Fraternity of old-timers: How ubiquitin regulates miRNA functions.

miRNA-mediated gene repression and ubiquitin-dependent processes are among the oldest and most versatile mechanisms that control multiple molecular pathways, rather than just protein turnover. These systems were discovered decades ago and have become among the most studied. All systems within cells are interconnected, and these two are no exception: the plethora of studies have demonstrated that the activity of the miRNAs system depends on players of the ubiquitin-centered universe of processes, and vice versa. This review focuses on recent progress that highlights that very similar mechanisms of regulation of miRNAs by ubiquitin-related processes are likely to be found in distantly related species, including animals, plants, and viruses. Most of them occur through the ubiquitination of Argonaute proteins, but some of the other miRNA system factors are also regulated. This suggests that their regulatory relationships are either ancient evolutionary acquisitions or have arisen independently in different kingdoms.

Therapeutic challenges in peripheral T-cell lymphoma.

Peripheral T-cell lymphoma (PTCL) is a rare and heterogeneous group of hematological malignancies. Compared to our knowledge of B-cell tumors, our understanding of T-cell leukemia and lymphoma remains less advanced, and a significant number of patients are diagnosed with advanced stages of the disease. Unfortunately, the development of drug resistance in tumors leads to relapsed or refractory peripheral T-Cell Lymphomas (r/r PTCL), resulting in highly unsatisfactory treatment outcomes for these patients. This review provides an overview of potential mechanisms contributing to PTCL treatment resistance, encompassing aspects such as tumor heterogeneity, tumor microenvironment, and abnormal signaling pathways in PTCL development. The existing drugs aimed at overcoming PTCL resistance and their potential resistance mechanisms are also discussed. Furthermore, a summary of ongoing clinical trials related to PTCL is presented, with the aim of aiding clinicians in making informed treatment decisions.

CD16+ as predictive marker for early relapse in aggressive B-NHL/DLBCL patients.

Assessing the prognosis of patients with aggressive non-Hodgkin B cell lymphoma mainly relies on a clinical risk score (IPI). Standard first-line therapies are based on a chemo-immunotherapy with rituximab, which mediates CD16-dependent antibody-dependent cellular cytotoxicity (ADCC). We phenotypically and functionally analyzed blood samples from 46 patients focusing on CD16+ NK cells, CD16+ T cells and CD16+ monocytes. Kaplan-Meier survival curves show a superior progression-free survival (PFS) for patients having more than 1.6% CD16+ T cells (p = 0.02; HR = 0.13 (0.007-0.67)) but an inferior PFS having more than 10.0% CD16+ monocytes (p = 0.0003; HR = 16.0 (3.1-291.9)) at diagnosis. Surprisingly, no correlation with NK cells was found. The increased risk of relapse in the presence of > 10.0% CD16+ monocytes is reversed by the simultaneous occurrence of > 1.6% CD16+ T cells. The unexpectedly strong protective function of CD16+ T cells could be explained by their high antibody-dependent cellular cytotoxicity as quantified by real-time killing assays and single-cell imaging. The combined analysis of CD16+ monocytes (> 10%) and CD16+ T cells (< 1.6%) provided a strong model with a Harrell's C index of 0.80 and a very strong power of 0.996 even with our sample size of 46 patients. CD16 assessment in the initial blood analysis is thus a precise marker for early relapse prediction.

Safety and efficacy of ibrutinib in combination with rituximab and lenalidomide in previously untreated follicular and marginal zone lymphoma: An open label, phase 2 study.

