Exosomal miR-155-5p drives ibrutinib resistance in B-cell lymphoma.

Ibrutinib, a Bruton Tyrosine Kinase (BTK) inhibitor, has shown effectiveness against various B-cell lymphoid malignancies. However, prolonged usage can induce resistance, affecting treatment outcomes. The oncogenic microRNA, miR-155-5p, is associated with poor prognosis in B-cell lymphomas, prompting our investigation into the mechanism of acquired ibrutinib resistance in these cells. We generated ibrutinib-resistant OCI-Ly1 cells (OCI-Ly1-IbtR) through continuous exposure to 1 µM and 2 µM of ibrutinib. We conducted microRNA profiling of OCI-Ly1-IbtR and isolated exosomes via ultracentrifugation. Comparative studies of microRNA levels in cells and exosomes, as well as exploration of targets of up-regulated microRNAs in OCI-Ly1-IbtR, were performed. Target validation involved transfection of candidate microRNAs, and co-culture experiments utilized OCI-Ly1 cells with exosomes from OCI-Ly1-IbtR. Elevated levels of miR-155-5p were observed in OCI-Ly1-IbtR and its exosomes, correlating with AKT and NF-κB activation. Transfection of miR-155-5p induced AKT/NF-κB pathway activation in OCI-Ly1, resulting in ibrutinib resistance, enhanced colony formation, and sustained BTK activity. Primary cell lines from ibrutinib-refractory B-cell lymphoma patients exhibited similar signaling protein activation. Target evaluation identified KDM5B and DEPTOR as miR-155-5p targets, confirmed by downregulation after transfection. We observed KDM5B and DEPTOR enrichment in Ago2 during ibrutinib resistance and miR-155-5p transfection. Co-culture experiments demonstrated exosome-mediated transfer of miR-155-5p, inducing ibrutinib resistance and KDM5B/DEPTOR downregulation in OCI-Ly1. Our findings suggest that miR-155-5p overexpression is associated with AKT and NF-κB pathway activation in ibrutinib-resistant cells, proposing a potential role for acquired miR-155-5p upregulation in B-cell lymphoma ibrutinib resistance.

Feasibility of Circulating Tumor DNA Detection in the Cerebrospinal Fluid of Patients With Central Nervous System Involvement in Large B-Cell Lymphoma.

We explored the utility of cerebrospinal fluid (CSF) circulating tumor DNA (ctDNA) sequencing as a noninvasive diagnostic tool for detecting central nervous system (CNS) involvement in patients with diffuse large B-cell lymphoma (DLBCL). Secondary CNS involvement in DLBCL, although rare (~5% of cases), presents diagnostic and prognostic challenges during systemic disease progression or relapse. Effective treatment is impeded by the blood-brain barrier. This was a prospective cohort study (Samsung Lymphoma Cohort Study III) involving 17 patients with confirmed CNS involvement. High-throughput sequencing was conducted using targeted gene panels designed to detect low-frequency variants and copy number alterations pertinent to lymphomas in ctDNA extracted from archived CSF samples. Despite challenges such as low DNA concentrations affecting library construction, the overall variant detection rate was 76%. Detected variants included those in genes commonly implicated in CNS lymphoma, such as MYD88. The study highlights the potential of CSF ctDNA sequencing to identify CNS involvement in DLBCL, providing a promising alternative to more invasive diagnostic methods such as brain biopsy, which are not always feasible. Further validation is necessary to establish the clinical utility of this method, which could significantly enhance the management and outcomes of DLBCL patients with suspected CNS involvement.

Combination of rituximab and methotrexate followed by rituximab and cytarabine in elderly patients with primary central nervous system lymphoma.

