non-Hodgkin Research Articles

CD38-SADA, a Self-Assembling and Dis-Assembling Bispecific Fusion Protein for Two-Step Pretargeted Radioimmunotherapy of Non-Hodgkin Lymphoma

CD38-SADA, a Self-Assembling and Dis-Assembling Bispecific Fusion Protein for Two-Step Pretargeted Radioimmunotherapy of Non-Hodgkin Lymphoma

CD5-Deleted Chimeric Antigen Receptor Cells (Senza5™ CART5) to Enhance Immunotherapy Against T-Cell Non-Hodgkin Lymphoma: A First-in-Human Phase I Clinical Trial

CD5-Deleted Chimeric Antigen Receptor Cells (Senza5™ CART5) to Enhance Immunotherapy Against T-Cell Non-Hodgkin Lymphoma: A First-in-Human Phase I Clinical Trial

Epidemiological Analysis of Water Contaminants and Their Correlation with Leukemia and Non-Hodgkin Lymphoma Incidence in Florida

Epidemiological Analysis of Water Contaminants and Their Correlation with Leukemia and Non-Hodgkin Lymphoma Incidence in Florida

Localized large B-cell lymphoma with MYC and BCL6 rearrangements as an unexpected finding in an appendectomy specimen.

Large B-cell lymphomas (LBLs) comprise a genetically heterogeneous group of clinically aggressive non-Hodgkin lymphomas, frequently exhibiting overlapping features with diffuse large B-cell lymphoma and Burkitt's lymphoma. We report a case of a 24-year-old, previously healthy male with a classical clinical presentation of acute appendicitis. The pathologic examination discovered a large B-cell lymphoma with MYC and BCL6 rearrangements in the excised appendix. The patient was assigned Stage IEA, IPI = 0 and received chemotherapy. This case depicts a very uncommon occurrence of fully localized LBL in a patient of an unusually young age and clinical presentation for this type of lymphoma.

The Effectiveness of Levofloxacin in Prevention of Febrile Episodes in Non-Hodgkin Lymphoma Patients Receiving Rituximab, Cyclophosphamide, Vincristine, Doxorubicin and Prednisolone (R-CHOP)

The Effectiveness of Levofloxacin in Prevention of Febrile Episodes in Non-Hodgkin Lymphoma Patients Receiving Rituximab, Cyclophosphamide, Vincristine, Doxorubicin and Prednisolone (R-CHOP)

Symptom Burden and Health-Related Quality of Life in Patients with Aggressive Non-Hodgkin Lymphoma in China: A Cross-Sectional Study

Symptom Burden and Health-Related Quality of Life in Patients with Aggressive Non-Hodgkin Lymphoma in China: A Cross-Sectional Study

PPM1D/Wip1 is amplified, overexpressed, and mutated in human non-Hodgkin's lymphomas.

Wip1, is a p53-dependent Ser/Thr phosphatase involved in the timely termination of DDR. The PPM1D gene encoding Wip1 is deregulated and thus gained an oncogene character in common human solid tumors and cell lines. This study assessed the oncogenic potential of the PPM1D gene in human non- Hodgkin's lymphomas (NHL), the most common hematological malignancy worldwide. FFPE human lymphoid hyperplasia (LH) (n = 17) and NHL tumor lymph node samples (n = 65) and human NHL cell lines were used to assess the oncogenic potential of the PPM1D gene in the present study. Copy number gain and mRNA expression analysis of the PPM1D/Wip1 gene were assessed by qRT-PCR analysis. Mutational analysis of Exon 6 of the PPM1D gene was performed by PCR amplification and Sanger sequencing. Expressions of Wip1 and p53 proteins were assessed by immunohistochemistry and Western blot analysis. We found that PPM1D gained gene copy number in NHL tumors by 0.7-8 times compared to the control (p < 0.01). Increased PPM1D/Wip1 gene copy number was associated with higher mRNA and protein expression in human NHL samples (p < 0.01). Overexpression of Wip1 in NHL tumors and NHL cell lines was associated with amplification level and was unaffected by p53 status. Furthermore, a heterozygous type insertion mutation was detected in exon 6 (c.1553_1554insA) of the PPM1D gene particularly in DLBCL samples. Wip1 may have oncogenic potential, perhaps playing a role in the onset and progression of human NHL. The possible significance of Wip1 overexpression to chemotherapy response in NHL remains an intriguing question that requires more exploration.

