B-cell non-Hodgkin Lymphoma Patients Research Articles

Predictive short/long-term efficacy biomarkers and resistance mechanisms of CD19-directed CAR-T immunotherapy in relapsed/refractory B-cell lymphomas.

Genetically modified T-cell immunotherapies are revolutionizing the therapeutic options for hematological malignancies, especially those of B-cell origin. Impressive efficacies of CD19-directed chimeric antigen receptor (CAR)-T therapy have been reported in refractory/relapsed (R/R) B-cell non-Hodgkin lymphoma (NHL) patients who were resistant to current standard therapies, with a complete remission (CR) rate of approximately 50%. At the same time, problems of resistance and relapse following CAR-T therapy have drawn growing attention. Recently, great efforts have been made to determine various factors that are connected to the responses and outcomes following CAR-T therapy, which may not only allow us to recognize those with a higher likelihood of responding and who could benefit most from the therapy but also identify those with a high risk of resistance and relapse and to whom further appropriate treatment should be administered following CAR-T therapy. Thus, we concentrate on the biomarkers that can predict responses and outcomes after CD19-directed CAR-T immunotherapy. Furthermore, the mechanisms that may lead to treatment failure are also discussed in this review.

Evaluation of Role of Hepatitis C Virus in the Pathogenesis of Hodgkin Lymphoma Patients

Background and Aim: Hepatitis C is a viral infection that cause liver’s inflammation. Numerous studies have found a significant frequency of hepatitis C virus (HCV) infection in non-lymphoma Hodgkin's patients. B-cell non-Hodgkin's lymphoma (B-NHL) development could be significantly caused by HCV. The purpose of the current study was to investigate the hepatitis C virus role in the pathogenesis Hodgkin lymphoma patients. Patients and Methods: This prospective study was carried out on 60 B-cell non-Hodgkin's lymphoma. (B-NHL) and 30 (healthy) control group in PAF Hospital Lahore Department of Internal Medicine and Oncology Department CMH, Lahore from May 2022 to October 2022. Study protocol was approved by institute ethical committee. Each individual provided written informed consent. All the patients were subjected to history taking, clinical examination, CBCs, kidney and liver function assessment, B2 microglobine, erythrocyte sedimentation rate determination, serum uric acid, abdominal ultrasound for lymphadenopathy and organomegaly, serum LDH, proper diagnosis and staging through CT abdomen, PCR, biopsy of bone marrow, and ELISA. Data analysis was done using SPSS version 27. Results: Of the total 60 B-NHL patients, there were 32 (53.3%) male and 28 (46.7%) females. The overall mean age was 42.8± 10.8 years with an age range 16-65 years. There were 20 (66.7%) male and 10 (33.3%) females in control group and their mean age was 28.4± 11.6 years with an age range 12-60 years. Based on ELISA test, the incidence of for positive and negative anti-HCV antibodies were 34 (56.7%) and 26 (43.3%) respectively. The incidence of positive and negative anti-HCV RNA was 36 (60%) and 24 (40%) respectively. Conclusion: The present study revealed that higher incidence of HCV infection play significant role in the pathogenesis of Hodgkin’s lymphoma patients. This increases the likelihood of HCV infection playing a role in the development of B-NHL. Keywords: Hepatitis C virus, Hodgkin lymphoma, Pathogenesis

CAR t-cell therapy in BOlogNa-NEUrotoxicity TReatment and Assessment in Lymphoma (CARBON-NEUTRAL): proposed protocol and results from an Italian study.

To investigate neurotoxicity clinical and instrumental features, incidence, risk factors, and early and long-term prognosis in lymphoma patients who received CAR T-cell therapy. In this prospective study, consecutive refractory B-cell non-Hodgkin lymphoma patients who received CAR T-cell therapy were included. Patients were comprehensively evaluated (neurological examination, EEG, brain MRI, and neuropsychological test) before and after (two and twelve months) CAR T-cells. From the day of CAR T-cells infusion, patients underwent daily neurological examinations to monitor the development of neurotoxicity. Forty-six patients were included in the study. The median age was 56.5years, and 13 (28%) were females. Seventeen patients (37%) developed neurotoxicity, characterized by encephalopathy frequently associated with language disturbances (65%) and frontal lobe dysfunction (65%). EEG and brain FDG-PET findings also supported a predominant frontal lobe involvement. The median time at onset and duration were five and eight days, respectively. Baseline EEG abnormalities predicted ICANS development in the multivariable analysis (OR 4.771; CI 1.081-21.048; p = 0.039). Notably, CRS was invariably present before or concomitant with neurotoxicity, and all patients who exhibited severe CRS (grade ≥ 3) developed neurotoxicity. Serum inflammatory markers were significantly higher in patients who developed neurotoxicity. A complete neurological resolution following corticosteroids and anti-cytokines monoclonal antibodies was reached in all patients treated, except for one patient developing a fatal fulminant cerebral edema. All surviving patients completed the 1-year follow-up, and no long-term neurotoxicity was observed. In the first prospective Italian real-life study, we presented novel clinical and investigative insights into ICANS diagnosis, predictive factors, and prognosis.

Efficacy and Safety of Dual-Targeting Chimeric Antigen Receptor-T Therapy for Relapsed or Refractory B Cell Lymphoid Malignancies: A Systematic Review and Meta-Analysis.

