NHL Patients Research Articles

Gene expression profiling in B-cell non-Hodgkin lymphomas

Abstract BACKGROUND: Gene expression profiling has become a fundamental tool in cancer diagnosis and management. B-cell non-Hodgkin lymphoma (B-NHL) is a group of malignant neoplasms originating from the lymphoid tissues, mainly the lymph nodes and the gene expression technique was used to unravel its complexity and aid in clinical decision-making. OBJECTIVES: The aims of this study were to find the significance of gene expression profiling focusing on colony-stimulating factor 1 receptor (CSF1R), myeloid differentiation factor 88 (MyD88), and tumor necrosis factor-α (TNF-α) as a promising approach in B-NHL diagnosis and their comparison with healthy controls. PATIENTS, MATERIALS AND METHODS: The current clinical prospective study was mediated from June 1, 2021, to December 30, 2022, of NHL patients in Kurdistan, Iraq. Seventy-three patients were recruited from Nanakali Hospital for Blood Diseases and Cancer, Erbil. The integration of gene expression biomarkers uses quantitative real-time polymerase chain reaction technique to diagnose B-NHL. Specifically, we focused on three key genes MyD88, TNF, and CSF1R whose expression profiles were analyzed in B-NHL patients and controls. We leveraged a dataset to explore gene expression patterns in B-NHL and applied classification algorithms to distinguish between B-NHL patients and controls. RESULTS: The initial results show the overall lower CSF1R expression in B-NHL as compared to the controls and a significant reduction in CSF1R expression in females (≤50 years and >50 years). The result considers lower CSF1R expression in B-NHL males (≤50 years) and higher but not significant in males (>50 years). CONCLUSIONS: These B-NHL-expressed genes may be considered potential diagnostic markers with their meaningful comparisons to control groups, and they could be proposed to guide the management of patients and facilitate their stratification into clinical trials.

Effect of Coenzym Q10 on Doxorubicin-induced Cardiotoxicity in Non Hodgkin's Lymphoma Patients

BACKGROUND : Non-Hodgkin's Lymphoma is a primary malignancy in the Lymph Nodes and lymphoid tissue originating from B lymphocytes, T lymphocytes and Natural Killer (NK) cells. Therapy for Non-Hodgkin's Lymphoma chemotherapy can be given alone or combined with radioactive therapy. Doxorubicin is a chemotherapy drug used for lymphoma with side effects, one of which is cardiotoxic effects. AIMS : To prove that coenzyme Q10 can reduce the cardiotoxic effect of doxorubicin chemotherapy in non-Hodgkin's lymphoma patients METHOD : Intervention study with a randomized pre and post test double blind control group design with 34 NHL patients undergoing chemotherapy. The treatment group received additional therapy with coenzyme Q10 300mg/day for 12 weeks while the controls received placebo. The cardiotoxic effects examined were assessed based on the results of Electrocardiography and Echocardiography. RESULT : The treatment group with coenzyme Q10 supplementation after the 4th chemotherapy showed a decrease in echocardiography results in 3 patients (18%) and in the control group 17 patients (100%). There was a significant difference in the echocardiography results of the treatment and control groups (p=0.001). There were no drug side effects in both groups CONCLUSION : Coenzyme Q10 supplementation provides an improvement in the cardiotoxic effects of doxorubicin in non-Hodgkin's lymphoma patients, on echocardiography, but not on Electrocardiography.

Predictive Factors for Early Immune Recovery in NHL Patients after Autologous Transplantation: A Multicenter Prospective Study.

