Treatment Of non-Hodgkin Lymphoma Research Articles

Primary Central Nervous System Burkitt's Lymphoma in a Pediatric Patient: A Case Report and Literature Review.

The objective of this research is to examine the therapy and outlook of pediatric primary central nervous system Burkitt lymphomas. This study involves a retrospective analysis of the clinical data of a child with primary central nervous system Burkitt lymphoma who underwent treatment in our department. In addition, pertinent literature was reviewed to provide a comprehensive understanding of the topic. The patient was admitted to the neurosurgery department with symptoms of headache and vomiting. Brain magnetic resonance imaging (MRI) revealed multiple lesions in the right frontal and temporal lobes, dorsal thalamus, and posterior medulla oblongata. Most of the tumor mass was surgically removed from the right ventricle and diagnosed as Burkitt lymphoma. Abnormal lymph nodes were not found outside of the central nervous system. The patient achieved complete remission (CR) after receiving 6 cycles of treatment (R-AA-BB-CC-AA-BB-CC) based on the regimen of the Southern Pediatric Non-Hodgkin Lymphoma Treatment Collaboration Group 2017. As of November 23, 2023, the patient remained alive with no evidence of recurrence. Primary central nervous system Burkitt lymphoma is rare in children, and there is no universally accepted treatment protocol. However, the regimen outlined by the South China Children's Cancer Group-Non-Hodgkin Lymphoma in 2017 (SCCCG-NHL-2017) can serve as a useful reference for treating pediatric non-Hodgkin lymphoma.

Efficacy and Safety of Bendamustine-Rituximab as Frontline Therapy for Indolent Non-Hodgkin Lymphoma: A Real-World, Single-Center, Retrospective Study.

Background The use of bendamustine with an anti-CD20 monoclonal antibody as frontline therapy for indolent non-Hodgkin lymphoma(NHL)has become a standard of care.We aimed to evaluate the real-world efficacy and safety of bendamustine-rituximab (BR) frontline therapy for indolent NHL. Patients and methods Patients with indolent NHL treated with frontline BR therapy in Hôpital du Sacré-Coeur de Montréal, from January 2015 to August 2018 were included in this retrospective study. Results Our cohort included 42 adults with a median age of 63 years. Follicular lymphoma was the most common histology (n = 31, 74%). Most patients had advanced disease (Lugano stage III or IV, 88%). The overall response rate was 84% (complete response = 62% and partial response = 22%). Median progression-free survival (PFS) was not reached. At 30 months, PFS was 74.8% and overall survival was 90%. Grade 3-4 neutropenia occurred in 21% of patients. Infection-related adverse events were observed in 17 patients (40%). Most were grade 1 and 2 events (84%).One case of grade 5 progressive multifocal leukoencephalopathy related to John Cunningham (JC) virus reactivation was observed. The most common non-infectious-related adverse events were mild nausea and fatigue. Conclusions The efficacy and safety of BR treatment for indolent NHL were comparable in our real-life cohort compared to prior studies. This supports BR as a standard of care for indolent NHL. Future studies should assess whether the use of granulocyte-colony stimulating factors as primary prophylaxis effectively mitigates the hematological and infection-related adverse events related to BR therapy.

Correlation Between the Hepatitis C Virus NS3 Protein and CD30 Expression in Diffuse Large B-cell Lymphoma.

One of the etiologies of non-Hodgkinlymphoma (NHL) is chronic infection related to lymphoma pathogenesis, with a high prevalence ofhepatitis C virus (HCV) infection seen. In determining the treatment and prognosis of NHL, cluster of differentiation 30 (CD30) immunohistochemical staining plays an important role. High levels of CD30are found in patients with HCV infection. This study aimed to determine the prevalence of CD30 and HCV expression and its correlation with clinicopathological characteristics of Indonesian diffuse large B-cell lymphoma (DLBCL) patients. A total of 86 formalin-fixed paraffin-embedded (FFPE) samples of DLBCL cases were collected over the course of two years from the Anatomical Pathology department at Dr. Sardjito General Hospital in the special region of Yogyakarta, Indonesia. Immunohistochemistry was performed to detect the two markers (CD30 and HCV). Chi-square tests were used to investigate the correlations between CD30 expression and clinicopathological features in DLBCL patients. The positivity rate of CD30 expression in 86 DLBCL samples was 25.6% (22/86) when using a 0% cut-off, and 7.0% (6/86) while using a 20% cutoff. The positivity rate of HCV expression in DLBCL samples was 34.9% (30/86). Positive CD30 expression, HCV expression and clinicopathological features (age, sex, Ann Arbor stage, extranodal involvement, and morphological variations) did not have statistically significant relationships (p>0.05). There was no statistically significant correlation between CD30 immunoreactivity (cut-off >0% or >20%) and HCV NS3 expression and clinicopathological features (age, sex, Ann Arbor stage, extranodal involvement, lactate dehydrogenase, Eastern Cooperative Oncology Group status and morphological variants) in DLBCL.