Dual-targeting chimeric antigen receptor (CAR)-T cell therapy has been proposed as a potential solution for overcoming antigen escape during anti-CD19 CAR-T treatment. We performed this systematic review and meta-analysis to investigate the efficacy and safety of this novel treatment in patients with B cell non-Hodgkin lymphoma (B-NHL) and B cell acute lymphoblastic leukemia (B-ALL). We systematically searched relevant literature based on databases (PubMed, Web of Science, Embase and Cochrane) and conference abstracts. The primary outcomes measured were the best objective response rate (ORR) or complete response (CR), 12-month overall survival (OS) and progression-free survival (PFS), cytokine release syndrome (CRS), and neurotoxicity. Fifteen registered prospective open-label clinical trials were included. Among the 260 patients with B-NHL, the pooled best ORR and CR were 77% (95% confidence interval [CI]: 0.71-0.82) and 52% (95% CI: 0.40-0.63), respectively, and the pooled 12-month PFS and OS were 54.0% (95% CI: 0.47-0.61) and 66.0% (95% CI: 0.56-0.77), respectively. In the 159 patients with B-ALL, the combined best CR was observed to be 92% (95% CI: 0.82-0.99) and the pooled 12-month PFS and OS were 65.0% (95% CI: 0.51-0.77) and 73.0% (95% CI: 0.56-0.92), respectively. Moreover, in B-NHL patients, grade ≥3 CRS was observed in 14.0% (95% CI: 0.04-0.29) of these patients, and 5.0% (95% CI: 0.02-0.08) showed grade ≥3 neurotoxicity; in the case of B-ALL patients, grade ≥3 CRS and neurotoxicity occurred in 11.0% (95% CI: 0.04-0.19) and 2.0% (95% CI: 0.00-0.06), respectively. This study demonstrates the safety and clinical efficacy of dual-targeting CAR-T cell therapies in B cell malignancies. Further, well-designed randomized controlled trials are required to establish the role of dual-targeting CAR-T cell therapy in patients with B cell malignancies.

HBsAg (-)/HBsAb (-)/HBeAg (-)/HBeAb (+)/HBcAb (+) predicts a high risk of hepatitis B reactivation in patients with B-cell lymphoma receiving rituximab based immunochemotherapy.

Patterns of hepatitis B virus reactivation (HBV-R) in HBsAg (-)/HBcAb (+) patients with B-cell non-Hodgkin lymphoma (NHL) receiving rituximab based immunochemotherapy have not been well described. The retrospective study included 222 HBsAg (-)/HBcAb (+) NHL patients as training cohort and 127 cases as validation cohort. The incidence of HBV-R in HBsAg (-)/HBcAb (+) B-cell NHL patients was 6.3% (14/222), of which that in HBsAg (-)/HBsAb (-)/HBeAg (-)/HBeAb (+)/HBcAb (+) population was 23.7% (9/38). Multivariate analysis showed that HBsAg (-)/HBsAb (-)/HBeAg (-)/HBeAb (+)/HBcAb (+) correlated with a high risk of HBV-R in B-cell lymphoma patients (training phase hazard ratio[HR], 10.123; 95% confidence interval [CI], 3.389-30.239; p < 0.001; validation phase HR, 18.619; 95% CI, 1.684-205.906; p = 0.017; combined HR, 12.264; 95% CI, 4.529-33.207; p < 0.001). Inthetrainingcohort,the mortality rate of HBsAg (-)/HBcAb (+) B-cell NHL caused by HBV-R was 14.3% (2/14) while that for HBV reactivated HBsAg (-)/HBsAb (-)/HBeAg (-)/HBeAb (+)/HBcAb (+) population was up to 44.4% (4/9). As a high incidence of HBV-R and high mortality after HBV-R was found in HBsAg (-)/HBsAb (-)/HBcAb (+)/HBeAg (-)/HBeAb (+) patients with B-cell NHL receiving rituximab based immunochemotherapy, prophylactic antiviral therapy is recommended for these patients.

Evaluation of Hexokinase 2 and Serum LDH in B-cell Non-Hodgkin’s Lymphoma Patients

Background and Objective: Tumor cells produce energy by glycolysis and Lactate Dehydrogenase and Hexokinase are the key part of glycolysis, The present study aimed to evaluate the expression of Hexokinase 2 and serum LDH in B-cell Non-Hodgkin’s Lymphoma patients Method: A total of 84 B-cell Non-Hodgkin’s Lymphoma Patients were enrolled in the study. HK-2 Marker was studied by Immunohistochemistry and LDH analysis was done by Cobas 6000 analyser method and correlated with Clinico-Pathological Parameters and Diagnostic panel. RESULT:73% of B-cell NHL patients had Abnormal LDH. It was significantly correlated with Multiple Disease site (P=0.002). In correlation with Diagnostic Panel (MIb1, CD10, CD2, MUM1, BCL6, BCL2) a higher trend of Abnormal LDH was seen in BCL-6 positive and BCL-2 negative Patients. 64% of patients had HK-2 expression. In correlation with Clinical parameters, it was significantly correlated with &gt;50 age group, while in correlation with pathological parameters A significant correlation observed with single disease site as compared to multiple disease site (P=0.004), In correlation with Diagnostic panel A higher trend of HK-2 Expression was observed in CD10 Negative and BCL-2 Negative Patients. Further Univariate survival analysis of LDH and HK-2 showed similar Overall survival in Abnormal and normal LDH level patients and HK-2 Positive and negative Patients respectively. Further Intercorrelation of both markers, showed almost similar expression of HK-2 between patients with normal LDH level and abnormal LDH level. CONCLUSION: Abnormal LDH level was closely associated with patients having disease at multiple sites, suggesting its activity to be associated with the advancement of the disease, HK-2 positivity was related with older age group, strengthens the findings of increased altered metabolic activity with older age, They are also associated with BCL-2 negativity that indicates that anti-apoptotic activity of BCL-2 might be responsible for that Though there was no significant correlation of LDH,, HK-2 with overall survival, majority of the patients who were dead had abnormal LDH and half of them showed positive HK-2 expression Briefly our data indicates that LDH and HK-2 can be useful parameter in defining clinical and prognostic aspects in NHL patient but needs further evaluation with larger groups of patients Keywords: NHL, Altered metabolism, Hexokinase, LDH