Early lymphocyte recovery as manifested by an absolute lymphocyte count at d+15 (ALC-15) ≥ 0.5 × 109/L after autologous hematopoietic stem cell transplantation (AHCT) has been associated with a better outcome. This prospective multicenter study aimed to clarify factors associated with ALC-15 ≥ 0.5 × 109/L after AHCT among 178 patients with non-Hodgkin lymphoma. The mobilization capacity, as manifested by peak blood CD34+ cell numbers > 45 × 106/L correlated with higher ALC-15 levels (p = 0.020). In addition, the amount of CD3+CD4+ T cells > 31.8 × 106/kg in the infused graft predicted ALC-15 ≥ 0.5 × 109/L (p < 0.001). Also, the number of infused graft CD3+CD8+ T cells > 28.8 × 106/kg (p = 0.017) and NK cells > 4.4 × 106/kg was linked with higher ALC-15 (p < 0.001). The two-year progression-free survival after AHCT was significantly better in patients with ALC-15 ≥ 0.5 × 109/L (74 vs. 57%, p = 0.027). The five-year OS in patients with higher ALC-15 was 78% vs. 60% in those with lower ALC-15 (p = 0.136). To conclude, the mobilization capacity of CD34+ cells and detailed measures of graft cellular content mark prognostic tools that predict ALC-15 ≥ 0.5 × 109/L, which is associated with a better outcome in NHL patients after AHCT.

Expression of mGluR5 in Pediatric Hodgkin and Non-Hodgkin lymphoma-A Comparative Analysis of Immunohistochemical and Clinical Findings Regarding the Association between Tumor and Paraneoplastic Neurological Disease.

Autoantibodies targeting the neuronal antigen metabotropic glutamate receptor 5 (mGluR5) have been identified in patients with Ophelia syndrome, which describes a co-occurrence of paraneoplastic limbic encephalitis and Hodgkin lymphoma (HL). Little data exist regarding frequency and function of mGluR5 in HL and its potential role in causing seropositive paraneoplastic disease. We studied a representative cohort of pediatric HL and NHL patients (n = 57) using immunohistochemistry and fluorescence staining to investigate mGluR5 expression. All lymphoma tissues displayed positive mGluR5 staining, with focus on Hodgkin-Reed-Sternberg (H-RS) cells. We did not detect any mGluR5 staining in tumor-free lymph nodes, which is consistent with the absence of GRM5 transcripts in RNA-sequencing data from non-malignant B and T cells. The frequent presence in pediatric lymphoma falls in line with reports of mGluR5 expression and associated tumor progression in other malignancies. We tested for correlation with clinical features, focusing on disease progression and neurological symptoms. Low mGluR5 expression in H-RS cells correlated with young patient age (<15 years) and positive histology for EBV infection. Paraneoplastic or neurological symptoms were found exclusively in HL patients. While an impact of mGluR5 on HL severity remains possible, a prognostic value of mGluR5 expression levels requires further investigation.

Emavusertib (CA-4948) in combination with ibrutinib in patients with relapsed/refractory primary central nervous system lymphoma (R/R PCNSL).

2087 Background: PCNSL is a rare and aggressive form of NHL in the central nervous system or vitreoretinal space. Despite high initial rates of responses to HD-MTX-based induction chemotherapies, most patients relapse in two years. R/R PCNSL is associated with poor prognosis, representing a clear unmet medical need, as there are no currently approved treatments for this disease. IRAK4 kinase activity is required for TLR and IL-1R signaling in a variety of myeloid and lymphoid cell types, including PCNSL. Recruitment of IRAK4 to these receptors and subsequent activation is facilitated by the MyD88 adaptor protein, which is mutated in ~70% of PCNSL. This leads to constitutive activation of the NF-κB signaling pathway, increased inflammation, and tumor growth. Emavusertib is a novel and potent oral inhibitor of IRAK4 and FLT3, which has demonstrated the ability to cross the blood-brain barrier in PCNSL xenografts. In preclinical studies, the combination of emavusertib with ibrutinib overcomes resistance to BTK inhibitors. This combination has an acceptable safety profile across a broad population of R/R NHL patients, including PCNSL. Here we present updated safety and efficacy data for emavusertib in combination with ibrutinib in patients with R/R PCNSL. Methods: The safety, clinical activity, and potential biomarkers of emavusertib in R/R PCNSL are being investigated in the ongoing open-label, Phase 1/2 TakeAim Lymphoma trial (NCT03328078). The eligible patients with R/R PCNSL received emavusertib (100-300 mg BID) in combination with ibrutinib (560 mg QD) in a 21-day cycle until tumor progression or unacceptable toxicity. Results: Here, we present updated data from R/R PCNSL patients with prior ibrutinib exposure who were treated with emavusertib in combination with ibrutinib. The median number of prior lines of anti-cancer therapies was 3 (range: 2-5), all patients were R/R to both frontline therapy and subsequent ibrutinib regimens. Prior responses to ibrutinib based regimens included only 1 CR. Here, we report a higher CR rate when these patients are subsequently treated with emavusertib in combination with ibrutinib.Results revealed no dose-limiting toxicities. Conclusions: Emavusertib in combination with ibrutinib was well tolerated with an acceptable safety profile and promising efficacy in R/R PCNSL patients with previous exposure to ibrutinib (BTKi). Enrollment in this trial is ongoing (NCT03328078). Clinical trial information: NCT03328078 .