The optimal treatment strategy for newly diagnosed primary central nervous system lymphoma (PCNSL) has yet to be established, especially in the elderly. In the current study, we conducted a phase II study to evaluate the efficacy and safety of rituximab plus high-dose MTX followed by rituximab plus cytarabine in patients aged ≥60 years newly diagnosed with PCNSL. Patients received an induction treatment of high-dose methotrexate plus rituximab followed by two cycles of a consolidation treatment of cytarabine plus rituximab. The primary end-point was a 2-year progression-free survival (PFS) rate. A total of 35 patients were recruited, and their median age was 73 (range: 60-81). After induction treatment, the complete and partial responses (PRs) were 56% and 20% respectively. Twenty-six patients proceeded to the consolidation treatment; the complete and PRs were 59% and 9% respectively. After a median follow-up duration of 36.0 months, the 2-year PFS rate was 58.7%. Treatment was generally well-tolerated as only three patients were withdrawn from the study due to toxicity, and no treatment-related mortality was reported. The 2-year overall survival rate was 77.9%. The current study may suggest the feasibility of administering high-dose MTX plus cytarabine in PCNSL patients aged ≥60 years and the potential role of additive rituximab.

Delphi consensus recommendations on treatment for advanced-stage marginal zone lymphoma in South Korea.

Due to the lack of treatment guidelines for the management of advanced-stage marginal zone lymphoma (MZL), only one chemoimmunotherapy-cyclophosphamide, vincristine, and prednisone plus rituximab (R-CVP)-is reimbursed in the first-line setting in South Korea. The aim of this study was to develop a consensus-based recommendation for the treatment of patients with advanced-stage MZL. Twelve hematologist oncologists participated in a two-round Delphi process to identify consensus on the management of patients with advanced-stage MZL in South Korea. Physicians rated their level of agreement with each statement on a four-point Likert scale. Statements were divided into two sections: definitions used in clinical practice and clinical management of patients with advanced-stage MZL. Consensus was reached for 23 of 33 (69.7%) and 5 of 13 statements (38.5%) in rounds 1 and 2, respectively. There was strong consensus (91.7%) that advanced-stage MZL subtypes are defined according to the Lugano staging system. First-line systemic treatment should be prescribed for patients with symptomatic advanced-stage MZL. Although there was unanimous agreement that R-CVP is the standard first-line treatment for advanced-stage MZL, physicians also agreed that bendamustine with rituximab (BR) has greater efficacy than R-CVP as first-line treatment (91.7%). For the treatment of relapsed/refractory advanced-stage MZL, BR and R-CVP can be repeated in patients with short (< 24 months) and long remission periods (≥ 24 months), respectively. This study provides insights on the management of patients with advanced-stage MZL in South Korea. This may enhance clinical decision-making, thus improving patient outcomes.

Clinical Impact of Microbiome Characteristics in Treatment-Naïve Extranodal NK/T-Cell Lymphoma Patients.

Purpose: Extranodal NK/T-cell lymphoma (ENKTL) predominantly manifests in East Asia and Latin America. Despite shared intrinsic factors, such as ethnic and genetic backgrounds, the progression of ENKTL can be influenced by extrinsic factors related to changing lifestyle patterns. Materials and Methods: This study collected stool samples from newly diagnosed (ND)-ENKTL patients (n=40) and conducted whole genome shotgun sequencing. Results: ND-ENKTL revealed reduced alpha diversity in ND-ENKTL compared to healthy controls (HCs) (p=0.008), with Enterobacteriaceae abundance significantly contributing to the beta diversity difference between ENKTL and HCs (p<0.001). Functional analysis indicated upregulated aerobic metabolism and degradation of aromatic compounds in ND-ENKTL. Enterobacteriaceae were associated not only with clinical data explaining disease status (serum CRP, stage, prognosis index of natural killer cell lymphoma (PINK), and PINK-E) but also with clinical outcomes (early relapse and short progression-free survival). The relative abundance of Enterobacteriaceae at the family level was similar between ENKTL and diffuse large B-cell lymphoma (DLBCL) (p=0.140). However, the ENKTL exhibited a higher abundance of Escherichia, in contrast to the prevalence of Enterobacter and Citrobacter in DLBCL. Linear regression analysis demonstrated a significant association between Escherichia abundance and PD-L1 levels in tissue samples (p=0.025), whereas no correlation with PD-L1 was observed for Enterobacteriaceae at the family level (p=0.571). Conclusion: ND-ENKTL exhibited an abundance of Enterobacteriaceae and a dominant presence of Escherichia. These microbial characteristics correlated with disease status, treatment outcomes, and PD-L1 expression, suggesting the potential of the ENKTL microbiome as a biomarker and cause of lymphomagenesis, which warrants further exploration.