Review of BCL2 inhibitors for the treatment of Waldenström's macroglobulinaemia and non-IgM lymphoplasmacytic lymphoma.

Lymphoplasmacytic lymphoma (LPL) is a relatively rare form of indolent B-cell non-Hodgkin's lymphoma, termed Waldenström's macroglobulinaemia (WM) in the presence of an IgM paraprotein. Although traditionally treated with combination chemoimmunotherapy, the management is evolving in the era of targeted molecular therapies including Bruton's tyrosine kinase inhibitors (BTKi). However, intolerance and refractoriness to BTKi mean newer agents are required, and the prognosis of so-called quadruple-refractory patients is poor. BCL2 is an anti-apoptotic, pro-survival protein that promotes lymphoma cell survival. Inhibition of BCL2 using first-in-class agent venetoclax has already altered the treatment paradigm in other conditions, including chronic lymphocytic leukaemia (CLL). In-vivo inhibition of BCL2 has been shown to lead to apoptosis of LPL/WM cells. Five studies have published results on the use of BCL2 inhibitors in WM to date, including oblimersen sodium, venetoclax, and sonrotoclax. Fixed-duration venetoclax resulted in high response rates, but many patients relapsed following the completion of therapy. The combination of venetoclax with ibrutinib resulted in higher and relatively deep response rates, but unexpected deaths due to ventricular events mean this combination cannot be explored. Two pivotal trials are currently evaluating the use of fixed-duration venetoclax, either in combination with rituximab or pirtobrutinib, whereas another multi-arm study is studying the use of continuous sonrotoclax monotherapy for R/R WM or in fixed-duration combination with Zanubrutinib for treatment-naïve patients. The potential role of BCL2 inhibitors in WM/LPL remains under study, with many hopeful that they may provide an additional chemotherapy-free oral alternative for patients requiring treatment. In an indolent condition with existing effective treatment regimens, including CIT and cBTKi, cost-effectiveness and toxicity profile will be key, although an additional treatment modality for quadruple-refractory patients with limited treatment options is urgently required.

The Effect of Polyunsaturated Fatty Acid (PUFA) Supplementation on Clinical Manifestations and Inflammatory Parameters in Individuals with Sjögren's Syndrome: A Literature Review of Randomized Controlled Clinical Trials.

Sjögren's syndrome is a chronic autoimmune disease that causes dry mouth and eyes and can lead to non-Hodgkin's lymphoma in 5-10% of cases after 10 years. Clinical trials have shown that the oral administration of polyunsaturated fatty acids (PUFAs) seems to have a beneficial effect on Sjögren's syndrome. This literature review provides an overview of the effects of PUFA supplementation on clinical manifestations and inflammatory parameters in Sjögren's syndrome. We conducted a literature review using the PubMed, Biomed Central, and Cochrane Library electronic databases and using search terms "Sjögren" AND "omega-3"; and "omega-6" AND "fatty acids" AND "oil". This literature review followed the PRISMA guidelines and included randomized clinical trials in humans with or without a control group using the oral administration of PUFA. From 26 articles found in the databases, a total of 6 articles were included. Of these six trials, five trials showed an effect on clinical manifestations and three trials on inflammatory parameters. Most of the studies did not show a significant effect on the parameters analyzed. One study showed a significant improvement in dry keratoconjunctivitis compared to the control group. The results suggest that PUFAs may improve inflammatory parameters in patients with Sjögren's syndrome. This literature review supports the idea that the oral administration of PUFA may possess a potential effect on clinical manifestations. However, due to the limited number of studies and the heterogeneity of clinical trial methodology, further investigations should be employed. Understanding the potential mechanism of action of PUFAs on clinical biomarkers in Sjögren's syndrome may clarify their importance in clinical practice for health professionals.

Tumour assessment of ROR1 levels in various adult leukaemia and lymphoma types.