Clinical and Radiographic Predictors of Progression and Survival in Relapsed/Refractory Lymphoma Patients Receiving Anti-CD19 CAR T-cell Therapy.

Chimeric antigen receptor (CAR) T-cell therapy has revolutionized treatment of relapsed/refractory (R/R) B-cell lymphomas, though certain patients do not respond to treatment or relapse afterwards. The purpose of this study is to determine patient variables that are predictive of response to CAR-T therapy. We conducted a retrospective review of 59 R/R B-cell non-Hodgkin lymphoma patients who received anti-CD19 CAR T-cell therapy. Risk factors for progression free survival (PFS) and overall survival (OS) were identified and multivariate logistic regression models for PFS and OS at 1 year were created using stepwise selection. The final multivariate logistic regression models were used to estimate the area under the receiver operating curve (AUROC). At median follow up of 25.6 months, median overall survival was not reached, and median progression free survival was 5.7 months. Stage IV disease (odds ratio (OR) 9.335, P = .025) was identified as a predictive variable for progression at day 365 with an AUC of 0.7922 (P < .001). IPI (OR 2.828, P=.014), ALC ≥ 0.50 at collection (OR 0.183, P=.043), CRP ≥ 11 (OR 6.177, P=.019), and tocilizumab administration (OR 0.062, P=.005) as predictors for death at day 365 with an AUC 0.8626 (P < .001). Clinical variables identify R/R lymphoma patients who are at risk for progression and poor overall survival after CAR T-cell therapy. IPI, CRP, ALC, and tocilizumab administration may be predictors of survival.

Be Cautious to Adopt a Second CAR T-Cell Infusion after Failure of CD19/CD22 Cocktail CAR T-Cell Therapy in Relapsed/Refractory B-NHL

Objective: Chimeric antigen receptor (CAR) T-cell infusion (CTI) has emerged as a breakthrough therapy for relapsed/refractory B-cell non-Hodgkin's lymphoma (R/R B-NHL) patients. Nevertheless, there are still a significant number of patients suffering treatment failure (failed to respond or eventually relapsed after a partial or complete response, PR/CR) post the first time CTI (CTI1). The issue how to salvage this group of patients should be urgently addressed. Our study aimed to provide clues for exploring the potentially effective salvage strategies and finally improving the prognosis of them by analyzing the efficacy and safety especially between the second time CTI (CTI2) and other different therapies (non-CTI2). Methods: Herein,a retrospective analysis was performed on total 61 patients after failure of CD19/22 cocktail CTI1 (ChiCTR-OPN-16008526) between January 2017 and May 2022 in our hospital. Among them, 27 of 61 patients with a prior determination of no antigen loss received CTI2 for compassionate use. The other 34 patients were administrated as non-CTI2 therapies. The clinical characteristics, efficacy, safety, survival analysis and outcome-related risk factors were all evaluated. Results: The CTI2 group achieved a higher overall response rate (ORR) at 30 days assessment (8/27 vs. 2/34, P=0.017). Nevertheless, the non-CTI2 group showed a better event-free survival (EFS) (P=0.007) (Figure1, left panel) and overall survival (OS) (P=0.048) (Figure1, middle panel) than the CTI2 group with a median follow-up of 6.7 months (range, 3-45.5) and 4.7 months (range, 1.1-53). Further analysis on copies of CAR transgene in peripheral blood at 90 days detection revealed that the better CAR T cells expansion was related to a better response in CTI2 group (P=0.012)(data not shown). Additionally, neither of the CTI2 and non-CTI2 was the independent risk factor of survival (HR: 1.665, 95%CI: 0.883-3.141, P=0.115). Either of Ann Arbor stage (HR: 1.970,9 5%CI: 1.944-3.997, P=0.029) or bulky disease (HR: 2.879, 95%CI: 1.321-6.276, P=0.008) at disease onset was the related independent risk factor instead. As shown in Figure1 right panel, the best responses to different salvage therapies suggested that the regimen (Polatuzumab vedotin,-pola, Bendamustine, Rituximab, pola+BR) was likely to be a potentially optimal non-CTI2 salvage therapy, even without statistically significant differences due to the limitation of the sample size. The adverse effects of CTI2 were generally similar to those of non-CTI2. Remarkably the infection-related mortality rate was significantly higher (59% vs. 21%, P=0.025) in CTI2 group. Conclusion: Our study provides novel insights and clues that clinicians should be cautious to adopt a CTI2 after failure of the CD19/22 cocktail CTI1 in R/R B-NHL. It is noteworthy that the choice of pola+BR regimen probably has an advantage in salvage strategies. Large-scale prospective studies are warranted in the future. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Pediatrics Non-Hodgkin's Lymphoma Survivors: Should We Worry about Quality of Life and Late Therapy Effects?