BACKGROUND: Follicular lymphoma (FL) and marginal zone lymphoma (MZL) are indolent non-Hodgkin lymphomas (iNHL). Median survival for iNHL is approximately 20 years. Because standard treatments are not curative, patients often receive multiple lines of therapy with associated toxicity-rationally designed, combination therapies with curative potential are needed. The immunomodulatory drug lenalidomide was evaluated in combination with rituximab for the frontline treatment of FL in the phase 3 RELEVANCE study. Ibrutinib, an oral Bruton tyrosine kinase inhibitor, is active in NHL and was evaluated in combination with lenalidomide, rituximab, and ibrutinib (IRR) in a phase 1 study. METHODS: The authors conducted an open-label, phase 2 clinical trial of IRR for previously untreated FL and MZL. The primary end point was progression-free survival (PFS) at 24 months. RESULTS: This study included 48 participants with previously untreated FL grade 1-3a (N = 38), or MZL (N = 10). Participants received 12, 28-day cycles of lenalidomide (15 mg, days 1-21 cycle 1; 20 mg, cycles 2-12), rituximab (375 mg/m2 weekly in cycle 1; day 1 cycles 2-12), and ibrutinib 560 mg daily. With a median follow-up of 65.3 months, the estimated PFS at 24 months was 78.8% (95% confidence interval [CI], 68.0%-91.4%) and 60-month PFS was 59.7% (95% CI, 46.6%-76.4%). One death occurred unrelated to disease progression. Grade 3-4 adverse events were observed in 64.6%, including 50% with grade 3-4 rash. CONCLUSIONS: IRR is highly active as frontline therapy for FL and MZL. Compared to historical results with lenalidomide and rituximab, PFS is similar with higher grade 3-4 toxicity, particularly rash. The study was registered with ClinicalTrials.gov (NCT02532257).

The academic point-of-care anti-CD19 chimeric antigen receptor T-cell product varnimcabtagene autoleucel (ARI-0001 cells) shows efficacy and safety in the treatment of relapsed/refractory B-cell non-Hodgkin lymphoma.

Varnimcabtagene autoleucel (var-cel) is an academic anti-CD19 chimeric antigen receptor (CAR) product used for the treatment of non-Hodgkin lymphoma (NHL) in the CART19-BE-01 trial. Here we report updated outcomes of patients with NHL treated with var-cel. B-cell recovery was compared with patients with acute lymphoblastic leukaemia (ALL). Forty-five patients with NHL were treated. Cytokine release syndrome (any grade) occurred in 84% of patients (4% grade ≥3) and neurotoxicity in 7% (2% grade ≥3). The objective response rate was 73% at Day +100, and the 3-year duration of response was 56%. The 3-year progression-free and overall survival were 40% and 52% respectively. High lactate dehydrogenase was the only covariate with an impact on progression-free survival. The 3-year incidence of B-cell recovery was lower in patients with NHL compared to ALL (25% vs. 60%). In conclusion, in patients with NHL, the toxicity of var-cel was manageable, while B-cell recovery was significantly prolonged compared to ALL. This trial was registered as NCT03144583.

The role of chimeric antigen receptor T cells targeting more than one antigen in the treatment of B-cell malignancies.

Several products containing chimeric antigen receptor T cells targeting CD19 (CART19) have been approved for the treatment of patients with relapsed/refractory non-Hodgkin's lymphoma (NHL) and acute lymphoblastic leukaemia (ALL). Despite very impressive response rates, a significant percentage of patients experience disease relapse and die of progressive disease. A major cause of CART19 failure is loss or downregulation of CD19 expression in tumour cells, which has prompted a myriad of novel strategies aimed at targeting more than one antigen (e.g. CD19 and CD20 or CD22). Dual targeting can the accomplished through co-administration of two separate products, co-transduction with two different vectors, bicistronic cassettes or tandem receptors. In this manuscript, we review the pros and cons of each strategy and the clinical results obtained so far.

Allogeneic stem cell transplantation and CAR-T in B-cell Non-Hodgkin Lymphoma: a two-center experience and review of the literature.