Optimization and characterization of Rituximab targeted multidrug loaded cyclodextrin nanoparticles against Non-Hodgkin Lymphoma

Currently, Non-Hodgkin Lymphoma (NHL) constitutes 85–90 % of all lymphomas. Clinical treatment of NHL is based on the “4-drug regimen” known as CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone). Rituximab (RTX) is added to increase the effectiveness and selectivity of the treatment and is the first-line standard treatment for NHL patients. However, success is often prevented by the development of drug resistance. In this study, it was aimed to overcome drug resistance by using two novel tumor-targeted derivatives: guanidine-amphiphilic cyclodextrin (ACD) and guanidine-cyclodextrin polymer (PCD) nanoparticles (NP). These constructs display promise in overcoming drug resistance and enhancing the effectiveness of R-CHOP treatment while potentially eliminating the need for corticosteroid. NP were found to be smaller than 200 nm by dynamic light scattering (DLS). Hemolytic activity and cytotoxicity data on L929 cells demonstrated the safety of the newly synthesized CD derivatives. Additional in vitro characterization studies, including surface charge, physical stability, drug loading capacity, drug release profile, and imaging, as well as conventional and 3D cell culture studies were carried out. Compared to drug solutions, the viability of Daudi human lymphoma cells was statistically significantly decreased in both drug-loaded ACD and PCD NP formulations (p < 0.05). Additionally, RTX-conjugated and drug-loaded ACD NPs exhibited the lowest cell viability due to RTX dependent cytotoxicity.

Abstract PO-036: Targeting the CBM signalosome with a MALT1 scaffolding inhibitor for treatment of non-Hodgkin lymphomas

Abstract Introduction: The CBM signalosome (CARDs/BCL10/MALT1) is an evolutionarily conserved key regulator of canonical NF-κB signaling. Activating mutations of the CBM signalosome constitutively activate NF-κB, driving tumorigenesis in B-cell Non-Hodgkin Lymphoma (B-NHL). Depletion of individual components of the CBM complex including MALT1 was shown preclinically to suppress NF-κB driven Activated B-Cell Diffuse Large B-Cell Lymphoma (ABC-DLBCL), inspiring many efforts to develop MALT1 inhibitors for therapeutic use. MALT1 is a dual function protein with two independent roles. Primarily, MALT1 is a scaffold protein organizing the CBM complex and directly transducing canonical NF-κB signaling. Secondarily, MALT1 is a paracaspase, fine-tuning multiple signaling pathways, including NF-κB, via substrate cleavage. Research indicates that targeting MALT1 scaffolding activity is likely the preferred approach for effectively suppressing NF-κB activity while minimizing impact on the immune system. Using our Smart AllosteryTM platform, we have developed potentially the first-in-class MALT1 scaffolding inhibitors targeting the CBM signalosome as a more directed approach to specifically block NF-κB signaling. Here, we disclose the distinctive mechanism of action of scaffolding inhibitors. Experiments: The mechanistic studies of MALT1 scaffolding inhibition were explored through comprehensive cellular assays and in vivo analyses. Engineered cell models were utilized to elucidate novel mechanisms of action. Results: We have developed a series of potent MALT1 scaffolding selective inhibitors with cellular IC50 values approximating 250nM for scaffolding activity, 80nM for NF-κB activity, and 590nM for AP-1 activity. Using TR-FRET, NanoBRET, and TurboID assays, we observed scaffolding inhibitors did not interrupt the interaction of MALT1-TRAF6. Rather, they induced a non-productive signalosome blocking NF-κB activity. Scaffolding inhibitors did not inhibit MALT1 protease activity; in fact, inhibition of MALT1 scaffolding activity modestly increased its protease activity, which is consistent with observations in MALT1 scaffolding mutant mice. This distinctive consequence of MALT1 scaffolding inhibition translated to no detrimental effects on T-cell activation or Treg differentiation, both of which are dependent on MALT1 protease activity and cause associated safety concerns with chronic MALT1 protease inhibitor treatment. The distinct and superior mode of action of MALT1 scaffolding inhibitors manifested in a more potent and broad anti-proliferative activity against a panel of B-NHL cell lines dependent on intrinsic BCR or NF-κB activity for growth. Conclusions: The potential first-in-class MALT1 scaffolding inhibitor offers what we believe is a best-in-class approach to targeting CBM-complex-driven NF-κB signaling. Scaffolding inhibitors effectively blocked both NF-κB and AP-1 signaling without impairing protease activity and avoided negative effects on T-cell function. Scaffolding inhibitors offer a promising therapeutic approach for NF-kB driven cancers. Citation Format: Yi Yao, Kevin Ling, Huili Xia, Huadong Sun, Yingzhi Bi, Jun Kuai, Joe Wahle, Wei Liu, Ken Carson, Gerry Harriman, Fang Wang. Targeting the CBM signalosome with a MALT1 scaffolding inhibitor for treatment of non-Hodgkin lymphomas [abstract]. In: Proceedings of the Fourth AACR International Meeting on Advances in Malignant Lymphoma: Maximizing the Basic-Translational Interface for Clinical Application; 2024 Jun 19-22; Philadelphia, PA. Philadelphia (PA): AACR; Blood Cancer Discov 2024;5(3_Suppl):Abstract nr PO-036.

Non‑Hodgkin's lymphomas of the lacrimal sac: Current insights and future directions (Review).