Background: The survival outcomes of mature B-cell non-Hodgkin lymphoma (NHL) patients have improved due to advances in treatment. Objectives: In this study, we aim to assess the frequency and trends of the late effects and their impact on the quality of life among these survivors at Children Cancer Hospital Egypt. Design and methods: A retrospective study including all patients diagnosed with Non-Hodgkin's lymphoma "Mature B" at CCHE 57357 in the period between January 2012 till December 2015. All of the patients were examined clinically and assessed for: Cognitive functions (by assessing IQ level using (Stanford-Binet Intelligence Scales, Fifth Edition ''SB5''), Cardiac function, Endocrine function (Thyroid functions, Growth curves), Pulmonary function (pulmonary function test), Lipid profile (triglyceride, cholesterol, HDL, LDL) and Quality of life assessment (PedsQL). Results: A total of 345 patients were diagnosed of having mature B cell lymphoma during the study period. 213 were evaluable with a male: female ratio 4:1. Staging: stage I (7.5%), II (14.1%), III (58.7%), IV (19.7%). patients < 5 years of age tend to have more affection than those > 5 years. The total mean QoL score 99 ± 0.058, the order of the affected domains, according to severity: physical functioning 92 ± 0.1, emotional functioning 92 ± 0.15, followed by social functioning 97 ± 0.08, school functioning 99 ± 0.06. IQ scores (low average 24.4%, high average 10.3%, average 63.8%). Pulmonary functions test was evaluated in 123 patients with affection detected in (57.7%) as follows: (mild degree 34.2%, moderate 14%, severe 9.3%). Cardiac reported with early onset 22% (from which 63% resolved, 36% persistent), late-onset 10.3%. Lipid profile was significantly affected, showing dyslipidemia 61.9% (high triglycerides 21.6%, low HDL 16%, high LDL 8.9%, and high total cholesterol 41.8%) while Growth affection: regarding weight (25.4% dropped 2 or more centiles, height (33.3% dropped 2 or more centiles). Conclusion: long term NHL survivors, pulmonary and cardiac functions should be followed up for possible affection. Lipid profiles and weight affection should be monitored closely. A survivorship program for NHL in children is recommended. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Humanized Nanobody Anti-CD72 CAR-T Cells Efficiently Eliminate B-Cell Malignancies Via Improved Affinity for CD72 but Induce Persistent Antigen Downregulation In Vivo

Background: Approximately 50% of pediatric B-cell acute lymphoblastic leukemia (B-ALL) and non-Hodgkin lymphoma patients treated with CD19 chimeric antigen receptor (CAR)-T cells relapse. CD22 CAR-T cells are curative only rarely. New immunotherapeutic targets are urgently needed. Our laboratory recently identified CD72 as a target on B-cell malignancies and developed a fully synthetic nanobody against CD72 (NbD4), demonstrating that NbD4 CAR-T cells (nanoCARs) are potent in vitro and in vivo (Nix et al., Cancer Discovery (2021)). We previously described the development of a humanized version of this nanobody binder (H24) that had improved efficacy in preliminary studies (Nix et al., ASH 2021). As we move CD72 nanoCARs toward clinical translation, in this follow-up study we aimed to compare H24 vs. NbD4 by 1) tumor clearance kinetics; 2) T-cell immunophenotypes; 3) in vivo mechanism of relapse; and 4) binding affinity to CD72. Methods: CD4/CD8 CAR-T cells were generated by lentiviral transduction. Single time point (24 hr) in vitro cytotoxicity was assessed across a range of effector:tumor (E:T) ratios. CAR-T elimination kinetics was determined by IncuCyte live cell imaging. CD45RA and CD62L flow cytometry was used to assess T-cell immunophenotypes. In vivo studies were performed by implanting 5e5 luciferase-labeled Jeko cells into NSG mice on Day -4, and administration of 3e6 CAR-T cells on Day 0. At sacrifice, flow cytometry was performed to evaluate CD72 expression on relapsed tumors. Relapsed Jeko was re-implanted into naïve NSG mice for 31 days. Binding affinity of recombinant NbD4 or H24 to biotinylated CD72 extracellular domain was determined by bio-layer interferometry. Results: In single time point assays, H24 nanoCARs eliminated SEM B-ALL cells with similar efficacy to CD19 CAR-Ts (not significant) and were more potent than NbD4 nanoCARs at a 1:10 E:T ratio (72% vs 44% cytotoxicity; p = 3e-4). Against a Jeko mantle cell lymphoma model, at a 1:1 E:T ratio, H24 nanoCARs were more potent than both CD19 CAR-Ts (96% vs 87%; p < 1e-4) and NbD4 nanoCARs (96% vs 70%; p < 1e-4). In live cell imaging assays, H24 nanoCARs eliminated SEM faster than CD19 CAR-Ts (Fig. 1a). After SEM co-culture, H24 nanoCARs secreted more IL-2 and IFNγ compared to NbD4 (IL-2 p < 1e-4; IFNγ p = 4e-4) and CD19 CAR-Ts (IL-2 p = 4e-4; IFNγ p = 3e-4). Versus SEM, both pre- and post-tumor proportions of naïve T cells (CD45RA+/CD62L+) were similar for H24, NbD4, and CD19 CAR-Ts. Bulk RNA-seq after exposure to SEM revealed that H24 nanoCARs upregulate genes relevant to T cell activation and effector T cell function, compared to CD19 CAR-Ts. In in vivo Jeko studies, we treated mice with NbD4 or H24 nanoCARs and extracted tumors after relapse. We found that both nanoCARs led to CD72 loss on tumors (Fig. 1b). Surprisingly, however, upon re-implantation into a new cohort of NSG mice, H24 relapse Jeko continued to maintain low CD72 expression, while re-implanted NbD4 relapse Jeko had restoration of CD72 in the absence of anti-CD72 immune pressure (H24 vs NbD4 CD72 expression p = 4e-2). Given more potent anti-tumor efficacy and more persistent CD72 suppression in murine models, we hypothesized that H24 has a higher binding affinity for CD72. Indeed, H24 demonstrated a dissociation constant (KD) versus CD72 of 33.0 ± 0.04 nM, while NbD4 was 50.4 ± 0.05 nM. These results support the notion that relatively low-affinity binders can still generate potent CAR-Ts, when compared to published values of KD <1 nM for the anti-CD19 scFv FMC63. Conclusions: We have developed a new, humanized anti-CD72 cellular therapy known as H24 nanoCARs. Humanizing the framework regions, while keeping the complementary determining regions (CDRs) identical to NbD4, was intended to reduce immunogenicity. We were surprised that eight amino acid substitutions in the framework regions, with no changes to CDRs, improved antitumor efficacy and binding affinity for CD72. These improved characteristics motivate our planned clinical translation of H24-based nanoCARs. We also found that CD72 downregulation occurs after CD72 nanoCAR treatment in mice, and that increased potency of H24 correlates with longer-term CD72 suppression on tumors. These findings will inform expected outcomes in future clinical trials and motivate further studies to prevent CD72 downregulation after nanoCAR treatment. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Efficacy and safety of copanlisib in relapsed/refractory B-cell non-Hodgkin lymphoma: A meta-analysis of prospective clinical trials.