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is still a potentially curative option for B-cell Non-Hodgkin Lymphoma (B-NHL) in the modern immunotherapy era. The objective of this study was to analyze long-term outcomes of patients with B-NHL who received allo-HSCT. We analyzed overall survival (OS), progression-free survival (PFS) and graft versus host disease (GVHD) relapse-free survival (GRFS) in 53 patients undergoing allo-HSCT from two institutions. The median follow-up of the study was 72 months (range 29-115 months). The median number of lines of therapy before allo-HSCT was 3 (range 1-6) and twenty-eight patients (53%) had received a previous autologous transplant. The 3-year PFS, OS and GRFS were 55%, 63%, and 55%, respectively. One-year non-relapse mortality was 26%. Karnofsky Performance Scale < 90 was associated with worse OS in multivariable analysis. A non-comparative analysis of a cohort of 44 patients with similar characteristics who received chimeric antigen receptor T-cell therapy was done, showing a 1-year PFS and OS were 60% and 66%, respectively. Our data shows that allo-HSCT is still a useful option for treating selected patients with R/R B-NHL. Our retrospective analysis and review of the literature demonstrate that allo-HSCT can provide durable remissions in a subset of patients with R/R B-NHL.

A study of the relationship between circulating cytokines (interleukin-2 receptor and tumor necrosis factor receptor 2) and risk of B-cell non-hodgkin lymphoma.

Mature B-cell non-Hodgkin lymphoma (B-NHL) occurs due to uncontrolled B-lymphocyte clonal expansion. Cytokines can directly stimulate B-cell proliferation and prevent B-cell apoptosis. Dysregulation of cytokines may play an important role in the development of B-NHL by enhancing chromosomal translocation, which is the hallmark of B-NHL. Both interleukin 2 and tumor necrosis factor-α are proinflammatory cytokines and play important roles in the growth, differentiation, and apoptosis of B cells.We conducted a prospective case-control study applied to 50 patients with B-NHL at Kasr Al Aini Hospital, Cairo University, and 50 age- and sex-matched controls. Clinical, laboratory and imaging data were collected. In all patients and controls, sIL-2R and sTNF-R2 levels were measured by enzyme-linked immunosorbent assay (ELISA). The Spearman correlation test was used to evaluate the correlation between the studied cytokines and clinical, laboratory and imaging findings. Sensitivity analysis was conducted to detect the cutoff values of the studied cytokines.Serum levels of sIL-2R and sTNF-R2 were significantly higher in patients than in controls. Additionally, their levels were significantly higher in aggressive types and advanced stages of lymphoma. Also, the studied cytokines were significantly correlated with different clinical and laboratory parameters of lymphoma. The level of sIL-2R and sTNF-R2 were closely related to the type of lymphoma (P value ˂ 0.001 and 0.012, respectively), further it was also associated with the natural history of lymphoma (aggressive vs. indolent) (P value ˂0.001 and 0.04 respectively).We concluded that Pretreatment levels of sIL-2R and sTNF-R2 may play a role in the natural history and prognosis of lymphoma. They may be used as a prognostic factor for B-NHL patients and may also help with treatment decisions.

Rituximab with standard LMB chemotherapy in pediatric high-risk mature B-cell non-Hodgkin lymphoma: A report from the JPLSG B-NHL14 trial.

BACKGROUND: The benefit of adding rituximab to standard lymphomes malins B (LMB) chemotherapy for children with high-risk mature B-cell non-Hodgkin lymphoma (B-NHL) has previously been demonstrated in an international randomized phase III trial, to which the Japanese Pediatric Leukemia/Lymphoma Study Group could not participate. METHODS: To evaluate the efficacy and safety of rituximab in combination with LMB chemotherapy in Japanese patients, we conducted a single-arm multicenter trial. RESULTS: In this study, 45 patients were enrolled between April 2016 and September 2018. A total of 33 (73.3%), 5 (11.1%), and 6 (13.3%) patients had Burkitt lymphoma/leukemia, diffuse large B-cell lymphoma, and aggressive mature B-NHL, not otherwise specified, respectively. Ten (22.2%) and 21 (46.7%) patients had central nervous system disease and leukemic disease, respectively. The median follow-up period was 47.5 months. Three-year event-free survival and overall survival were 97.7% (95% confidence interval, 84.9-99.7) and 100%, respectively. The only event was relapse, which occurred in a patient with diffuse large B-cell lymphoma. Seven patients (15.6%) developed Grade 4 or higher non-hematologic adverse events. Febrile neutropenia was the most frequent Grade 3 or higher adverse event after the pre-phase treatment, with a frequency of 54.5%. CONCLUSION: The efficacy and safety of rituximab in combination with LMB chemotherapy in children with high-risk mature B-NHL was observed in Japan.

