoptosis-related markers (Bcl-2, Bax, caspase-3, cleaved caspase-3) and signaling molecules (Gli1, PIK3IP1, Akt, phosphorylated Akt) were quantitatively examined by western blotting. Corresponding mRNA levels were quantified by qRT-PCR. GANT61 treatment inhibited proliferation in a dose- and time-dependent manner, induced cell cycle arrest, and promoted apoptosis in ALK + ALCL cell lines. Notably, PIK3IP1 expression was markedly reduced compared with normal lymphocyte controls, while GAS1 expression showed significant upregulation in ALK + ALCL cell lines. Gene Set Enrichment Analysis (GSEA) demonstrated significant enrichment of the PI3K/Akt and Hh signaling pathways. Mechanistically, GANT61 upregulated PIK3IP1 while downregulating both Gli1 protein level and Akt phosphorylation. The Gli-targeting agent GANT61 may inhibit ALK + ALCL cell growth, trigger cell cycle arrest and induce apoptosis through Gli1 inhibition, potentially leading to PIK3IP1 upregulation and subsequent attenuation of PI3K/Akt pathway activity. These findings indicate that the Hh-PIK3IP1-Akt signaling axis may participate in ALK + ALCL tumorigenesis, showing that conventional target drugs can be employed for ALK + ALCL treatment.

Angioimmunoblastic T-cell lymphoma (AITL) is a rare and aggressive peripheral T-cell lymphoma that is prone to early progression and recurrence and has a poor overall prognosis. Notably, early mortality (EM) and risk factors for AITL are currently unclear. We performed a retrospective analysis of AITL data from 2000 to 2021 in the Surveillance, Epidemiology, and End Results databases. Early death was defined as death within two years from the date of diagnosis. Histograms and pie charts were used to present the distribution of overall early mortality (O-EM) and lymphoma-specific early mortality (LS-EM). Cox regression model was used to screen the risk factors. Cumulative event rate curves were used to analyze the effect of treatment on EM. In total, 2,413 patients diagnosed with AITL were included in this study. Among the deceased patients, the O-EM was 46.6%, with an LS-EM of 39.7%. EM increased significantly with age, was higher among white person than among other racial groups, and was higher among males than among females. Significant independent risk factors for both O-EM and LS-EM included sex, age, SEER historic stage, radiation therapy, and chemotherapy. The combination of chemotherapy and radiotherapy can decrease O-EM and LS-EM rates in males, aged 40–69 years, and patients with localized and regional SEER historic stages. AITL demonstrates elevated EM. However, the integration of radiotherapy with chemotherapy can significantly reduce the EM among male patients aged 40–69 years with SEER historical stage as localized and regional.

Background

Standard R-CHOP immunochemotherapy for diffuse large B-cell lymphoma (DLBCL) with gastrointestinal (GI) involvement is associated with an increased risk of severe GI complications, including perforation and acute hemorrhage. This study evaluates a modified treatment regimen aimed at reducing these risks without compromising therapeutic efficacy.

Methods

We retrospectively analyzed 65 DLBCL patients with GI involvement. Group 1 (n = 33) received a 3-day pre-phase dexamethasone (DEX) followed by a fractionated R-CHOP regimen (cyclophosphamide, doxorubicin, and vincristine split on days 1 and 4) in cycle 1, then transitioned to standard R-CHOP from cycle 2 onwards. Group 2 (n = 32) received six cycles of standard R-CHOP without pretreatment.

Results

No treatment-related GI perforation or acute hemorrhage occurred in Group 1, compared with an incidence of 18.7% in Group 2 (p = 0.03). There were no significant differences in overall response rate (84.9% vs. 82.7%), 5-year progression-free survival (73.0% vs. 68.1%; p = 0.62), or 5-year overall survival (83.7% vs. 78.0%; p = 0.58). Hematologic toxicities were comparable between groups, and no treatment-related deaths occurred in Group 1.