Non-Hodgkin's lymphoma (NHL) of the lacrimal sac is a rare, yet clinically significant entity within the spectrum of ocular malignancies. While primary lacrimal sac lymphoma is uncommon, it poses unique diagnostic and therapeutic challenges due to its anatomical location and potential for aggressive behavior. Despite advancements being made in the current understanding and treatment of NHL, research that specifically addresses the involvement of the lacrimal sac is currently lacking. Thus, the present review aimed to provide insight into the epidemiology, clinical presentation, diagnostic modalities, histopathological features, treatment strategies and prognosis of lacrimal sac NHL. Through a methodical analysis of previous literature, the present review highlights the diverse spectrum of NHL subtypes that affect the lacrimal sac, including diffuse large B-cell lymphoma, extranodal marginal zone lymphoma, mantle cell lymphoma and follicular lymphoma. Moreover, the present review discusses the role of advanced imaging techniques in accurate staging and treatment planning, including computed tomography (CT), magnetic resonance imaging and positron emission tomography-CT. The present review also discusses evolving treatment approaches, such as surgical intervention, chemotherapy, radiotherapy, immunotherapy, combinations of the aforementioned treatments and targeted therapy. In addition, the present review highlights the significance of multidisciplinary collaboration in attaining optimal outcomes for individuals with lacrimal sac NHL. The present review aimed to provide a basis for 'further investigations into novel treatment modalities and prognostic markers that may aid in guiding personalized management strategies, ultimately improving outcomes for patients with NHL.

Research of active compounds from Allii Macrostemonis Bulbus and potential targets against Non-Hodgkin's Lymphoma based on Network pharmacology.

Non-Hodgkin's Lymphoma (NHL) is a series of lymphoid malignancies in some aggressive subtypes with unsatisfactory treatment effects. Allii Macrostemonis Bulbus (Xie Bai) is a traditional Chinese medicine with anti-cancer activities, which may potentially suppress aggressive NHL. This study tries to discover active components and targets of Xie Bai in treating NHL by network pharmacology-based approaches. Compounds and related targets of Xie Bai were collected from the Traditional Chinese Medicine Database and Analysis Platform. Target genes associated with NHL were searched by GeneCards and DisGeNET, then the overlapped targets were further analyzed by STRING tool, GO, and KEGG pathway enrichment analysis. Molecular docking was employed to verify the interaction between compounds and targets. 11 bioactive compounds were successfully identified, with 30 targets that were screened out for the treatment of NHL. Functional enrichment analysis suggested that Xie Bai exerted its potential effects against NHL via pathways in cancer, such as PI3K/ AKT, p53, and MAPK signaling pathways. Molecular docking results showed that 3 active compounds (quercetin, beta-sitosterol, and naringenin) had good affinity with selected 6 targets（TP53, AKT1, CASP3, CCND1, HPK1, and NLRP3). Identifying six potential genes could accurately be docked with Xie Bai and had close interactions with NHL, which may provide insight into further research and new treatment strategy.

The development of a prediction model based on random survival forest for the prognosis of non- Hodgkin lymphoma: A prospective cohort study in China

Background and objectiveThe pathological staging of non-Hodgkin lymphoma (NHL) is complex, the clinical manifestations are varied, and the prognosis differ considerably. To provide a useful reference for early detection and effective treatment of NHL, we developed a random survival forest (RSF) prognostic model based on machine learning (ML) algorithms using prospective cohort data collected from Chongqing Cancer Hospital from Jan 1, 2017 to Dec 31, 2019 (n = 1449) to compare with the traditional cornerstone method Cox proportional hazards (CPH) model and evaluate the predictability of the model. MethodsPatients were randomly split into a training cohort (TC) and validation cohort (VC) based on 65/35 ratio. The least absolute shrinkage and selection operator (LASSO) regression analysis was used to extracted the important features. And the RSF was modeled to explore the prognostic factors impacting the overall survival (OS) of patients with NHLs in the TC and validated in the VC. The C-index, the Integrated Brier Score (IBS), Kaplan-Meir method, the receiver operating characteristic (ROC) curve, and the area under the ROC curve (AUC) were selected to measure performances and discriminations of the models. In addition, individual survival probability predicted for NHL patients. ResultsAccording to the features extracted by LASSO model and univariable Cox model, 16 variables were selected to develop the RSF model with log-rank splitting rule, which were age, ethnicity, medical insurance, Ann Arbor stage, pathology, targeted-therapy, chemo-therapy, peripheral blood neutrophil count to lymphocyte count ratio (NLR), peripheral blood platelet count to lymphocyte count ratio (PLR), serum lactate dehydrogenase (LDH), CD4/CD8, platelet (PLT), absolute neutrophil count (ANC), lymphocyte (LYM), B-symptoms, and (CPR) were important prognostic factors. Compared to the CPH model (C-index = 0.748, IBS = 0.166), the RSF model (C-index = 0.786, IBS = 0.165) is outperformed in predictability and accuracy. The AUC of the RSF model to estimate the 1-, 3-, and 5-year OS in TC were 0.847, 0.847, and 0.809, respectively; while those in the CPH were 0.816, 0.803, and 0.750, respectively. ConclusionsTo provide practical implications for the implementation of individualized therapy, the study constructed a high-performed RSF model and reveal that it outperformed the traditional model CPH. And the RSF model ranked the risk variables. In addition, we stratified the risk of NHL patients and estimated individual survival probability based on the RSF model.