Receptor tyrosine kinase-like orphan receptor 1 (ROR1) is a tumour target currently used for the development of novel therapeutic modalities, such as antibody-drug conjugates, chimeric antigen receptor T-cell therapies, and others. Success of these new drugs depends on the selection of relevant indications based on ROR1 tumour prevalence, staining heterogeneity, and subcellular localization, among other parameters. We investigated ROR1 immunophenotype using validated antibody clones for immunohistochemistry (IHC) and flow cytometry (FC), analyzing 292 tumour specimens from 7 haematological malignancies and triple negative breast cancer (TNBC) as a reference solid tumour indication. ROR1 prevalence varied significantly across distinct tumour types, showing 100% of ROR1 positivity in all chronic lymphocytic leukaemia (n = 48) and hairy cell leukaemia (n = 14) specimens analyzed via FC with ranges between 1.1-99.8% and 0.8-62.1%, respectively. Samples analysed via IHC showed ROR1 membrane/cytoplasmic positivity in 44% of mantle cell lymphoma tumour samples (n = 27; H-score range: 10-285 in positive cases); 30% in TNBC (n = 46; H-score range: 1-200); 15% in diffuse large B-cell lymphoma (n = 45; H-score: 40-250); and 11% in follicular lymphoma (n = 34; H-score: 2-300). Finally, all acute myeloid leukaemia (n = 52) and most T-cell non-Hodgkin lymphoma (n = 31/32) tested samples were negative for ROR1 via IHC. In conclusion, ROR1 shows a heterogeneous tumour cell expression profile across multiple leukaemias and lymphomas, making it a tumour target that would require different patient selection strategies to develop novel therapeutic modalities.

The Prognostic and Risk Factors for Children With High-Risk Mature B-Cell Non-Hodgkin's Lymphoma: A Retrospective Multicenter Study.

Our previous study (CCCG-BNHL-2015) reported the treatment strategies and outcomes of pediatric B-cell non-Hodgkin's lymphoma (B-NHL) in China which showed that children in low-risk groups already have a dramatically favorable prognosis. However, for high-risk groups, the prognosis still needs to be improved. In this study, we aimed to identify the factors influencing prognosis in high-risk groups (stage III and stage IV). Our results revealed that gender, lactate dehydrogenase (LDH) level, stage at the time of diagnosis, and early complete remission (CR) achievement were significant factors influencing prognosis (p < 0.05). The 3-year EFS rate for R4 group patients without rituximab treatment was only 25.0% ± 20.4%. Among all patients in stage IV, the 5-year EFS rates for those with involvement of only bone marrow (BM) or central nervous system (CNS) were 83.0% ± 4.5%, 81.8% ± 8.2%, but the 5-year EFS rates for those with both BM and CNS involved were only 37.5% ± 15.3% (p = 0.002). For stage III patients with LDH ≥ 4N, the 5-year EFS rates for those achieving CR and those not achieving CR after 2 treatment cycle were 88.9% ± 5.2% and 67.9% ± 7.3%(p = 0.036). Therefore, R4 group patients benefited from rituximab treatment. However, children at stage III, LDH ≥ 4N not achieving CR after the 2nd treatment cycle, and those with both BM and CNS involved are still at a very high risk of treatment failure. This study serves as a crucial reference for optimizing risk stratification, refining treatment categorizations, and optimizing treatment protocols.

Utilizing medical thoracoscopy for the diagnosis of B-cell lymphoma presenting with pleural effusion: A case series.

A third of patients with non-Hodgkin's lymphoma (NHL) develop pleural effusion during the disease course for various reasons. In most cases, lymphoma-related pleural effusion is a manifestation of widespread systemic disease, signifying a high tumour burden and therefore, a poorer prognosis. On the other hand, primary pleural lymphomas (PPLs) exhibit exclusive or dominant involvement of serous cavities, without detectable solid tumour masses. PPL is an uncommon disease and is of two types: primary effusion lymphoma (PEL) and diffuse large B-cell lymphoma associated with chronic inflammation (DLBCL-CI). PPLs not related to PELs and DLBCL-CIs are exceedingly rare. Herein, we describe four patients with biopsy proven B-cell NHL. One had no extra-pleural involvement at the time of diagnosis, indicating PPL. In all cases, histopathological examination of pleural biopsies obtained via medical thoracoscopy (MT) were crucial in clinching the final diagnosis. Clinicians are alerted to the potential relationship between exudative effusion and NHL as well as the role of MT in the diagnosis of B-cell NHL.