Conclusion

A pre-phase of dexamethasone followed by fractionated R-CHOP in the first cycle, before transitioning to standard R-CHOP, significantly reduces the incidence of GI complications while preserving therapeutic efficacy in DLBCL patients with GI involvement. This approach offers a safer induction strategy without compromising survival outcomes.

Peripheral T-cell lymphoma (PTCL) is a heterogeneous subtype of non-Hodgkin lymphoma with a poor prognosis. Red blood cell distribution width (RDW) is a hematological parameter reflecting variability in erythrocyte volume and has been associated with prognosis in various diseases. Therefore, we conducted a retrospective study on 629 newly diagnosed patients with PTCL to explore the relationship between baseline RDW, prognosis, and response to first-line treatment. The cutoff value for baseline RDW was 14.45%. Patients with baseline RDW ≥ 14.45% had a lower overall response rate than those with RDW < 14.45% (41.98% vs. 78.75%, P < 0.001). Univariate and multivariate logistic regression analyses indicated that baseline RDW ≥ 14.45% was associated with a poorer treatment response. Multivariate Cox analysis identified baseline RDW ≥ 14.45% as an independent prognostic factor in PTCL. Therefore, baseline RDW is an easily accessible and inexpensive marker for prognostic risk stratification in patients with PTCL.

Polycythaemia vera (PV) is a myeloproliferative neoplasm (MPN) which can progress to myelofibrosis (MF), a phenomenon termed post-PV MF. Ruxolitinib is a Janus activated kinase (JAK) inhibitor that targets JAK1/2 mutations and is approved for treatment of high-risk MF. This is a case report of a patient with post-PV MF who developed acute psychotic disorder five months after commencing ruxolitinib and whose mental status returned to baseline within one week of stopping ruxolitinib. Importantly, there was no history of mental health disorder and no identifiable triggers for his presentation. Ruxolitinib has not previously been implicated in the development of psychosis but is known to cross the blood-brain barrier and affect multiple cell signalling pathways within the central nervous system. Together, this makes an association between ruxolitinib and neuropsychiatric symptoms plausible, yet further understanding of causal mechanisms is warranted.

Discussion remains concerning the safety and tolerability of anti-thymocyte globulin (ATG)-based immunosuppressive therapy (IST) in older patients with aplastic anaemia (AA). Using data of 127 consecutive patients from the Dutch adult AA registry, we evaluated long-term treatment success of standard ATG-based IST as first-line treatment with a multi-state model. Only one death was potentially associated with ATG. Overall survival at 5 years was 79%. We defined Transplantation-, Treatment- and Disease-Free Survival (TT-DFS) as the ultimate success of this treatment. This means that a patient is alive, is currently transfusion-independent without having received an allogeneic stem cell transplantation, has not developed AML or MDS, and has stopped all medication for AA. The probability of TT-DFS was 42% at 5 years after start of IST. In patients younger than 40 years (n = 36) and in patients aged 60 or above (n = 53), this was 58% and 34%, respectively. Older age, more severe AA and absence of a PNH-clone of ≥ 1% all reduced the likelihood of reaching TT-DFS. These analyses on unselected nationwide data indicate that ATG-based IST is effective and safe also in older patients. They suggest that age, AA severity and presence of a PNH-clone should be taken into account when considering this treatment in older patients.