Incidence of any infections and SARS-CoV-2 infections in patients receiving treatment for follicular lymphoma and diffuse large B-cell lymphoma: Real-world evidence from a large US national claims database.

e19061 Background: Non-Hodgkin’s lymphoma is a heterogeneous group of conditions, including the indolent subtype follicular lymphoma (FL) and the aggressive subtype diffuse large B-cell lymphoma (DLBCL). Infections associated with NHL are a major concern due to effects of the underlying disease and its treatment and have been reported to increase with increasing lines of therapy (LoT). However, the risk of infections overall and SARS-COV-2 infections specifically is not well characterized in patients who have received multiple LoTs. The goal of the study was to estimate the exposure-adjusted incidence rates (EAIR) of infections during the COVID-19 pandemic by type, severity and LoT received in patients treated for FL or DLBCL in the real-world setting. Methods: We identified patients in the Optum Clinformatics claims data from October 1, 2015, to June 30, 2023. Patients were aged ≥18 years, enrolled continuously for 365 days before index (start of LoT), and had ≥2 ICD-10 diagnosis codes for FL or DLBCL in the 365 days before index. The EAIR (per 100 person-years, PY) was estimated for infections by type (any infections and SARS-COV-2 [after 1/1/2020]), severity (hospitalized or fatal hospitalizations), and number of LoTs received. Results: A total of 4,799, 1,025 and 510 FL patients were included in the 1L (1 LoT), 2L, and 3L+ cohorts, respectively. The EAIR of infections resulting in hospitalization in 1L, 2L, and 3L+ cohorts were 20.6 (95% confidence interval (CI): 19.0-22.3), 30.2 (25.5-35.9), and 44.2 (35.4-55.3) per 100-PY for any infection; and 4.6 (4.0-5.4), 4.4 (3.0-6.5) and 8.3 (5.3-13.2) per 100-PY for SARS-COV-2 infections, respectively. The EAIR of fatal hospitalizations were 4.0 (3.4-4.8), 8.6 (6.4-11.5), and 13.9 (9.7-20.0) per 100-PY for any infection; and 1.3 (1.0-1.7), 1.6 (0.8-3.0), and 4.1 (2.2-7.9) per 100-PY for SARS-COV-2 infections. A total of 8,058, 2,114 and 977 DLBCL patients were included in 1L, 2L, and 3L+ cohorts, respectively. The EAIR of infections resulting in hospitalization in 1L, 2L, and 3L+ cohorts were 64.2 (60.7-67.8), 85.2 (76.9-94.3), and 113.4 (98.4-130.7) per 100-PY for any infection; and 6.3 (5.5-7.2), 7.3 (5.6-9.6), and 15.1 (11.3-20.2) per 100-PY for SARS-COV-2 infections respectively. The EAIR of fatal hospitalizations were 12.0 (10.8-13.3), 23.0 (19.5-27.1), and 27.8 (22.1-34.9) per 100-PY for any infection; and 1.6 (1.2-2.1), 2.7 (1.7-4.2), and 4.8 (2.9-8.0) per 100-PY for SARS-COV-2 infections in 1L, 2L and 3L+ cohorts, respectively. Conclusions: This real-world analysis demonstrated substantial morbidity and mortality associated with overall and SARS-COV-2 infections among NHL patients, with a higher incidence in DLBCL compared to FL, and with increasing LoTs.