Epstein-Barr virus and immune status imprint the immunogenomics of non-Hodgkin lymphomas occurring in immune-suppressed environments.

Non-Hodgkin lymphomas (NHL) commonly occur in immunodeficient patients, both those infected by human immunodeficiency virus (HIV) and those who have been transplanted, and are often driven by Epstein-Barr virus (EBV) with cerebral localization, raising the question of tumor immunogenicity, a critical issue for treatment responses. We investigated the immunogenomics of 68 lymphoproliferative disorders from 51 immunodeficient (34 post-transplant, 17 HIV+) and 17 immunocompetent patients. Overall, 72% were large B-cell lymphoma and 25% were primary central nervous system lymphoma, while 40% were EBV+. Tumor whole-exome and RNA sequencing, along with a bioinformatics pipeline allowed analysis of tumor mutational burden, tumor landscape and tumor microenvironment and prediction of tumor neoepitopes. Both tumor mutational burden (2.2 vs. 3.4/Mb, P=0.001) and numbers of neoepitopes (40 vs. 200, P=0.00019) were lower in EBV+ than in EBV- NHL, regardless of the immune status. In contrast both EBV and the immune status influenced the tumor mutational profile, with HNRNPF and STAT3 mutations observed exclusively in EBV+ and immunodeficient NHL, respectively. Peripheral blood T-cell responses against tumor neoepitopes were detected in all EBV- cases but in only half of the EBV+ ones, including responses against IgH-derived MHC-class-II restricted neoepitopes. The tumor microenvironment analysis showed higher CD8 T-cell infiltrates in EBV+ versus EBV- NHL, together with a more tolerogenic profile composed of regulatory T cells, type-M2 macrophages and an increased expression of negative immune-regulators. Our results highlight that the immunogenomics of NHL in patients with immunodeficiency primarily relies on the tumor EBV status, while T-cell recognition of tumor- and IgH-specific neoepitopes is conserved in EBV- patients, offering potential opportunities for future T-cell-based immune therapies.

Autoimmune Diseases and Risk of Non-Hodgkin Lymphoma: A Mendelian Randomisation Study.

Non-Hodgkin lymphoma (NHL) is one of the most common haematologic malignancies in the world. Despite substantial efforts to identify causes and risk factors for NHL, its aetiology is largely unclear. Autoimmune diseases have long been considered potential risk factors for NHL. We carried out Mendelian randomisation (MR) analyses to examine whether genetically predicted susceptibility to ten autoimmune diseases (Behçet's disease, coeliac disease, dermatitis herpetiformis, lupus, psoriasis, rheumatoid arthritis, sarcoidosis, Sjögren's syndrome, systemic sclerosis, and type 1 diabetes) is associated with risk of NHL. Two-sample MR was performed using publicly available summary statistics from cohorts of European ancestry. For NHL and four NHL subtypes, we used data from UK Biobank, Kaiser Permanente cohorts, and FinnGen studies. Negative associations between type 1 diabetes and sarcoidosis and the risk of NHL were observed (odds ratio [OR] 0.95, 95% confidence interval [CI]: 0.92-0.98, p = 5 × 10-3, and OR 0.92, 95% CI: 0.85-0.99, p = 2.8 × 10-2, respectively). These findings were supported by the sensitivity analyses accounting for potential pleiotropy and weak instrument bias. No significant associations were found between the other eight autoimmune diseases and NHL risk. These findings suggest that genetically predicted susceptibility to type 1 diabetes, and to some extent sarcoidosis, might reduce the risk of NHL. However, future studies with different datasets, approaches, and populations are warranted to further examine the potential associations between these autoimmune diseases and the risk of NHL.

Risk of second primary cancers in nodal non-Hodgkin lymphoma patients by primary lymph node location: a retrospective cohort population-based study.