PRDM16 (PR Domain Containing 16) is a transcription factor that plays a critical role in hematopoietic stem cell maintenance. In acute myeloid leukemia (AML), PRDM16 overexpression is linked to specific cytogenetic risk groups and poor prognosis. However, in NPM1-mutated AMLs, PRDM16 expression varies widely, with no consensus on its prognostic significance. To understand molecular and clinical associations of PRDM16 expression in this relevant subgroup, we screened 503 adult NPM1-mutant AML patients. High PRDM16 expression was associated with mutations in DNMT3A (57% vs 22%; p < 0.0001) and FLT3-ITD (51% vs 37%; p = 0.0258), and therefore a higher rate of ELN2022 intermediate-risk (42% vs 26%; p = 0.01), compared to low PRDM16 expression. Accordingly, PRDM16 overexpression was not associated with clinical outcome in multivariable analysis adjusting for ELN2022 risk in the unselected NPM1-mutant AML cohort. However, within the double-mutant NPM1/FLT3-ITD subgroup (n = 200), low PRDM16 expression was an independent prognostic factor for longer survival (hazard ratio [95%-CI] 0.467 [0.270–0.807]; p = 0.006). On a molecular level, low PRDM16 expression was associated with mutations in epigenetic regulators (TET2, IDH1/2) and increased PRDM16 promoter methylation, suggesting impaired TET/IDH-mediated DNA-demethylation as underlying mechanism. Notably, IDH1 R132C and IDH2 R140Q alterations particularly contributed to higher PRDM16 promoter methylation and reduced expression. These results suggest an association of PRDM16 overexpression with the NPM1/FLT3-ITD/DNMT3A triple-mutant AML genotype, typically linked to high leukemia stem cell frequencies and poor prognosis. Importantly, within this adverse AML subtype low PRDM16 expression is an independent prognostic marker for favorable outcome, supporting an anti-leukemic mechanism in AMLs with repressed PRDM16 transcription.

Graphical Abstract

Ravulizumab is a second-generation C5i engineered from eculizumab to achieve immediate, complete, and sustained inhibition of terminal complement activity in PNH. The REACTION observational cohort study describes the effectiveness and tolerability of ravulizumab in Italian patients who were previously treated with eculizumab. Eighty-one PNH patients were enrolled in this study. The primary endpoint was the percentage change in lactate dehydrogenase (LDH) from baseline to the end of observation (52 weeks follow-up). Among secondary endpoints, transfusion avoidance, breakthrough hemolysis (BTH) and patients’ quality of life (QoL) were evaluated. The median (25–75 percentiles) percentage change in LDH at 52 weeks follow-up was -2.6 (-11.5–13.4) U/L, with 92.3% of the patients presenting LDH within or < 1.5 × upper limit of normal (ULN). Overall, 20 (25.0%) patients required transfusion during the eculizumab period and 15 (18.8%) during the ravulizumab. Seven BTH events were observed, 5 during eculizumab period and 2 (triggered by other medical conditions) during ravulizumab, suggesting the reduction of pharmacokinetic BTH during ravulizumab treatment. EORTC-QLQ-C30 and FACIT-Fatigue scores were similar to the general population, and patients’ preference indicated ravulizumab as the favorite treatment. The REACTION study confirmed the effectiveness of ravulizumab in maintaining stable disease and hemolysis control in the real-world setting. Clinical trial registration. NCT05274633, 02-Mar-2022.

Recurrent chromosomal translocations are hallmarks of many hematological malignancies, including lymphomas and leukemias. Accurate breakpoint detection is essential for diagnostics, treatment optimization, and disease monitoring. Long-read sequencing (Oxford Nanopore Technologies) enables unambiguous mapping and translocation identification. We designed a Cas9-based enrichment panel targeting common translocations in lymphoid malignancies. To accommodate both well-defined and promiscuous translocation partners, we employed single-side and dual-side sequencing strategies. Using well-established lymphoid cell lines, we benchmarked three enrichment approaches: (i) Cas9 read-out, (ii) Cas9 excision with multiplexing, and (iii) adaptive sampling. Cas9-mediated enrichment achieved superior on-target coverage, particularly in densely targeted regions (such as the IGH locus), while single-probe targets showed lower coverage depth. Adaptive sampling offered higher throughput, flexibility, and better pore occupancy, however with limited breakpoint detection. Cas9 excision has been demonstrated as a fast and reliable method to detect canonical translocation partners in clinical lymphoma samples. Our findings indicate that long-read enrichment strategies are suitable for targeting breakpoint hotspots, although the choice of approach depends heavily on the laboratory's specific goal. We propose a decision algorithm for selecting the optimal method based on experimental and clinical needs: Cas9-mediated enrichment suits focused diagnostic intent, while adaptive sampling is preferable for broader research use.