The evolution of cardiac function in patients with non-Hodgkin’s lymphoma under chemotherapy

In clinical practice, the treatment of non-Hodgkin’s lymphoma (NHL) often involves the combination of several chemotherapy agents, radiotherapy and immunotherapy. While these multimodal approaches improve the efficacy of pathology-specific treatment, they also increase the risk of cardiovascular complications, the most common of which is ventricular dysfunction induced by anti-tumor therapy. Aim of the study: Evaluation of the impact of anti-tumor treatment of NHL on the trajectory of left and right ventricular echocardiographic function. Materials and methods: 127 randomly selected patients from the hematology departments of the PSMI Institute of Oncology were included in the study. Patients were investigated during 3 visits by comprehensive echocardiography, the first visit was up to the onset of anti-tumoral treatment, the 2nd visit was 1 month after initiation and the 3rd visit at 6 months after the debut of chemotherapy. Results: During the anti-tumor treatment, a statistically significant decrease in left ventricular systolic indicators was attested by following parameters: left ventricular ejection fraction (LV EF), mean left ventricular S’, the ratio between the maximum velocity of the E wave and the flow propagation velocity (E/Vp), with an ANOVA p-value &lt;0.001. Regarding the right ventricular systolic function, the indices reflected by TAPSE and S’ right ventricular free wall were reduced statistically significantly also (p ANOVA &lt;0.001). The given analysis confirmed the impairment of ventricular relaxation throughout the treatment, the increase in left ventricular filling pressures, the ratio E/A and E/e’ showed a statisticallysignificant increase, parameters such as the deceleration time of the E wave, the relaxation isovolumetric time, the ratio e’/a’ did not register a statistically significant dynamic (p ANOVA = 0,897; 0,705 and 0,145 respectively). 6 months after the start of treatment, cardiac dysfunction associated with cancer therapy (CTRCD) was found in 18 patients (14,2%), 8 (6,3%) presented a moderate asymptomatic form, 7 (5,7%) had a mild asymptomatic form and 3 (2,4%) a symptomatic one.Conclusion: The left ventricular systolic function was statistically significantly reduced under the impact of the applied treatment, which was confirmed by the LV EF, the mean S’ value at the LV and the E/Vp ratio, the diastolic function having an impact through the E/A and E/e’ ratio. Regarding the function of the right ventricle, we attested statistically significant changes only in the longitudinal contraction parameters. CTRCD was confirmed in 18 patients.

Clinical and sociodemographic factors associated with digital health literacy in patients with non-Hodgkin lymphoma or colorectal carcinoma.

1562 Background: Digital health literacy (DHL), the capacity to find and understand health information using electronic media, is an emerging social determinant of health. Because DHL may impact patients’ ability to benefit from digital health tools and technology-based models of care, it is important to understand how DHL varies in people with cancer. Methods: Patients (N=105) who received systemic treatment for non-Hodgkin lymphoma (NHL) or colorectal carcinoma (CRC) in the past year were recruited from 3 cancer clinics. Participants self-reported DHL (on the electronic Health Literacy Scale, eHEALS), general health literacy (3-item Health Literacy Screening questionnaire), sociodemographic characteristics, and clinical trial enrollment. Independent-samples t-tests (two-tailed; α level of 0.05) and correlations were used to test binary associations between sociodemographic and clinical factors with DHL. Linear regression models were used to test whether associations between clinical factors and DHL remained when adjusting for covariates (based on potential relationships with DHL, p&lt;0.25). Results: Of the 105 participants, 50 (48%) had NHL and 55 (52%) had CRC. Participants were primarily middle-aged to older adults (median age 63, IQR 53-69.5), male (54%), and white/Caucasian (62%), with a college-level education or higher (54%). The mean eHEALS score was 26.9 (SD=8.24, range: 8-40). Higher DHL was related to higher education level ( r s=0.29, p=0.004) and better general health literacy ( r=0.25, p=0.009). Older participants tended to have lower DHL, though this pattern was not statistically significant ( r=-0.12, p=0.21). DHL did not vary significantly by gender, race/ethnicity, or household income in this sample (all ps&gt;0.46). Patients with NHL (mean=24.6, SD=8.10) reported lower DHL than patients with CRC (mean=28.9, SD=7.91; t(103)=2.72, p=0.008); this pattern was similar when controlling for age, education, and general health literacy (unstandardized b=3.07, SE=1.65, p=0.07). Interestingly, the small subset of patients who reported participating in a clinical trial (N=10) reported lower DHL than patients who had not ( t(100)=3.08, p=0.003). In the adjusted model, patients reporting trial enrollment still showed lower DHL above and beyond the effects of age, education, general health literacy, and disease type ( b=-10.45, SE=3.20, p=0.002). Conclusions: In this convenience sample, DHL varied by cancer type, general health literacy, and education level, suggesting interventions to increase DHL may be well-suited for those with NHL and/or lower education level. Further, these factors may affect technology-based care, an important consideration in eHealth intervention development. This study also indicated a possible link between clinical trial enrollment and lower DHL that should be explored in future studies with larger samples.

B-NHL Cases in a Tertiary Pediatric Hematology-Oncology Department: A 20-Year Retrospective Cohort Study.