Racial disparities in the incidence and survival outcomes in diffuse large B-cell lymphoma in adolescents and young adults.

Diffuse large B-cell Lymphoma (DLBCL) is an aggressive subtype of non-Hodgkin lymphoma (NHL). The disease generally occurs in older patients. Although at a lower prevalence, the disease also occurs in the adolescent and young adult group (AYA). There is paucity of data in the literature on racial and ethnic disparities in the incidence and survival outcomes of DLBCL in the AYA group. The objective of our study is to demonstrate the disparities in these outcomes. Utilizing SEER, we obtained data on patient demographics, incidence, and survival from 2000 to 2020. We observed statistically significant reduced incidence of DLBCL in all racial groups, except the non-Hispanic Asian and Pacific Islander group (NHAPI). The non-Hispanic Black group (NHB) had one of the lowest survival despite showing the largest decrease in incidence in DLBCL. The differences in the survival could be secondary to socioeconomic factors, however other reasons need to be explored. The increased incidence among the NHAPI group mirrors that of large population-based studies in East Asian countries, however, underlying reasons have not been elucidated.

Quality of life and late therapy effects in pediatric non-Hodgkin lymphoma survivors: Insights from a single-institution study.

BACKGROUND AND AIM: The survival outcomes of pediatric patients with mature B-non-Hodgkin lymphoma (NHL) have improved due to advances in treatment. We aimed to assess the frequency and severity of late effects and their impact on quality of life among pediatric NHL survivors. PATIENTS AND METHODS: This retrospective study included patients diagnosed with mature B-NHL at Children's Cancer Hospital of Egypt (CCHE) 57357 from January 2012 through December 2015. Patients received treatment according to the modified LMB 96 protocol. The minimum follow-up period was 5 years. Assessments for toxicity and quality of life were conducted at regular intervals during and after treatment. Patients were assessed for toxicity including pulmonary dysfunction, cardiac dysfunction, lipid profile abnormalities, endocrine dysfunction (thyroid function, vitamin D levels, growth curves), and cognitive function (intelligence quotient [IQ] level using Stanford-Binet Intelligence Scales-5th Edition, and quality of life (QoL) assessment (PedsQoL). RESULTS: A total of 273 patients were eligible, and 206 were evaluable. Median age was 5.45 (range: 2.4-18), with a male-to-female ratio 4:1. Pulmonary function abnormalities were detected in 119/203 (58.6%); most had mild dysfunction (72/119, 60.5%), while 17% had severe dysfunction. Cardiac toxicity occurred in 10% of the patients (n = 20). IQ testing showed that 52 patients had a low average IQ score, while 151 patients had either average or above average scores. The total mean QoL score was 99 ± 0.058 classified as "satisfactory." However, significant impairment of the physical domain of quality of life was observed among group C patients compared to A/B (p = .033), older age at diagnosis (p = .042), and those with pulmonary dysfunction (p < .001). Total score of quality of life was significantly impaired among patients with pulmonary dysfunction (p = .009), likewise older age at diagnosis (p = .017) and those with low average IQ scores (p = .033). CONCLUSION: Childhood mature B-NHL survivors are at significant risk for late effects; pulmonary dysfunction and low average IQ that can subsequently impact QoL.

Childhood and Adolescent Relapsed/Refractory Aggressive B-Cell Lymphomas With t(8;14) and BCL2 Expression, Burkitt Lymphoma Versus Diffuse Large B-Cell Lymphoma: A Diagnostic Challenge.

We present 2 diagnostically challenging cases of pediatric/adolescent relapsed/refractory aggressive mature B-cell non-Hodgkin lymphoma (B-NHL) within the spectrum of Burkitt lymphoma and diffuse large B-cell lymphoma and illustrate the different therapeutic regimens that are employed for pediatric and adult cancer centers. Both cases displayed varying-sized lymphoma cells with occasional single prominent nucleoli and heterogeneous BCL2 expression. Cytogenetics revealed complex karyotypes with t(8:14)(q24.2;q32) and IGH::MYC rearrangement by FISH. Next generation sequencing revealed deleterious TP53 and MYC mutations. We concluded that both could be diagnosed as "DLBCL-NOS with MYC rearrangement" using the current pathologic classifications, 2022 International Consensus Classification (ICC) and World Health Organization Classifications of Haematolymphoid Tumors (WHO-HAEM5). This report illustrates diagnostic challenges and treatment dilemmas that may be encountered, particularly for adolescent and young adults (AYA).