Copanlisib is an intravenously administered pan-class I PI3K inhibitor that has been demonstrated to have appreciable effects in the treatment of patients with lymphoma. The purpose of this meta-analysis was to evaluate the efficacy and safety of copanlisib for treating patients with relapsed/refractory (R/R) B-cell non-Hodgkin lymphoma (B-NHL). PubMed, Web of Science, EMBASE, and the Cochrane Central Register of Controlled Trials were searched for relevant studies published prior to July 2022. The efficacy evaluation included complete response rate (CR), partial response rate (PR), rate of stable disease (SDR), overall response rate (ORR), disease control rate (DCR), rate of progressive disease (PDR), median progression-free survival (PFS), and median overall survival (OS). Any grade adverse events (AEs) and grade ≥3 AEs were synthesized to assess its safety. Eight studies with a total of 652 patients with R/R B-NHL were identified. The pooled CR, PR, ORR, SDR, DCR, and PDR from all 8 articles were 13%, 40%, 57%, 19%, 86%, and 9%, respectively. The CR and ORR of combination therapy with rituximab were higher than those with copanlisib monotherapy for R/R B-NHL (34% vs. 6%, p<0.01; 89% vs. 42%, p<0.01). For patients with R/R indolent B-NHL, CR and ORR were lower with copanlisib monotherapy than with combination therapy with rituximab (7% vs. 34%, p<0.01; 58% vs. 92%, p<0.01). In R/R B-NHL patients receiving copanlisib monotherapy and combination therapy with rituximab, the risk of any grade AEs was 99% and 96%, respectively, and the risk of grade ≥3 AEs was 84% and 91%, respectively. The common any grade AEs included hyperglycemia (66.75%), hypertension (48.57%), diarrhea (35.06%), nausea (34.98%) and fatigue (30.33%). The common grade ≥3 AEs included hyperglycemia (45.14%), hypertension (35.07%), and neutropenia (14.75%). The comparison of AEs between the copanlisib monotherapy and the combination therapy with rituximab showed that hyperglycemia of any grade (p<0.0001), hypertension of any grade (p=0.0368), fatigue of any grade (p<0.0001), grade ≥3 hypertension (p<0.0001) and grade ≥3 hyperglycemia (p=0.0074) were significantly different between the two groups. Our meta-analysis demonstrated that the efficacy of both copanlisib monotherapy and combination therapy with rituximab in patients with R/R B-NHL was satisfactory, while treatment-related AEs were tolerable. Compared with copanlisib monotherapy, combination therapy with rituximab showed superior efficacy for treating R/R B-NHL, and its safety was manageable. https://inplasy.com/inplasy-2022-10-0008/, identifier INPLASY2022100008.