Non-Hodgkin lymphoma (NHL) is among the five most common pediatric cancer diagnoses in children and adolescents and consists of a heterogeneous group of lymphoid tissue malignancies -with B-cell-derived NHL accounting for nearly 80% of cases. Novel and high-throughput diagnostic tools have significantly increased our understanding of B-NHL biology and molecular pathogenesis, leading to new NHL classifications and treatment options. This retrospective cohort study investigated 17 cases of both mature B-cell NHL (Burkitt lymphoma or BL; Diffuse large B-cell lymphoma or DLBCL; Primary mediastinal large B-cell lymphoma or PMBCL; Follicular lymphoma or FL) and immature B-cell progenitor NHL (B-lymphoblastic lymphoma or BLL) that were treated in a tertiary Pediatric Hematology-Oncology Department during the last 20 years. Modern NHL protocols for children, adolescents, and young adults, along with the addition of rituximab, are safe and efficient (100% overall survival; one relapse). Elevated ESR was more prevalent than elevated LDH. Analyses have focused on immune reconstitution (grade ≥3 infections, lymphocyte and immunoglobulin levels recovery) and body-mass-index changes post-treatment, late effects (in 53% of patients), and the presence of histology markers BCL2, BCL6, CD30, cMYC, and Ki-67%. One patient was diagnosed with a second malignant neoplasm (papillary thyroid cancer).

Recent Advances in Nanobiotechnology for the Treatment of Non-Hodgkin's Lymphoma.

Lymphoma is the eighth most common type of cancer worldwide. Currently, lymphoma is mainly classified into two main groups: Hodgkin's lymphoma (HL) and non-Hodgkin's lymphoma (NHL), with NHL accounting for 80% to 90% of the cases. NHL is primarily divided into B, T, and natural killer (NK) cell lymphoma. Nanotechnology is developing rapidly and has made significant contributions to the field of medicine. This review summarizes the advancements of nanobiotechnology in recent years and its applications in the treatment of NHL, especially in diffuse large B cell lymphoma (DLBCL), primary central nervous system lymphoma (PCNSL), and follicular lymphoma (FL). The technologies discussed include clinical imaging, targeted drug delivery, photodynamic therapy (PDT), and thermodynamic therapy (TDT) for lymphoma. This review aims to provide a better understanding of the use of nanotechnology in the treatment of non-Hodgkin's lymphoma.

E054 Rituximab dose minimisation in rheumatoid arthritis, a retrospective outcome analysis

Abstract Background/Aims Rituximab was originally developed as a non-Hodgkin lymphoma treatment and rheumatology adopted the same dosing for rheumatoid arthritis(RA); two 1000mg doses two weeks apart for each maintenance cycle. UHSussex utilises self-referral for maintenance rituximab dosing once disease control lessens. Evidence demonstrates patients treated with lower dose rituximab still enjoy good disease control with less immunosuppression, reduced hospital attendance and reduction in drug expenditure. Following one two-dose cycle, stable RA patients were prescribed a single 1000mg dose from 2020 onwards. A retrospective outcome analysis was completed in August 2022; however, results were highly impacted by Covid-19 and a repeat analysis was required. Aim: to assess impact of a single 1000mg dose rituximab regime on patient sustained outcomes, dose intervals, Disease Activity Scores (DAS) and drug expenditure. Methods The pharmacy database was used to identify RA patients receiving rituximab from March 2020 to August 2023. Patients received at least one standard two-dose cycle before switching to a single infusion. Patients were excluded if lost to follow up (under care of rheumatology for less than a year following dose switching) or considered clinically unstable. Patient letters and departmental records were accessed for disease scores and treatment intervals. Results Table1: Results from the two analysis periods From the original cohort (31/59)53% remained on single dosing. Switch back tended to occur within 18 months of switching. DAS scores were not collected reliably and were omitted. Conclusion Covid-19 impacted services and attitudes during the initial study period. Many patients stopped treatment, particularly rituximab, due to the prolonged duration of effect, excluding them from analysis. The dose-interval increase during the first analysis was considered a result of the pandemic. Patients and clinicians delayed infusions; minimising immunosuppression due to perceived increased risk of Covid-19. The continued interval increase in the second analysis may identify a patient cohort in deep remission eligible for therapy review. The study highlights poor practice in collecting and recording DAS scores and appropriate patient-clinician interaction opportunities. 53% of patients remained on single infusions in August 2023 resulting in resource savings, reduced hospital attendance, immunosuppression and significant cost savings demonstrating the rationale for this option. Disclosure S. Butler: Honoraria; Abbvie, Janssen. H. Smith: Honoraria; Novartis, Abbvie.

Establishment of cluster of differentiation 20 immobilized cell membrane chromatography for the screening of active antitumor components in traditional Chinese medicine