Abstract CT244: HR001, a novel CD19-targeted CAR-T cell therapy for patients with relapsed/refractory non-Hodgkin's lymphoma: primary results of a phase II study (HRAIN01-NHL01-II)

Abstract Background: HR001 is a CD19-targeted CAR-T cell for patients with relapsed and refractory non-Hodgkin's (R/R NHL). Here, we report the primary results of the phase 2 study (HRAIN01-NHL01-II). Methods: HRAIN01-NHL01-II is an open-label, single-arm, and multicenter (17 centers) study in China. It enrolled R/R NHL patients treated with at least two lines of therapy (must-have anthracycline and CD20-targeted agents) or after autologous hematopoietic stem cell transplantation. All patients received a single infusion of HR001 at the 2.0 × 106 CAR+T cells/kg dose. The disease response was evaluated by the independent review committee with Lugano response criteria [2014]. Results: As of May 16th, 2023, 81 R/R NHL patients with ECOG 0-1 at baseline received the infusion HR001 from the Jinshan manufacturing facility [51.9% male; median age 53.4 years (range 23~74); 3.7% CD19 negative; 91.4% diffuse large B-cell lymphoma; 79.0% III-IV of Ann Arbor classification or Lugano] with a median follow-up of 160 days (range 7 to 454). The median time to best response was 30 days (range 28-358). The 3-month, 6 month and best objective response rate (ORR) was 53.1%(95% CI: 41.7-64.3), 45.7%(95% CI: 34.6-57.1) and 74.1% (95% CI: 63.1-83.2) respectively. The 3-month, 6 month and best complete response rate (CRR) was 32.1%(95% CI: 22.2-43.4), 29.6%(95% CI: 20.0-40.8) and 49.4%(95% CI: 38.1-60.7) respectively. Median duration of response (DOR) and progression-free survival (PFS) were 339 days (95% CI: 149-NE) and 176 days (95% CI: 91-NE) respectively. The overall survival (OS) was not reached. The most common treatment-related adverse events (AEs) happened in the hematologic system. The cytokine release syndrome (CRS) occurred in 95.1% of patients, with ≥3 grade CRS observed in 3.7% of patients. Immune effector cell-associated neurotoxicity syndrome (ICANS) happened in 8.6% of patients, without any ≥ 3 grade ICANS reported. The treatment-related mortality was 1.2%. The median time to CAR T-cell peak expansion was 240 hours (120~672) after infusion, median maximum expansion (Cmax) was 17413.9 copies/μg DNA (124.9~136382.2), and median AUC0-28d was 3201014.0 copies/μg DNA (205082.8~18400016.2). Positive tests for the anti-drug antibody (ADA) were noted in 14.8% of patients, while neutralizing antibody (Nab) tests were positive in 3.7% of patients. Among Nab-positive patients, the complete response was maintained until follow-up. Conclusions: Patients with R/R NHL could benefit from the HR001 treatment with satisfactory objective response, durable remission, and favorable safety profile. Citation Format: Yian Zhang, Yuhua Li, Kai Hu, Wuping Li, Hongwei Xue, Qi Deng, Zheng Ge, Liangquan Geng, Xianmin Song, Kang Yu, Hongmei Jing, Bing Chen, Xin Li, Zhimin Zhai, Jianping Shen, Jiang Cao, Qingming Wang, Peng Liu. HR001, a novel CD19-targeted CAR-T cell therapy for patients with relapsed/refractory non-Hodgkin's lymphoma: primary results of a phase II study (HRAIN01-NHL01-II) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT244.

Retrospective Investigation of Human Papillomavirus Cervical Infection and Lymphoma Incidence: A Clinical and Pathological Evaluation