Pre-clinical efficacy of CD20-targeted chimeric antigen receptor T cells for non-Hodgkin's lymphoma

BackgroundA 4-1BB/CD3-ζ-costimulated CAR-T against CD20 (CAR-T20) was subjected to a systemic efficacy evaluation in a cell co-culture model, and NOD-SCID IL-2 receptor gamma null mice (short for NSG mice) were xenografted with human Burkitt's lymphoma Raji cells.MethodsCAR-T20 cells were incubated with target cells (K562, K562 CD20 or Raji cells) at ratios of 10:1 and 5:1 for 24 h, and the killing rate was estimated by an LDH cytotoxicity assay. To evaluate the effect of CAR-T20 on the survival time of tumor-bearing animals, 30 NSG mice were employed, and Raji-Luc cells (5 × 105 cells per mouse) were administered prior to CAR-T20 administration. The survival time, optical intensity of Raji-Luc cells, clinical symptoms, and body mass of the animals were observed. Another 144 male NSG mice were employed to investigate the proliferation and antitumor effects of CAR-T20. Human cytokine and murine cytokines were detected at 1, 7, 14, 21, 28, 42, 56 and 90 days post-CAR-T administration, while biochemistry index analysis, T-cell and CAR-T-cell detection in peripheral blood, and histopathological examination were performed at 14, 28, 56 and 90 days post-administration.ResultsCAR-T20 cells had a specific killing effect on CD20-expressing cells in vitro. At a dose of 1 × 106 per mouse or above, CAR-T20 prolonged the median survival time from 14 days to more than 3 months, inhibited the proliferation of Raji cells in mice, and alleviated the clinical manifestations and weight loss caused by the Raji-Luc cell load. CAR-T20 at a dose of 2 × 106 per mouse or above inhibited the proliferation of Raji cells in mice for up to 111 days post-administration without recurrence. The numbers of T cells and CAR-T cells in the animals administered CAR-T20 increased significantly when Raji cells were markedly proliferated and subsequently decreased when Raji cells were predominantly inhibited. CAR-T20 increased human IFN-γ, murine TNF and murine IL-6 levels and decreased human IL-10 levels in tumor-bearing mice. The incidences of xenografted tumors in organs/tissues were also reduced effectively by CAR-T20.ConclusionThe effective dose of CAR-T20 in mice starts from 1 × 106 per mouse, equivalent to a clinical dose of 5 × 106/kg. Together, our data support the clinical translation of CAR-T20 for R/R B-cell NHL patients.

Role of high acquisition flow cytometry in the detection of marrow involvement in patients with extramedullary B cell non-Hodgkins lymphoma: a comparison with marrow aspirate cytology, trephine biopsy, and PET

Detection of marrow infiltration is crucial in extramedullary B cell non-Hodgkin lymphoma (B-NHL). We studied the efficiency of high acquisition flow cytometry (FCM) in detecting marrow involvement in B-NHL patients and compared its performance with marrow aspiration (BMA) cytology, marrow biopsy (BMB), and positron emission tomography (PET). No case with marrow infiltration was found to be BMB positive and FCM negative. BMA cytology showed poor sensitivity and specificity. Only 50% of FCM positive cases showed evidence of marrow involvement by PET. Neither the nature of lymphoma nor the burden of the marrow disease showed a correlation with PET positivity. Four cases that were positive only by PET had findings in areas other than the iliac region. We found more cogent and convincing results with high event acquisition in FCM. This study shows that a combination of PET and FCM with high event acquisition is the best way for assessing marrow involvement in B-NHL cases.

P684: PHASE 1 STUDY OF LP-108, A SELECTIVE BCL-2 INHIBITOR, IN PATIENTS WITH RELAPSED OR REFRACTORY B-CELL NON-HODGKIN LYMPHOMA

Background: Targeting BCL-2 family proteins is a well-recognized therapeutic approach. Globally approved BCL-2 inhibitor venetoclax has shown efficacies in certain hematologic malignancies (HMs) but requires weekly ramp-up to the target dose to mitigate the risk of tumor lysis syndrome (TLS). LP-108 is a novel, highly potent, orally bioavailable, and selective BCL-2 inhibitor that has shown promising preclinical antitumor activity in various HMs. Aims: To present preliminary results from an ongoing phase 1 study of LP-108 under daily dose ramp-up in patients with relapsed or refractory (r/r) B-cell non-Hodgkin lymphoma (NHL) (NCT04356846). Methods: This is an open-label, multicenter, phase I study to assess the safety, pharmacokinetics (PK) and preliminary efficacy of LP-108 in Chinese patients with r/r B-cell NHL, consisting of a dose-escalation phase and a dose-expansion phase. Adult r/r B-cell NHL patients requiring therapy are eligible if they had received at least one prior line of treatment (except BCL-2i). LP-108 is orally administered once daily in 28-day cycles until disease progression, unacceptable toxicity, or per investigator discretion. All patients provided and signed informed consent. Results: As of February 18, 2022, 19 patients have been enrolled and were evaluable for safety, with disease types of MCL (n = 7), CLL/SLL (n = 7), DLBCL (n = 2), FL, WM, and MALT (n = 1 each), and median age of 61 years (range, 39 to 83). Patients had received a median of 3 prior lines of therapy (range, 1~6), of which 13 (68%) patients were previously BTKi exposed. No dose-limiting toxicity (DLT) has been observed in patients who were treated with LP-108 up to 600 mg, thus the maximum tolerated dose (MTD) was not identified. With median duration of treatment of 55 days (range, 4~472), treatment-related adverse events (TRAEs) were reported in 17 patients (89.4%), most of which were grade 1 to 2 in severity. TRAEs of any grade occurred ≥20% of patients were neutropenia (36.8%), leukopenia (31.5%), ALT elevation (31.5%), AST elevation (26.3%), hyperphosphatemia (21%), hyperuricemia (21%), and diarrhea (21%). Grade 3 or 4 TRAEs were reported in 7 patients (36.8%), including neutropenia, thrombocytopenia, lymphopenia, laboratory TLS, and rash. Serious TRAEs included rash, thrombocytopenia, and laboratory TLS, each occurring in 1 patient. No patient discontinued treatment due to toxicity, and no clinical TLS was observed. No deaths occurred during treatment or within 28 days of the end of treatment. At doses ≥200 mg, 3 of 10 efficacy evaluable patients achieved an objective response (1 CR and 2 PR), 4 patients had stable disease (2 with substantially reduced lymphomegaly), and 3 patients had progressive disease. Rapid reduction in ALC was observed in CLL patients (pending imaging assessment) during ramp-up and the first cycle of treatment at doses as low as 20mg. At data cutoff, 11 patients remain on treatment and 8 patients discontinued treatment due to disease progression or patient decision. The PK profile showed that plasma exposure proportionally increased with doses ranging from 20 to 600 mg (mean AUC24h range, 1.26~46.5 h*μg/ml, mean Cmax range, 0.087~2.67 μg/ml). Plasma concentrations peaked approximately 4 to 10 hours after dosing, and the average terminal half-life of LP-108 was approximately 11.8 hours (range, 6.9~16.6). Image:Summary/Conclusion: LP-108 showed favorable safety profile up to 600 mg with daily dose ramp-up schedule, and antitumor activity in patients with r/r B-cell NHL. Dose escalation beyond 600 mg and further dose expansion are ongoing.