Non-Hodgkin lymphoma (NHL) is a diverse group of blood cancers with increasing incidence and survival rates due to advancements in treatment and early detection. However, NHL survivors are at significant risk of developing second primary cancers, which can adversely impact their long-term survival. This retrospective population-based cohort study utilized data from the Surveillance, Epidemiology, and End Results database, covering 17 geographic areas in the United States from 2000 to 2021. The authors included patients diagnosed with nodal NHL as a first primary cancer and excluded those diagnosed at autopsy or via death certificate only. Standardized Incidence Ratios, Absolute Excess Risks, and Person-Years at Risk were calculated to evaluate the risk of developing SPCs according to the primary lymph node site and stratified by latency periods following the initial NHL diagnosis. The cohort included 54012 NHL patients. The authors' results showed that for most SPCs, the risk of development was different for different primary NHL lymph node locations. The highest risks were observed for thyroid cancer, acute myeloid leukemia, and Hodgkin lymphoma. Notably, the risk for thyroid cancer was highest in the first year post-diagnosis, while hematological malignancies such as acute myeloid leukemia and Hodgkin lymphoma showed elevated risks in the intermediate and late latency periods. NHL survivors are at an increased risk of developing SPCs, influenced by the primary lymph node site and latency period. These findings highlight the need for tailored surveillance strategies and preventive measures to mitigate the long-term risks of SPCs in NHL survivors. Further research is necessary to elucidate the underlying mechanisms and to develop targeted interventions for this high-risk population.

ARI0003: Co-transduced CD19/BCMA dual-targeting CAR-T cells for the treatment of non-Hodgkin lymphoma

CD19 CAR-T therapy has achieved remarkable responses in relapsed/refractory non-Hodgkin lymphoma (NHL). However, challenges persist, with refractory responses or relapses after CAR-T administration linked to CD19 loss or downregulation. Given the co-expression of CD19 and BCMA in NHL, we hypothesized that dual targeting could enhance long-term efficacy. We optimized different dual-targeting approaches, including co-transduction of two lentiviral vectors, bicistronic, tandem, and loop and pool strategies, based on our academic anti-CD19 (ARI0001) and anti-BCMA (ARI0002h) CAR-T cells. Comparison with anti-CD19/CD20 or anti-CD19/CD22 dual targeting was also performed. We demonstrate that anti-CD19/BCMA CAR-T cells can be effectively generated through the co-transduction of two lentiviral vectors after optimization to minimize competition for cellular resources. Co-transduced Tcells, called ARI0003, effectively targeted NHL tumor cells with high avidity, outperforming anti-CD19 CAR-T cells and other dual-targeting approaches both invitro and invivo, particularly in low CD19 antigen density models. ARI0003 maintained effectiveness post-CD19 CAR-T treatment in xenograft models and in spheroids from relapsed CART-treated patients. ARI0003 CAR-T cells were effectively manufactured under Good Manufacturing Practice conditions, with a reduced risk of genotoxicity compared to other dual-targeting approaches. A first-in-human phase 1 clinical trial (CARTD-BG-01; this study was registered at ClinicalTrials.gov [NCT06097455]) has been initiated to evaluate the safety and efficacy of ARI0003 in NHL.

Pediatric Mature B-Cell Non-Hodgkin Lymphomas in India: A Retrospective Multicenter Pooled Analysis of Treatment Approaches and Outcomes

BackgroundPublished data on outcomes ofpediatric mature B-cell non-Hodgkin lymphoma (B-NHL) from India is limited and difficult to interpret due to small sample size and non-uniform treatment protocols.This study aims to do a pooled analysis of published patient data from multiplecenters across India to provide a clearer understanding of survival rates and treatment-related toxicities with respect to the treatment protocols in this population. MethodsA pooled analysis of patient-level data from 505 children with mature B-NHL, including Burkitt lymphoma (n=395), diffuse large B-cell lymphoma (DLBCL, n=52), and other subtypes (n=58), treated from 2000 to 2022 at seven major cancer centers in India, was conducted. Outcomes assessed were grade 3/4 toxicities, toxic deaths, relapse/progression, and survival rates. ResultsMost patients (401/505) presented with advanced disease; bone marrow and CNS involvement were observed in 13.9% and 6.9% of cases, respectively. Treatment protocols primarily included LMB (n=208), BFM (n=191), and MCP (n=61). Grade 3/4 toxicities were reported in 79.2% of patients, with higher rates observed with LMB protocol (92.1%) compared to BFM (70.8%) and MCP (70.1%) (p<0.001). Toxic death rates were similar across protocols. Overall survival (OS) and event-free survival (EFS) at a median follow-up of 17 months were 69.4±2.2% and 64.9±2.2%, respectively, with no significant differences in relapse/progression rates or stage-specific OS between protocols (p=0.28 and 0.51). ConclusionsThis pooled analysis shows that although treatment-related toxicities differ by protocol, overall survival outcomes were similar across the LMB, BFM, and MCP regimens, despite being lower than those reported in Western studies.Uniform standardized protocols may further improve outcomes for pediatric B-NHL in India.