Objective: Human papillomavirus (HPV) persistence is considered the main risk factor for neoplastic progression, and evidence suggests that regulatory T cells play an important role in the failure of viral elimination. Regulatory T cells may be involved in maintaining a microenvironment favourable for viral persistence and neoplasticity, through a deregulation of the local immune response. The association between altered immune function and the development of chronic infections, cancer (solid and haematological), and autoimmune diseases is documented in the literature. The purpose of this retrospective analysis was to evaluate the possible correlation between HPV cervical infection and lymphoma incidence in women attending colposcopy due to an abnormal Pap smear during a period of 15 years. Design: This is a cross-sectional study. Participants: We investigated retrospectively the incidence of haematological diseases in women aged 21–84 with an abnormal Pap smear who referred to our centre between 2004 and 2019. Setting: This study was conducted at the university hospital. Methods: In our analysis, we included women with diagnoses of HL and NHL after the detection of abnormal Pap smears and HPV infections. We excluded patients with a diagnosis of lymphoma preceding the date of the abnormal Pap smear and HPV test. Results: We divided the patients into two groups in order to analyse the standard incidence ratio (SIR): HL patients (19/7,064, 0.26%) and NHL patients (22/7,064, 0.31%). In our sample, we reported a significant risk of developing lymphoma compared to the general population, both for HL and NHL disease, at age <45 years. Regarding HL, the SIR of disease in women <45 years was 4.886 (95% CI 2.775–9.6029) and in women between 45 and 59 years was 2.612 (95% CI 0.96–7.108804). On the other hand, for NHL in women <45 years, we reported an SIR of about 3.007 (95%, CI 1.273–7.101575), in women aged 45–59 years, the SIR was 4.291 (95% CI 2.444–7.534399), and in women aged 60–74 years, the SIR was 3.283 (95% CI 1.054–10.22303). Limitations: This retrospective analysis was conducted in a single centre in Northern Italy and did not consider all interregional differences existing in the country in terms of HPV genotypes, ethnicity, and population characteristics. Regarding the analysis of SIR for HL and NHL, we did not divide the disease into subtypes because of the small sample of cases. Finally, we considered in our analysis only women with an abnormal Pap smear and not the general population. Conclusions: Women with chronic and persistent HPV infections may have a higher relative risk of developing lymphoma. This possible association may be caused by the deregulation of the immune system response against HPV and the failure of viral clearance, especially in younger women.

High monocytic MDSC signature predicts multi-drug resistance and cancer relapse in non-Hodgkin lymphoma patients treated with R-CHOP.

Non-Hodgkin Lymphoma (NHL) is a heterogeneous lymphoproliferative malignancy with B cell origin. Combinatorial treatment of rituximab, cyclophsphamide, hydroxydaunorubicin, oncovin, prednisone (R-CHOP) is the standard treatment regimen for NHL, yielding a complete remission (CR) rate of 40-50%. Unfortunately, considerable patients undergo relapse after CR or initial treatment, resulting in poor clinical implications. Patient's response to chemotherapy varies widely from static disease to cancer recurrence and later is primarily associated with the development of multi-drug resistance (MDR). The immunosuppressive cells within the tumor microenvironment (TME) have become a crucial target for improving the therapy efficacy. However, a better understanding of their involvement is needed for distinctive response of NHL patients after receiving chemotherapy to design more effective front-line treatment algorithms based on reliable predictive biomarkers. Peripheral blood from 61 CD20+ NHL patients before and after chemotherapy was utilized for immunophenotyping by flow-cytometry at different phases of treatment. In-vivo and in-vitro doxorubicin (Dox) resistance models were developed with murine Dalton's lymphoma and Jurkat/Raji cell-lines respectively and impact of responsible immune cells on generation of drug resistance was studied by RT-PCR, flow-cytometry and colorimetric assays. Gene silencing, ChIP and western blot were performed to explore the involved signaling pathways. We observed a strong positive correlation between elevated level of CD33+CD11b+CD14+CD15- monocytic MDSCs (M-MDSC) and MDR in NHL relapse cohorts. We executed the role of M-MDSCs in fostering drug resistance phenomenon in doxorubicin-resistant cancer cells in both in-vitro, in-vivo models. Moreover, in-vitro supplementation of MDSCs in murine and human lymphoma culture augments early expression of MDR phenotypes than culture without MDSCs, correlated well with in-vitro drug efflux and tumor progression. We found that MDSC secreted cytokines IL-6, IL-10, IL-1β are the dominant factors elevating MDR expression in cancer cells, neutralization of MDSC secreted IL-6, IL-10, IL-1β reversed the MDR trait. Moreover, we identified MDSC secreted IL-6/IL-10/IL-1β induced STAT1/STAT3/NF-κβ signaling axis as a targeted cascade to promote early drug resistance in cancer cells. Our data suggests that screening patients for high titre of M-MDSCs might be considered as a new potential biomarker and treatment modality in overcoming chemo-resistance in NHL patients.