CD20-specific chimeric antigen receptor-expressing T cells as salvage therapy in rituximab-refractory/relapsed B-cell non-Hodgkin lymphoma

Background aimsThe infusion of chimeric antigen receptor (CAR) T cells that target specific tumor-associated antigens is a promising strategy that has exhibited encouraging results in clinical trials. However, few studies have focused on the effectiveness and safety of CD20 CAR T cells in rituximab-refractory/relapsed (R/R) B-cell non-Hodgkin lymphoma (B-NHL) patients, particularly those treated with rituximab for a short time. This prospective study aimed to assess the effectiveness and toxicity of CD20 CAR T cells in R/R B-NHL patients previously treated with rituximab. MethodsThe authors conducted a prospective, single-center phase I study on the effectiveness and toxicity of CD20 CAR T cells in rituximab-treated R/R B-NHL patients (no. ChiCTR2000036350). A total of 15 patients with R/R B-NHL were enrolled between November 21, 2017, and December 1, 2021. ResultsAn overall response rate of 100% was shown in enrolled patients, with 12 (80%) achieving complete remission and three (20%) achieving partial remission for the best response. The median follow-up time was 12.4 months. Progression-free survival and overall survival were not yet reached by the data cutoff day. No patient developed grade 4 cytokine release syndrome, and only one patient had immune effector cell-associated neurotoxicity syndrome. ConclusionsAll enrolled B-NHL patients who were previously R/R to rituximab achieved different degrees of clinical response with tolerable toxicities. Notably, patients who had received rituximab within 3 months had a poorer prognosis.

Impact of CD19 CAR T-cell product type on outcomes in relapsed or refractory aggressive B-NHL

AbstractCD19-targeted chimeric antigen receptor-engineered (CD19 CAR) T cells are novel therapies showing great promise for patients with relapsed or refractory (R/R) aggressive B-cell non-Hodgkin lymphoma (B-NHL). Single-arm studies showed significant variations in outcomes across distinct CD19 CAR T-cell products. To estimate the independent impact of the CAR T-cell product type on outcomes, we retrospectively analyzed data from 129 patients with R/R aggressive B-NHL treated with cyclophosphamide and fludarabine lymphodepletion followed by either a commercially available CD19 CAR T-cell therapy (axicabtagene ciloleucel [axicel] or tisagenlecleucel [tisacel]), or the investigational product JCAR014 on a phase 1/2 clinical trial (NCT01865617). After adjustment for age, hematopoietic cell transplantation-specific comorbidity index, lactate dehydrogenase (LDH), largest lesion diameter, and absolute lymphocyte count (ALC), CAR T-cell product type remained associated with outcomes in multivariable models. JCAR014 was independently associated with lower cytokine release syndrome (CRS) severity compared with axicel (adjusted odds ratio [aOR], 0.19; 95% confidence interval [CI]; 0.08-0.46), with a trend toward lower CRS severity with tisacel compared with axicel (aOR, 0.47; 95% CI, 0.21-1.06; P = .07). Tisacel (aOR, 0.17; 95% CI, 0.06-0.48) and JCAR014 (aOR, 0.17; 95% CI, 0.06-0.47) were both associated with lower immune effector cell-associated neurotoxicity syndrome severity compared with axicel. Lower odds of complete response (CR) were predicted with tisacel and JCAR014 compared with axicel. Although sensitivity analyses using either positron emission tomography- or computed tomography-based response criteria also suggested higher efficacy of axicel over JCAR014, the impact of tisacel vs axicel became undetermined. Higher preleukapheresis LDH, largest lesion diameter, and lower ALC were independently associated with lower odds of CR. We conclude that CD19 CAR T-cell product type independently impacts toxicity and efficacy in R/R aggressive B-NHL patients.