Nivolumab in Relapsed or Refractory Primary CNS Lymphoma: Multicenter, Retrospective Study.

Purpose: Given that 40~50% of primary central nervous system lymphoma (PCNSL) tissues exhibit aberrancy on 9p24.1, immune-checkpoint inhibitors (ICI) may work for the disease. Materials and Methods: To define the role of ICIs in PCNSL, we carried out a nationwide retrospect analysis for 22 patients who had been treated with nivolumab monotherapy for relapsed or refractory PCNSL. Results: The median age at diagnosis was 66, and male: female ratio was 1:1. Patients received nivolumab after a median of 3 lines (range, 2 - 6) of therapy and at the median age of 67 (range, 37 - 82). Eleven patients (50%) were refractory to the last treatment prior to nivolumab. With a median follow-up duration of 22.3 months (95% CI, 13.1 - 31.5), nine patients (41%) had an objective response (6 complete responses, 3 partial responses), and the median duration of response was 20.9 months (95% CI, 1.7 - 40.0). The median progression-free survival and overall survival were 2.1 months (95% CI, 0.2 - 4.0) and 18.9 months (95% CI, 5.0 - 32.8), respectively. Nivolumab was generally well-tolerated as no patients required dose reduction and only 2 patients required delay of treatment. Conclusion: Our study suggests that nivolumab can be a reasonable option with the durable response for RR PCNSL.

Assessing the Efficacy of Bortezomib and Dexamethasone for Induction and Maintenance Therapy in Relapsed/Refractory Cutaneous T-Cell Lymphoma: A Phase II CISL1701/BIC Study.

Purpose: This multicenter, open-label, phase II trial evaluated the efficacy and safety of bortezomib combined with dexamethasone for the treatment of relapsed/refractory cutaneous T-cell lymphoma (CTCL) in previously treated patients across 14 institutions in South Korea. Patients and Methods: Between September 2017 and July 2020, 29 patients with histologically confirmed CTCL received treatment, consisting of eight 4-week cycles of induction therapy followed by maintenance therapy, contingent upon response, for up to one year. The primary endpoint was the proportion of patients achieving an objective global response. Results: Thirteen (44.8%) of the 29 patients achieved an objective global response, including two complete responses. The median progression-free survival (PFS) was 5.8 months, with responders showing a median PFS of 14.0 months. Treatment-emergent adverse events were generally mild, with a low incidence of peripheral neuropathy and hematologic toxicities. Despite the trend toward shorter PFS in patients with higher mutation burdens, genomic profiling before and after treatment showed no significant emergence of new mutations indicative of disease progression. Conclusion: This study supports the use of bortezomib and dexamethasone as a viable and safe treatment option for previously treated CTCL, demonstrating substantial efficacy and manageability in adverse effects. Further research with a larger cohort is suggested to validate these findings and explore the prognostic value of mutation profiles.

Long-term survival outcomes of 'watch and wait' in patients with bronchus-associated lymphoid tissue lymphoma: a multicenter real-world data analysis in Korea.