Non-Hodgkin lymphoma (NHL) is a heterogeneous group of malignant tumors occurring in B or T lymphocytes, and no small molecule-positive drugs to treat NHL have been marketed. Cluster of differentiation 20 (CD20) is an important molecule regulating signaling for the life and differentiation of B lymphocytes and possesses the characteristics of a drug target for treating NHL. 2-Methoxyestradiol induces apoptosis in lymphoma Raji cells and CD20 protein is highly expressed by Raji lymphoma cells. Therefore, in this study, a CD20-SNAP-tag/CMC model was developed to validate the interaction of 2-methoxyestradiol with CD20. 2-Methoxyestradiol was used as a small molecule control compound, and the system was validated for good applicability. The cell membrane chromatography model was combined with high-performance liquid chromatography ion trap time-of-flight mass spectroscopy (HPLC-IT-TOF-MS) in a two-dimensional system to successfully identify, analyze, and characterize the potential active compounds of Schisandra chinensis (Turcz.) Baill. extract and Lysionotus pauciflorus Maxim. extract, including Schisandrin A, Schizandrol A, Schizandrol B, Schisantherin B, and Nevadensin, which can act on CD20 receptors. The five potential active compounds were analyzed by non-linear chromatography. The thermodynamic and kinetic parameters of their interaction with CD20 were also analyzed, and the mode of interaction was simulated by molecular docking. Their inhibitory effects on lymphoma cell growth were assessed using a Cell Counting Kit-8 (CCK-8). Nevadensin and Schizandrin A were able to induce apoptosis in Raji cells within a certain concentration range. In conclusion, the present experiments provide some bases for improving NHL treatment and developing small molecule lead compounds targeting CD20 with low toxicity and high specificity.

Abstract 1865: HDP-102 - a CD37-targeting Amanitin-based-ADC for the treatment of NHL - non-clinical data package

Abstract Background: Antibody-drug conjugates (ADC) are gaining importance as anti-cancer therapy. Most ADCs are based on cytotoxic warheads targeting only proliferating cells. In contrast, HDP´s proprietary ATAC platform utilizes amatoxins as payload. Amatoxins are specific inhibitors of eukaryotic RNA polymerase II, suppressing a key function in the protein metabolism not limiting their cytotoxicity to proliferating cells. Furthermore, there are no known resistance mechanisms against amatoxins in mammalian cells (i.e. multi drug resistance transporters), making ATACs a promising new class of anti-cancer ADCs. Here we present pre-clinical data on the anti-CD37 ATAC HDP-102. CD37 is a transmembrane protein expressed exclusively on immune cells, mainly mature B-cells, and in many B-cell malignancies, including Non-Hodgkin’s Lymphoma (NHL). Material and Methods: HDP-102: anti-CD37 ADC based on cysteine-reactive, site-specific amatoxin-linker constructs produced by HDP Cytotoxicity assays: CellTiter Glo 2.0 (Promega) assays on CD37pos cell lines MEC-2, Raji-luc, Ramos and CD37neg Nalm-6 cells Efficacy studies: Disseminated MEC-2 and Raji-Luc mouse xenograft tumor models in single dose experiments Tolerability study in Cynomolgus monkeys: i.v. HDP-102 treatment on days 1 and 22; blood sampling for PK analysis; necropsy and histopathology on days 28 and 64 Results: HDP-102 showed full-blown cytotoxicity with EC50 values in the low nanomolar range in all CD37pos cell lines in vitro but no cytotoxicity on CD37neg cells. In vivo, the anti-tumor efficacy of HDP-102 was evaluated in disseminated CDX models of NHL. A single dose of 0.5 mg/kg HDP-102 already led to complete tumor remission in all animals in a Raji-luc model and 60% survival on day 100 in a MEC-2 model, demonstrating the high potency of HDP-102 in NHL models. In a tolerability study in Cynomolgus monkeys, i.v. administration of HDP-102 was well tolerated up to 2.5 mg/kg without clinical signs of toxicity. Microscopically, decreased cellularity in lymphoid tissue was the main finding, caused by the targeted effect of HDP-102 on CD37pos cells. The HNSTD of 2.5 mg/kg together with the potent anti-tumor efficacy of HDP-102 leads to a therapeutic window of ~200 for HDP-102. Conclusion: CD37 is an ideal target for ADCs due to its high prevalence in B-cell malignancies and limited expression on healthy cells. We have demonstrated that the anti-CD37 ATAC HDP-102 is a promising drug candidate for the treatment of NHL. HDP-102 showed excellent anti-tumor efficacy in CDX models even after single doses. Pharmacological activity of HDP-102 was also seen in Cynomolgus monkeys as evidenced by depletion of B-cells in lymphoid organs. Furthermore, HDP-102 was well tolerated in monkeys. Taken together, based on pre-clinical data, HDP-102 is a promising new treatment option for NHL patients combining a good safety profile with strong anti-tumor efficacy. Citation Format: Sarah-Jane Neuberth, Kristin Decker, Christian Orlik, Irina Dranova, Anikó Pálfi, Torsten Hechler, Andreas Pahl, Michael Kulke. HDP-102 - a CD37-targeting Amanitin-based-ADC for the treatment of NHL - non-clinical data package [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1865.

The Non-Hodgkin Lymphoma Treatment and Side Effects: A Systematic Review and Meta-Analysis.

This paper aims to review studies regarding side effects found during Non-Hodgkin Lymphoma treatment, to suggest the drug class most associated with these effects, as well as the most prevalent side effect grade. This review is registered in PROSPERO (IDCRD42022295774) and followed the PICOS strategy and PRISMA guidelines. The search was carried out in the databases PubMed/MEDLINE, Scientific Electronic Library Online, and DOAJ. Medical Subject Headings Terms were used and quantitative studies with conclusive results regarding side effects during the non-Hodgkin lymphoma treatment were selected. Patent information was obtained from google patents. Monoclonal antibodies were the main drug class associated with side effects during NHL therapy. The combination of Rituximab (Rituxan®; patent EP1616572B) and iInotuzumab (Besponsa®; patent EP1504035B3) was associated with a higher incidence of thrombocytopenia (p<0.05), while the combination of Rituximab and Venetoclax (Venclexta®; patent CN107089981A) was associated with a higher incidence of neutropenia (p<0.05) when compared to Bendamustine combinations (Treanda ™; patent US20130253025A1). Meta-analysis revealed a high prevalence of grade 3-4 neutropenia and thrombocytopenia in men. Finally, Americans and Canadians experienced a higher prevalence of these side effects, when compared to others nationalities (p<0.05). Patents regarding the use of monoclonal antibodies in NHL treatment were published in the last year. Monoclonal antibodies associated with neutropenia (grade 3-4) and thrombocytopenia, especially in North American men treated for NHL, and with an average age of 62 years demonstrated importance in this study.