Hypofractionated Radiotherapy for Hematologic Malignancies during the COVID-19 Pandemic and Beyond.

Radiotherapy is integral in the management of hematological malignancies (HM). Standard radiotherapy dose fractionation regimens range between 20 and 50 Gy in 10-25 fractions over 2-5 weeks. This study presents the outcomes of patients with HM treated with hypofractionation radiotherapy (HFRT) during the COVID-19 pandemic. Patients (n = 36) were treated with HFRT between January 2020 and September 2022. The outcomes measured were the overall response rate (ORR), freedom from local progression (FFLP), and overall survival (OS). The median follow-up was 13.2 months. Thirty-three patients (92%) had non-Hodgkin (NHL) or Hodgkin lymphoma (HL). Eighteen patients (50%) had aggressive and nine (25%) had indolent NHL. Nineteen patients (53%) presented with stage I/II and fifteen (42%) with stage III/IV disease. Twenty-five (69.4%) and eleven (30%) received consolidative and definitive RT, respectively. Twenty patients (56%) received treatment to the neck and/or thorax and nine (25%) to the abdomen or pelvis. The total dose ranged from 18 to 42.5 Gy in 6-17 fractions/2.67-5 Gy per fraction. The median dose in 2 Gy fractions for an alpha/beta (α/β) ratio of 10 amounted to 39 Gy (SD ± 13.86) and 43.6 Gy (SD ± 12) for an α/β of 3. The most commonly used fractionation scheme was 39 Gy in 13 fractions. ORR was 94.4% for the entire cohort, and 100, 94.4, and 83.3% for indolent NHL, aggressive NHL, and HL patients. The two-year FFLP was 76% (95% CI: 34-93%) for the entire cohort and 100, 87 (95% CI: 56.4-96.5%), and 42% (95% CI: 1.1-84.3%) for the indolent NHL, aggressive NHL, and HL patients. Two-year OS for the entire cohort was 80% (95% CI: 59.9-90.5%) and 100, 66.1 (95% CI: 36.4-84.4%), and 100% for the indolent NHL, aggressive NHL, and HL patients. Only one patient presented with grade two pulmonary toxicity. HFRT in HM provides excellent local control to be validated in a larger prospective study.

Autoimmune Hemolytic Anemia in Patients of Non Hodgkin’s Lymphoma

The study was conducted to determine the frequency of autoimmune haemolytic anaemia in non-Hodgkin’s lymphomas. A cross sectional study on 100 patients of Non-Hodgkin Lymphoma was conducted in Pathology department, KEMU, Lahore. The mean age among the patients was 50.14 ±17.053 years. The mean haemoglobin was 10.73g/dl ± 2.74 . Out of 100, 88 patients had Coomb’s Test negative and 12 patients had a positive result. Those having a positive coomb’s test showed a higher retic count i.e., 5.05 ± 2.37. The average bilirubin levels in all NHL patients were 0.901 0.995 mg/dL, with a substantially higher mean of 2.15 1.19 mg/dL among patients who tested positive for Coomb's. The LDH levels of those immensely high 764.5 ± 441.Post stratification chi square testing showed no significant relationship was found between autoimmune hemolytic anemia among NHL patients. Age and gender have no significant effect. However, disease stage can be a risk factor. Therefore, it is emphasized that all patients of NHL, regardless of age and gender, must be thoroughly investigated.