Fatal anterior mediastinal mass in a pregnant lady.

We report a fatal case of a 26-year-old nulliparous woman who presented with an anterior mediastinal mass in her late pregnancy. She had complained of a progressively increasing neck swelling and occasional dry cough in the early second trimester, which was associated with worsening dyspnoea, reduced effort tolerance and orthopnoea. Ultrasound of the neck showed an enlarged lymph node, and chest X-ray revealed mediastinal widening. At 35 weeks' gestation, the patient was referred to a tertiary centre for a computed tomography (CT) scan of the neck and thorax under elective intubation via awake fibreoptic nasal intubation as she was unable to lie flat. However, she developed sudden bradycardia, hypotension and desaturation soon after being positioned supine, which required resuscitation. She succumbed after 3 days in the intensive care unit. An autopsy revealed a large anterior mediastinal mass extending to the right supraclavicular region, displacing the heart and lungs, encircling the superior vena cava and right internal jugular vein with tumour thrombus extending into the right atrium. Histopathology examination of the mediastinal mass confirmed the diagnosis of a primary mediastinal large B-cell lymphoma. This report emphasizes the severe and fatal outcome resulting from the delay and misinterpretation of symptoms related to a mediastinal mass.

Influence of Biomarkers on Mortality among Patients with Hepatic Metastasis of Colorectal Cancer Treated with FOLFOX/CAPOX and FOLFIRI/CAPIRI, Including Anti-EGFR and Anti-VEGF Therapies.

Background and objectives: Colorectal cancer is a major global health concern, with a significant increase in morbidity and mortality rates associated with metastatic stages. This study investigates the prognostic significance of various clinical and laboratory parameters in patients with metastatic CRC. Materials and Methods: A retrospective cohort of 188 CRC patients with hepatic metastasis from the OncoHelp Association in Timisoara was analyzed from January 2016 to March 2023. Data on demographics, clinical characteristics, and biomarkers, such as lymphocyte counts, as well as various inflammation indices, were examined. Statistical analyses included univariate and multivariate logistic regression, Kaplan-Meier survival analysis, and ROC curve assessments. Results: Our findings indicate significant associations between survival outcomes and several biomarkers. Higher BMI and lymphocyte counts were linked with better survival rates, while higher values of Neutrophil-Hemoglobin-Lymphocyte (NHL) score, Neutrophil-Lymphocyte Ratio (NLR), Platelet-Lymphocyte Ratio (PLR), and Systemic Immune-Inflammation Index (SII) were predictors of poorer outcomes. Notably, the presence of hepatic metastasis at diagnosis was a critical factor, significantly reducing overall survival. Conclusions: The study has expanded the current understanding of prognostic factors in CRC, advocating for a multi-dimensional approach to prognostic evaluations. This approach should consider not only the traditional metrics such as tumor stage and histological grading but also incorporate a broader spectrum of biomarkers. Future studies should aim to validate these findings and explore the integration of these biomarkers into routine clinical practice, enhancing the precision of prognostic assessments and ultimately guiding more personalized treatment strategies for CRC patients.

TRIM-NHL protein, NHL-2, modulates cell fate choices in the C. elegans germ line.