Phase I Study of Duvelisib Study for Cytokine Release Syndrome Prophylaxis in Patients Receiving Chimeric Antigen Receptor T Cell Treatment for Non-Hodgkin Lymphoma

Phase I Study of Duvelisib Study for Cytokine Release Syndrome Prophylaxis in Patients Receiving Chimeric Antigen Receptor T Cell Treatment for Non-Hodgkin Lymphoma

Impact of Modern Low Dose Involved Site Radiation Therapy on Normal Tissue Toxicity in Cervicothoracic Non-Hodgkin Lymphomas: A Biophysical Study.

This biophysical study aimed to determine fitting parameters for the Lyman-Kutcher-Burman (LKB) dose-response model for normal tissue complication probability (NTCP) calculations of acute side effects and to investigate the impact of reduced radiation doses on the probability of their occurrence in supradiaphragmatic non-Hodgkin lymphoma (NHL) irradiation. A cohort of 114 patients with NHL in the cervicothoracic region, treated between 2015 and 2021 at the University Hospitals of Münster, Hamburg, and Essen, with involved site radiation therapy (ISRT), were included. Among them, 68 patients with aggressive NHL (a-NHL) received consolidative radiation therapy with 24-54 Gy following (R-)CHOP chemotherapy. Additionally, 46 patients with indolent NHL (i-NHL) underwent radiotherapy with 22.5-45.0 Gy. Two treatment plans were prospectively created for each patient (a-NHL: 30.0/40.0 Gy; i-NHL: 24.0/30.0 Gy). NTCP were then calculated using the optimized LKB model. The adapted dose-response models properly predicted the patient's probability of developing acute side effects when receiving doses ≤ 50 Gy. In addition, it was shown that reduced radiation doses can influence the NTCP of acute side effects depending on the aggressiveness of NHL significantly. This study provided a foundation to prospectively assess the probability of adverse side effects among today's reduced radiation doses in the treatment of NHL.

Key Findings from a Transformative Quality Improvement Initiative on Advancing CAR T-Cell Treatment in Non-Hodgkin Lymphoma

Background Chimeric antigen receptor (CAR) T-cell therapy can transform outcomes for eligible patients with relapsed/refractory non-Hodgkin lymphoma (NHL). However, community-based care teams face challenges, including identifying eligible patients and coordinating referral and care, hindering integration into clinical practice. PRIME conducted a quality improvement (QI) initiative to better understand the challenges community oncology teams encounter in coordinating CAR T-cell therapy for patients with NHL and to bridge the gap between tertiary referral centers and large CAR T-cell centers. Methods This QI initiative included baseline provider surveys (n = 60), pre- and post-surveys of providers (n = 55) participating in team-based audit-feedback (AF) sessions (Table 1) and 90-day follow-up surveys. Survey questions were designed to evaluate practice patterns, challenges, and barriers to providing CAR T cell therapy to NHL patients. Care teams from each clinic, along with a CAR T-cell expert from the regional academic center and nationally renowned expert NHL CAR T-cell physician, participated in AF sessions to (a) assess system-specific practice gaps identified via the provider surveys, (b) prioritize areas for improvement, and (c) develop action plans for addressing root causes. Results Provider Surveys: Providers' top reported challenges managing patients with NHL were individualizing treatment plans (33%), patient nonadherence/lack of follow-up (23%), and patient health literacy (20%). Specific barriers to using CAR T-cell therapy included identifying patients eligible for treatment (45%), gaining approval from the insurance company (40%), and transferring the patient to a CAR T-cell center for infusion (27%). When asked about clinical practices, 48% of providers reported discussing novel therapies for NHL in detail with their patients, and 51% of providers often or always refer eligible patients for CAR T-cell therapy. While 45% of providers rated the level of collaboration/communication between CAR T-cell centers and oncology clinics as very good/excellent, more than half felt it could be better, citing insufficient sharing of patient information (38%), and lack of expertise in CAR T-cell administration among clinic staff (18%) as common challenges. Small Group AF Sessions: HCPs participating in the A/F sessions reported key challenges of treatment with CAR T-cell therapy as gaining approval from insurance companies (33%), managing patients post-treatment (26%), and identifying patients eligible for treatment (22%) (Figure 1).Improvement in very high/high confidence were noted in identifying eligible patients for CAR T-cell therapy (51% to 84%) and managing adverse/late effects of CAR T-cell therapy in patients with NHL (46% to 85%). Action plans outlined to achieve CAR T-Cell therapy goals included: increase efforts to facilitate timely patient referrals for CAR T-cell therapy, improve communication between referral centers and CAR T-cell therapy performing centers, and enhance patient knowledge and expand supportive care discussions for CAR T-cell therapy. Follow-up Surveys: In 90-day follow up surveys (n = 12), 92% of respondents reported good/very good/excellent communication and collaboration between CAR T-cell centers and oncology clinics. Additionally, 75% report improved identification of eligible patients for CAR T-cell therapy. Despite these improvements, clinics top challenge of gaining approval from the insurance company for CAR T-cell therapy (33%) persists. Conclusions Through this QI initiative, clinical teams created and implemented action plans to close gaps in identifying eligible patients, coordinating CAR T-cell therapy referral and approval, and providing counseling and obtaining consent among hematology/oncology team members. Following the initiative, meaningful confidence gains were noted in identifying eligible patients for CAR T-cell therapy and managing adverse/late effects of treatment. Action plans developed by HCPs following this QI initiative, will be addressed in future initiatives to support evidence-based integration of CAR T-cell therapies into NHL care to optimize patient outcomes. Study Sponsor Statement The study reported in this abstract was funded by an independent educational grant from Bristol Myers Squibb, who had no role in the study design, execution, analysis, or reporting.