Efficacy and Safety of Axicabtagene Ciloleucel (Axi-cel) for the Treatment of Relapse/Refractory Non-Hodgkin Lymphoma: Real-World Data in Chinese Population

Background: Autologous CD-19 directed chimeric antigen receptor (CAR) T-cell therapy has become the standard of care of patients with relapsed/refractory (R/R) large B-cell lymphoma (LBCL) who have received two or more prior lines of therapy. In June 2021, Axi-cel was approved by the China National Medical Products Administration (NMPA) for the treatment of these patients as the first commercial CAR-T product in China. To better understand the efficacy and safety of commercial Axi-cel in Chinese R/R NHL patients in a real-world setting, we conducted this multi-center, non-interventional study (ChiCTR2100047990). The accrual goal is 200 patients, and the primary endpoint is mOS. Here we made the pre-specific interim analysis and the reported the clinical outcomes. Methods: We included R/R NHL patients treated with commercial Axi-cel at 17 authorized treatment centers from November 2021 to February 2023. All the patients signed written informed consent. We reported best objective response rate (bORR), best complete response (bCR) rate and adverse events of special interest (AESI), including cytokine release syndrome (CRS) and neurological events (NE). Results: To the cut-off date of June 8, 2023, a total of 101 R/R NHL patients had undergone efficacy evaluation at month 3. The median age of patients was 56.5 (22, 80) years, with 23 patients (22.8%) aged 65 years or older. Fifty-nine patients were male. The baseline characteristics of these patients included 81 (80.2%) with diffuse large B-cell lymphoma, 4 (4.0%) with primary mediastinal B-cell lymphoma, and 7 (6.9%) with high-grade B-cell lymphoma. More than 50% of patients had an International Prognostic Index (IPI) score ≥3. The median number of prior treatment was 2. Thirty-eight patients (37.6%) had received 3 or more previous therapies and 10 patients (9.9%) had undergone autologous stem cell transplantation (ASCT). The primary refractory subgroup reached 46 (45.5%), and 41(40.6%) patients were refractory to second-line or subsequent therapy. Notably, compared to the baseline characteristics of Axi-cel real-world studies for R/R LBCL in other countries, a greater proportion of Chinese patients had an ECOG PS score ≥2 (32.7%), HBsAg (+) with normal HBV-DNA (23.1%), HBsAg (-) accompany with HBcAb (+) (37.1%). Bridging therapy was given in 73 patients (72.3%), while combination anti-lymphoma therapy was used after Axi-cel infusion and before disease progression in 52 patients (51.5%). The median follow-up was 12.7 months. The bORR and bCR rate was 83.2% (95%CI, 74.4 - 89.9) and 63.4% (95%CI, 53.2 - 72.7), respectively (Fig 1). The bORR was consistent across covariates including disease type, cell of origin and refractory subgroup, ECOG PS score ≥2, HBsAg (+) and normal HBV-DNA, and HBsAg (-) accompany with HBcAb (+), etc.. The median duration of response (DOR) was 13.7 months (95% CI, 11.1 - NA). mDOR was not reached in bCR patients (95% CI, 11.2 - NA), while patients with best response as PR have a median DOR as 4.7 months (95% CI, 1.8- 6.7). Median progression-free survival (PFS) was 14.6 months (95% CI, 7.6 - NA). Patients with ECOG PS score ≥2 had a shorter median PFS [7.6 months (95%CI 3.0 - NA)] compared to patients with PS 0-1 [14.6 months (95%CI 12.1 - NA)]. Median PFS also differed among patients based on their response at month 3. Patients with CR/PR/non-response at month3 had a median PFS of NR (95% CI, 12.1 - NA), NR (95%CI, 6.1 - NA) and 3.0 months (95%CI, 2.4 - 3.3), respectively (Fig 2). The median OS was not reached, and the estimated OS at 12 months was 80.4% (95%CI, 70.5 - 87.2). No new safety signals were observed in the Chinese population. The most common adverse events of grade ≥3 were decreased white blood cell count (82.2% of patients), neutropenia (81.3%) and lymphocytopenia (68.2%). CRS of any grade occurred in 90 patients (84.1%), with 15 patients (14.0%) experiencing grade ≥3. NE of any grade occurred in 27 patients (25.2%), with only 1 patient (0.9%) experiencing grade 4. No grade 5 CRS or NE appeared. Conclusions: This pre-specific interim analysis demonstrated the consistent efficacy of Axi-cel in Chinese R/R NHL patients, while NE of any grade and ≥grade 3 were lower. Similar to the result of the ZUMA-1 study, response at month 3 may predict PFS in Chinese R/R NHL patients treated with Axi-cel in real-world practice.