Many tissues contain multipotent stem cells that are critical for maintaining tissue function. In Caenorhabditis elegans, germline stem cells allow gamete production to continue in adulthood. In the gonad, GLP-1/Notch signaling from the distal tip cell niche to neighboring germ cells activates a complex regulatory network to maintain a stem cell population. GLP-1/Notch signaling positively regulates production of LST-1 and SYGL-1 proteins that, in turn, interact with a set of PUF/FBF proteins to positively regulate the stem cell fate. We previously described sog (suppressor of glp-1 loss of function) and teg (tumorous enhancer of glp-1 gain of function) genes that limit the stem cell fate and/or promote the meiotic fate. Here, we show that sog-10 is allelic to nhl-2. NHL-2 is a member of the conserved TRIM-NHL protein family whose members can bind RNA and ubiquitinate protein substrates. We show that NHL-2 acts, at least in part, by inhibiting the expression of PUF-3 and PUF-11 translational repressor proteins that promote the stem cell fate. Two other negative regulators of stem cell fate, CGH-1 (conserved germline helicase) and ALG-5 (Argonaute protein), may work with NHL-2 to modulate the stem cell population. In addition, NHL-2 activity promotes the male germ cell fate in XX animals.

The necrotrophic effector ToxA from Parastagonospora nodorum interacts with wheat NHL proteins to facilitate Tsn1-mediated necrosis.

The plant pathogen Parastagonospora nodorum secretes necrotrophic effectors to promote disease. These effectors induce cell death on wheat cultivars carrying dominant susceptibility genes in an inverse gene-for-gene manner. However, the molecular mechanisms underpinning these interactions and resulting cell death remain unclear. Here, we used a yeast two-hybrid library approach to identify wheat proteins that interact with the necrotrophic effector ToxA. Using this strategy, we identified an interaction between ToxA and a wheat transmembrane NDR/HIN1-like protein (TaNHL10) and confirmed the interaction using in planta co-immunoprecipitation and confocal microscopy co-localization analysis. We showed that the C-terminus of TaNHL10 is extracellular whilst the N-terminus is localized in the cytoplasm. Further analyses using yeast two-hybrid and confocal microscopy co-localization showed that ToxA interacts with the C-terminal LEA2 extracellular domain of TaNHL10. Random mutagenesis was then used to identify a ToxA mutant, ToxAN109D , which was unable to interact with TaNHL10 in yeast two-hybrid assays. Subsequent heterologous expression and purification of ToxAN109D in Nicotiania benthamiana revealed that the mutated protein was unable to induce necrosis on Tsn1-dominant wheat cultivars, confirming that the interaction of ToxA with TaNHL10 is required to induce cell death. Collectively, these data advance our understanding on how ToxA induces cell death during infection and further highlight the importance of host cell surface interactions in necrotrophic pathosystems.

Patients with indolent lymphomas are at high risk of infections: experience from a German outpatient clinic.

BACKGROUND: Patients with indolent B-cell non-Hodgkin lymphomas (B-NHLs) have an increased risk of infections which is caused by pathomechanisms of the diseases itself but also as a result of anti-tumor therapy. Especially the effects of anti-CD20 antibodies are well understood as these lead to decreased antibody production. Most studies regarding immunodeficiency in B-NHLs were conducted with multiple myeloma and chronic lymphocytic leukemia patients. As these studies not always represent the general population we collected and analyzed real world data from patients with indolent lymphomas and a control group (CG). RESULTS: Patients with B-NHLs undergoing therapy or who were regularly monitored in a watch and wait approach had, over the time of one year, an increased rate of infections compared to the CG of 145 healthy volunteers (mean: 11.66 vs. 7.13 infections per 1000 days). Consistent with this finding B-NHL patients received more antibiotic treatment (mean: 11.17 vs. 6.27 days) and were more often hospitalized than persons from the CG (mean: 5.19 vs. 0.99 days per 1000 days). Lymphoma patients without immunodeficiency had a lower infection rate than patients with non-symptomatic and symptomatic immunodeficiency (mean: 10.91 vs. 12.07 and 12.36 per 1000 days). The number of infections differed statistically significant for the subgroups and CG (7.13 per 1000 days). Patients with symptomatic immunodeficiency were mostly treated with regular immunoglobulin substitutions and infection rates were comparable to those of patients with asymptomatic immunodeficiency. CONCLUSIONS: Our data suggest the use of an approach with regular immune monitoring including the measurement of immunoglobulin levels and regular appointments for clinical assessment of all indolent lymphoma patients in order to identify patients with increased risk of infections. It also raises the question if patients with immunodeficiency should be treated more often with regular immunoglobulin substitution, but so far more studies are necessary to answer this question.