A Multicenter, Prospective Clinical Study of the R-CDOP Regimen in Previously Untreated Non-Hodgkin Lymphoma with High Tumor Burden

Background: The treatment of non-Hodgkin lymphoma (NHL) with high tumor burden is facing severe challenges. The response rate and survival of R-CHOP treatment still need to be further explored in these patients. Pegylated liposomal doxorubicin (PLD) is a promising alternative drug to the current regimen, with a safety and efficacy profile through the enhanced permeability and retention effect and longer circulation1-3, and especially less cardiotoxic compared with traditional anthracyclines4. We conducted this prospective study to evaluate the efficacy and safety of PLD combined with R-COP (R-CDOP) regimen in treatment for previously untreated (TN) NHL with high tumor burden. Methods: This study was a single-arm, multicenter, prospective clinical trial (NCT05040555). TN Patients with CD20+ diffuse large B-cell lymphoma or grade 3b follicular lymphoma with high tumor burden were recruited. Patients are considered to have high tumor burden if they meet at least one of the following criteria: (1) presence of at least three lymph nodes with a diameter of 3 cm or more; (2) presence of any lymph nodes or extranodal masses with a diameter of 7 cm or more; (3) presence of hepatomegaly and splenomegaly confirmed by PET-CT; Spleen: female &amp;gt; 15cm, male &amp;gt; 16cm); (4) presence of pleural and peritoneal effusions determined through cytological examination, flow cytometry, or diagnosed by PET-CT, (5) LDH levels exceeding 3 times the upper limit of normal value, and (6) PET-CT TMTV exceeding 220cm3. The patients received PLD (30-35mg/ m2, d1) plus Rituximab (375mg/m2, d0), Cyclophosphamide (750mg/ m2, d1), Vindesine (3mg/ m2, d1) / Vincristine (1.4mg/m2, d1) and Prednisone (60mg/ m2, d1-5) Q3W for 4 (Limited-stage lymphoma) or 6 (Advanced lymphoma) cycles with an additional 2 cycles of Rituximab therapy. The primary endpoints was objective response rate (ORR). The secondary endpoint were complete response rate (CRR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS) and safety. Results: At the data cut-off of 5 June 2023, 44 eligible pts were enrolled (Table 1). The ORR and CRR was 84.2% (32/38) [95%CI, 68.8%-94.0%] and 60.5% (23/38) [95%CI, 43.4-76.0%], respectively. The DCR was 89.5% (34/38) [95%CI, 75.2%-97.1%]. The median PFS was 14.4 months [95%CI, 4.7%-24.2%], and the median OS was not reached. The median PFS and OS will be updated after long-term follow-up. The most common grade 3/4 AEs were neutropenia (29.5%), leucopenia (25.0%) and anemia (11.4%). Left ventricular ejection fraction (LVEF) declined in 1(1/44, 2.3%) pt, but did not fall below 50%. Congestive heart failure was not occurred. Dose adjustment and treatment delay due to AE occurred in only one pt, and no treatment termination due to AE occurred except for 1 patient death. Conclusions: The preliminary results of the study indicate that the R-CDOP regimen is safe and shows promising efficacy for treating TN NHL with a high tumor burden. References： 1. Hashizume H, Baluk P, Morikawa S, et al. Openings between defective endothelial cells explain tumor vessel leakiness. Am J Pathol. 2000;156 (4):1363-1380 2. Gabizon A, Shmeeda H, Grenader T. Pharmacological basis of pegylated liposomal doxorubicin: impact on cancer therapy. Eur J Pharm Sci. 2012;45(4):388-398. 3. Sadzuka Y, Sugiyama I, Tsuruda T, et al. Characterization and cytotoxicity of mixed polyethyleneglycol modified liposomes containing doxorubicin. Int J Pharm. 2006;312(1-2):83-89. 4. Lu B, Shen L, Ma Y, et al. Cardiovascular adverse events associated with cyclophosphamide, pegylated liposomal doxorubicin, vincristine, and prednisone with or without rituximab ((R)-CDOP) in non-Hodgkin's lymphoma: A systematic review and meta-analysis. Front Pharmacol. 2022;13:1060668.