Glycolytic activity following anti-CD19 CAR-T cell infusion in non-Hodgkin lymphoma.

Energy metabolism of chimeric antigen receptor-T cells (CAR-T) activation in humans remains unexplored. As a glycolytic activity surrogate, we investigated the dynamics of peripheral blood (PB) lactate in the first weeks post-CAR-T infusion. In 17 patients treated with CD28 harbording anti-CD19 CAR-T for relapsed/refractory non-Hodgkin lymphomas, PB lactate levels increased following CAR-T infusion. Elevated lactate levels correlated with longer CAR-T persistence and higher CD8+/CD4+ ratio. Peripheral blood lactate kinetics may reflect immune cells activation and be useful for bedside monitoring.

Simultaneous diagnosis of adult-onset Still's disease and lymphoma: A case report and systematic review of the literature.

Differentiating Adult-Onset Still's Disease (AOSD) from lymphoma is challenging. A 23-year-old female presented with polyarthralgia, fever, rash, lymphadenopathy, and abnormal labs. She met AOSD criteria and was diagnosed with non-Hodgkin lymphoma. Treatment led to improvement. The differentiation between Adult-onset Still's Disease (AOSD) and lymphoma remains challenging in our context. The Faustrel score facilitates the simultaneous diagnosis of these conditions. A 23-year-old woman presented with chronic polyarthralgia in a febrile context. A physical examination revealed peripheral joint syndrome, a maculopapular rash on the trunk, and peripheral lymphadenopathy. Laboratory tests showed neutrophils leukocytosis, hyperferritinemia, and a glycosylated ferritin fraction of 12%. A lymph node biopsy revealed a malignant non-Hodgkin lymphoma, and the patient met the diagnostic criteria for AOSD according to Faustrel. She received corticosteroid therapy and four courses of Rituximab. After 6 months, clinical and biological improvements were noted. It is essential to consider the possibility of an association between atypical clinical presentations of lymphoma and AOSD.

Profiles of Fatigue and Psychological Symptoms in Long-Term Childhood, Adolescent, and Young Adult Cancer Survivors-The NOR-CAYACS Study.

Long-term childhood, adolescent, and young adult cancer survivors (CAYACS) are at risk of fatigue and psychological problems. However, their interactions remain largely unexplored. Understanding how they cluster can inform treatment and person-centered follow-up care. We aimed to identify and describe profiles of co-occurring fatigue and psychological symptoms and investigate their associations with health-related quality of life (HRQOL) in CAYACS. NOR-CAYACS (The Norwegian Childhood, Adolescents and Young Adult Cancer Survivors study) was a nationwide survey involving adult survivors of any childhood cancer (aged < 19 years at diagnosis) and selected young adult cancers (breast and colorectal cancers, non-Hodgkin lymphoma, leukemias, and malignant melanomas, aged 19-39 years at diagnosis) identified through the Cancer Registry of Norway. We included 1893 survivors aged ≥ 18 years, ≥ 5 years since diagnosis. We performed latent profile analysis with six continuous outcomes: physical and mental fatigue, depression, anxiety, post-traumatic stress symptoms, and fear of recurrence. We identified an overall "Low" (64%), a "Moderate fatigue/high anxiety" (18%), a "High fatigue/moderate distress" (13%), and an overall "High" (5%) symptom burden profile. The "High" profile exhibited lowest physical- and mental-HRQOL with T-scores -9.8 (95% confidence interval [95% CI]: -12.5, -7.1) and -25.0 (95% CI: -26.7, -23.3) compared to the "Low" profile. We identified four profiles, two characterized by high fatigue and two near normative fatigue levels, each with different psychological symptom burden. Greater symptom burden corresponded to lower HRQOL, with high fatigue profiles showing lower physical HRQOL. These profiles help identify at-risk individuals and allow for targeting interventions and follow-up care to survivors' unique constellation of symptoms.