Elevated circulating myeloid-derived suppressor cells associated with poor prognosis in B-cell non-Hodgkin's lymphoma patients.

IntroductionMyeloid‐derived suppressor cells (MDSCs) are a heterogeneous cell population with the ability to suppress immune responses. MDSCs usually cluster in cancer, inflammation, and autoimmune diseases. Although there have been some studies on MDSCs in non‐Hodgkin lymphoma (NHL), the correlation between the peripheral levels of MDSCs in patients with various subtypes of B cell NHL and clinical features and prognosis remains inconclusive. This study aimed at the issue.Methods101 patients with B cell NHL and 15 age‐matched healthy controls were included in this study. Flow cytometric detection of monocytic‐MDSCs (M‐MDSCs) and granulocytic‐MDSCs (G‐MDSCs) was done.ResultsIn this study, we found that counts of circulating M‐MDSCs and G‐MDSCs were significantly increased in different clinical statuses of B‐NHL patients compared to healthy controls. Similarly, a significant increase in the levels of M‐MDSCs and G‐MDSCs was found among the diverse types of B‐NHL compared with healthy donors. Stratification studies indicated MDSCs expansion was closely associated with disease progression (tumor stage, LDH levels and B syndromes). Moreover, the overall survival time of patients with G‐MDSCs (%) ≥ 98.70% was shorter than patients with G‐MDSCs (%) < 98.70% in newly diagnosed B‐NHL subgroup, meanwhile, there was a significant difference in survival of patients with M‐MDSCs (%) ≥ 7.19% compared to patients with M‐MDSCs (%) < 7.19% in relapsed B‐NHL subgroup.ConclusionOur results suggested that M‐MDSCs and G‐MDSCs may be a potential and efficient index to evaluate the prognosis of B‐NHL patients.

Cachexia is a risk factor for negative clinical and functional outcomes in patients receiving chimeric antigen receptor T-cell therapy for B-cell non-Hodgkin lymphoma.

Cachexia is a muscle-wasting syndrome that is known to impact the clinical course of several cancer populations but has not been specifically investigated in patients receiving chimeric antigen receptor T (CAR-T) cell therapy. In this study, we investigated the relationship between cachexia markers and several cancer and functional outcomes in a pilot population of aggressive B-cell non-Hodgkin lymphoma patients receiving CAR-T. We found that the prognostic nutritional index was linked to progression-free survival, overall survival, and disability-free survival, while several additional weight and serum-based markers of cachexia were also associated with negative outcomes. These data prompt further investigation of cachexia markers in populations receiving CAR-T cell therapy.

BNT162b2 mRNA COVID-19 vaccine booster induces seroconversion in patients with B-cell non-Hodgkin lymphoma who failed to respond to two prior vaccine doses.

This prospective study evaluated seroconversion rates in response to BNT162b2 (Pfizer-BioNTech) COVID-19 vaccine booster in 44 B-cell non-Hodgkin lymphoma (B-NHL) patients who failed to respond to two prior doses [42 previously exposed to anti-CD20monoclonal antibodies (moAbs) including 13 under maintenance treatment]. Seroconversion was obtained in 29.5% of the patients. Longer time from last anti-CD20moAb (>6months) and diagnosis of aggressive lymphoma compared to other, incurable B-NHLs were associated with increased seroconversion rates (47.8% vs.10.5%, p=0.019 and 50% vs. 17.9%, p=0.025 respectively). Thus, seronegative patients with B-NHL that completed anti-CD20 therapy more than 6months prior to the booster have greater chances to achieve seroconversion.

Genetic variations in tumor necrosis factor related apoptosis-inducing ligand receptor-1 (TRAIL-R1) gene and the susceptibility to b-cell non-hodgkin lymphoma (B-NHL) in Egypt1

BACKGROUND: Dysregulated apoptosis is a hallmark of cancer development and progression. TRAIL and its receptors (R1 and R2) are key players in the extrinsic apoptotic pathway. Genetic alteration or blockade of TRAIL-R1 may alter its apoptotic function, and subsequently provide growth advantage to neoplastic cells. OBJECTIVE: to investigate the possible association between -C626G, -A683C and -A1322G single nucleotide polymorphisms (SNPs) of TRAIL-R1 gene and the susceptibility to B-NHL in a cohort of Egyptians. METHODS: Genotypic analysis was performed for 100 newly diagnosed B-NHL patients and 150 age and gender matched healthy controls. RESULTS: The polymorphic alleles of -C626G and -A1322G conferred almost twofold increased risk of B-NHL (OR = 1.76; 95%CI = 1.01–3.22 and OR = 1.89; 95%CI = 1.01–3.75 respectively). There was no statistical difference in the distribution of TRAIL-R1-A683C alleles/genotypes between B-NHL patients and controls. B-NHL risk increased when -C626G and -A1322G polymorphic genotypes were co-inherited (OR = 3.57; 95%CI = 1.29–9.84). The risk conferred by -C626G SNP increased for DLBCL (OR = 3.39, 95% CI: 1.61–7.16). CONCLUSION: TRAIL-R1–C626G and -A1322G polymorphisms could be considered as molecular risk factors for B-NHL especially DLBCL. The data provided by the current study constitute an initial millstone towards developing a large-scale dataset for genetic variations that could contribute to lymphomagenesis in Egyptian population.