CAR T-cell therapy in large B cell lymphoma.

CD19-targeted chimeric antigen receptor (CAR) T-cells have revolutionized the treatment of lymphoid malignancies, including large B cell lymphoma (LBCL). Following seminal early phase multicenter clinical trials published between 2017 and 2020, three CD19-CAR T-cell products received FDA and EMA approval designations in lymphoma in the third-line setting, paving the way for follow-up studies in the second-line. Meanwhile, investigations into the applications of CAR T-cell therapy have further broadened to treating high-risk patients even prior to completion of first-line conventional chemo-immunotherapy. Furthermore, as early trials excluded patients with central nervous system involvement with lymphoma, several studies have recently shown promising efficacy of CD19-CAR T-cells in primary and secondary CNS lymphoma. Here we provide a detailed overview on clinical data supporting the use of CAR T-cells in patients with LBCL.

Infectious complications following CAR-t cell therapy for B cell non-Hodgkin lymphoma: a single-center experience and review of the literature.

Chimeric antigen receptor T-cell (CAR-T) therapy targeting CD19 has significantly improved outcomes in the treatment of refractory or relapsed (R/R) B-cell non-Hodgkin lymphoma (NHL). Several risk factors including CAR-T cell-related toxicities and their treatments often lead to infectious complications (ICs); however, the pattern and timeline is not well established. We evaluated ICs in 48 patients with R/R B-cell NHL following CAR-T cell therapy at our institution. Overall, 15 patients experienced 22 infection events. Eight infections (4 bacterial, 3 viral and 1 fungal) occurred within the first 30 days and 14 infections (7 bacterial, 6 viral, 1 fungal) between days 31 to 180 following CAR-T infusion. Most infections were mild-to-moderate and fifteen infections involved the respiratory tract. Two patients developed mild-to-moderate COVID-19 infection and one patient a cytomegalovirus reactivation after CAR-T infusion. Two patients developed IFIs: one case each of fatal disseminated candidiasis and invasive pulmonary aspergillosis at day 16 and 77, respectively. Patients with more than 4 prior antitumor regimens and patient's ≥ 65 years had a higher infection rate. Infections in patients with relapsed/refractory B-cell NHL are common after CAR-T despite the use of infection prophylaxis. Age ≥ 65 years and having > 4 prior antitumor treatments were identified as risk factors for infection. Fungal infections carried significant impact in morbidity and mortality, suggesting a role for increase fungal surveillance and/or anti-mold prophylaxis following high-dose steroids and tocilizumab. Four of ten patients developed an antibody response following two doses of SARS-CoV-2 mRNA vaccine.

RNA-seq analysis reveals candidate genes associated with proliferation, invasion, and migration in BCL11A knockdown B-NHL cell lines.

B-cell lymphoma/leukemia 11A (BCL11A) is highly expressed in B-cell non-Hodgkin lymphoma (B-NHL), blocks cell differentiation, and inhibits cell apoptosis. However, little is known about BCL11A in the proliferation, invasion, and migration of B-NHL cells. Here, we found increased expression of BCL11A in B-NHL patients and cell lines. Knockdown of BCL11A suppressed the proliferation, invasion, and migration of B-NHL cells in vitro and reduced tumor growth in vivo. RNA sequencing (RNA-seq) and KEGG pathway analysis demonstrated that BCL11A-targeted genes were significantly enriched in the PI3K/AKT signaling pathway, focal adhesion, and extracellular matrix (ECM)-receptor interaction (including COL4A1, COL4A2, FN1, SPP1), and SPP1 was the most significantly downregulated gene. qRT‒PCR, western blotting, and immunohistochemistry revealed that silencing BCL11A reduced the expression level of SPP1 in Raji cells. Our study suggested that high level of BCL11A may promote B-NHL proliferation, invasion, and migration, and the BCL11A-SPP1 regulatory axis may play an important role in Burkitt's lymphoma.