Bronchus-associated lymphoid tissue (BALT) is a rare cause of extranodal marginal zone lymphoma (MZL). Although most patients with BALT lymphoma (BALToma) show an indolent clinical course and are monitored without treatment, there are limited real-world data on the long-term outcome of "watch-and-wait' strategy in comparison with other treatments. The survival outcomes of patients newly diagnosed with BALToma at three tertiary hospitals in Korea undergoing two treatment strategies were analyzed: group A, patients who were monitored without any treatment or received only radiotherapy after diagnosis; and group B, patients receiving any kind of systemic chemotherapy after diagnosis, regardless of their history of any local treatment such as surgery or radiotherapy. Of the 67 patients included in our analysis, the 10-year progression-free survival (PFS) and 10-year overall survival (OS) rates were 65.3% and 83.2%, respectively. The 10-year PFS rates for observation or localized treatment and systemic chemotherapy were 78.7% and 56.9%, respectively (p = 0.044). Ten-year OS rates for observation or localized treatment and systemic chemotherapy were 100% and 71.7%, respectively (p = 0.016). Multivariate analysis showed that bilateral lung (HR 2.462, p = 0.047) and extrapulmonary organ (HR 4.485, p = 0.004) involvement were the only significant factors associated with poor PFS. Prognostic factor analysis for OS did not yield significant results. Patients with BALToma show a favorable prognosis, suggesting that observation or localized therapy alone may be effective for patient management. However, patients with bilateral lung or extrapulmonary involvement may require careful monitoring for disease progression and more aggressive treatment approaches.

QuantiFERON monitor predicts early cytomegalovirus infection and viral burden in allogeneic hematopoietic stem cell transplantation.

INTRODUCTION: Cytomegalovirus (CMV) infection is a major cause of transplantation-related morbidity and mortality. This study assessed the utility of the QuantiFERON monitor (QFM; Qiagen) for the prediction of early CMV infection and viral burden. METHODS: QuantiFERON-CMV (QF-CMV; Qiagen) and QFM were measured at the post-allogeneic hematopoietic stem cell transplantation (HSCT) week 4. CMV DNA was measured at every visit until post-HSCT week 24. The QFM cutoff specific to CMV infection was established. RESULT: At the post-HSCT week 4, the QFM cutoff predicting CMV infection was 86.95 IU/mL. While QF-CMV results at the post-HSCT week 4 were associated with high-level CMV infection (CMV DNA ≥ 5,000 IU/mL) but not with CMV infection (CMV DNA ≥ 500 IU/mL), QFM was associated with both CMV infection and high-level CMV infection. Both indeterminate QF-CMV and nonreactive QFM were associated with increased peak CMV DNA. CONCLUSION: Low QFM is a risk factor for CMV infection and increased CMV viral loads. QFM at post-HSCT week 4 can be utilized as an assay to predict the risk and burden of early CMV infection in HSCT recipients, in conjunction with other risk factors.

The Effect of the Lacticaseibacillus paracasei BEPC22 and Lactiplantibacillus plantarum BELP53 Combination (BN-202M) on Body Fat Percentage Loss in Overweight Individuals: A Randomized, Double-Blind, Placebo-Controlled Study.

BN-202M is derived from humans and consists of two strains, Lacticaseibacillus paracasei BEPC22 and Lactiplantibacillus plantarum BELP53. Body fat reduction effect and safety of BN-202M were assessed in overweight participants. A total of 150 participants were randomly assigned to the BN-202M and placebo groups at a 1:1 ratio. Dual-energy X-ray absorptiometry was used to objectively measure body fat. After 12 weeks of oral administration, the body fat percentage (-0.10 ± 1.32% vs. 0.48 ± 1.10%; p = 0.009) and body fat mass (-0.24 ± 1.19 kg vs. 0.23 ± 1.05 kg; p = 0.023) of the BN-202M group decreased significantly compared to those of the placebo group. The body weight (-0.58 kg, p = 0.004) and body mass index (BMI; -0.23, p = 0.003) was found to decrease significantly at 12 weeks in the BN-202M group, but not in the placebo group. Metabolome analysis revealed that ß-alanine, 3-aminoisobutyric acid, glutamic acid, and octopamine decreased in the weight-decreased BN-202M post-intake group. In the gut microbiota analysis, Akkermansia showed a statistically significant increase in the BN-202M group post-intake compared to the placebo group. No serious adverse events were observed in either group. These results suggest that BN-202M is safe and effective for reducing body fat and weight.