Mitoxantrone Hydrochloride Liposome Injection Combined with Carmustine, Etoposide, and Cytarabine As Conditioning of Autologous Hematopoietic Stem Cell Transplantation in NHL Patients：a Prospective Single-Arm Clinical Trial

Background：High-dose chemotherapy and autologous stem-cell transplantation (ASCT) is standard consolidation therapy for aggressive lymphoma.Choosing the most effective conditioning regimen prior to ASCT can lead to longer survival in these patients.Mitoxantrone liposome is an anthraquinone antibiotic anti-tumor drug. Previous studies have shown that mitoxantrone liposome monotherapy or combined with other drugs has achieved good efficacy for T-cell lymphoma, but there are no reports of its application in conditioning. Objective:This is a prospective single-arm clinical study to evaluate the efficacy and safety of mitoxantrone hydrochloride liposome injection combined with carmustine, etoposide, cytarabine (modified BEAM protocol) as conditioning of autologous hematopoietic stem cell transplantation for NHL patients (NCT05681403). Methods: Patients with non-Hodgkin lymphoma who planned to undergo ASCT were eligible to participate in the trial if they were 18 to 60 years of age.The patients received mitoxantrone hydrochloride liposome injection 24 mg/m 2,ivgtt,d-7, carmustine 300 mg/m 2,ivgtt,d-6, etoposide200 mg/m 2,ivgtt,d-5~ -2,cytarabine 200 mg/m 2 q12h,ivgtt,d-5~ -2 as conditioning regimen.The primary end point was the relapse rate within three years and the secondary end point was adverse events of modified BEAM protocol. Results：Twenty-five NHL patients (median age 39 years old,17 males and 8 females) were enrolled,including 40% DLBCL, 12% MCL, 4% primary mediastinal B-cell lymphoma,4%B lymphoblastic lymphoma,4%Marginal zone B-cell lymphoma,12% PTCL-NOS, 8% ALK +ALCL,8% NK/T lymphoma, 8% AITL,4% ALK -ALCL and 4% Sézary syndrome. 18 cases achieved complete remission before ASCT, while 7 cases received partial remission before ASCT. The median of neutrophil recovery time was 11 days(7-15) and the median of platelet recovery was 12days (7-60).Nausea,vomit,constipation,blue skin and cough were the most frequently reported conditioning related AEs (88%,16%,12%,12% and 8% of patients,respectively), and other AE included 1 case of hypoxemia, 1 case of hypotension, 1 case of palpitation, 1 case of rash. Except one patient experienced a grade 3 vomit ,the others were grade 1-2 and improved after symptomatic treatment. Nine patients experienced febrile neutropenia and 2 cases of sepsis, 4 cases of respiratory infection, and 3 cases of oral mucositis. All partial remission patients achieved complete remission post-HSCT and one of them relapsed 7 months after ASCT.The others were all in complete remission during follow-up. Conclusion:Mitoxantrone hydrochloride liposome injection combined with carmustine, etoposide, cytarabine (modified BEAM protocol) was a well-tolerated and effective conditioning regimen for NHL and the study is ongoing and updated results will be presented in the future.

EX103, a Novel CD20xCD3 Bispecific Antibody, Showed a Favorable Safety and Potent Single-Agent Antitumor Activity in Heavily Pretreated Relapsed/Refractory Patients with B-Cell Non-Hodgkin Lymphoma

Introduction Non-Hodgkin lymphoma (NHL) is one of the most common cancers in the United States, and relapsed or refractory (R/R) B cell NHL had a poor prognosis. In recent years, T cell engaging bispecific antibody (TCB) emerged as a promising therapy. Nevertheless, severe cytokine release syndrome (CRS) remains to be a significant challenge in TCB treatment. To overcome this issue, we designed a new CD20xCD3 bispecific antibody (EX103) with a lower affinity to CD3. In the non-human primate tox study, EX103 induced much lower IL-6 release. Preliminary data from dose escalation part of Phase I clinical study demonstrates that EX103 has an encouraging safety and robust single-agent antitumor activity trend, even at low doses, in heavily pretreated R/R B-NHL patients. Method The dose-escalation part (8 dose cohorts, ranging from 1.2 to 36 mg) of this Phase I, multicenter, single-arm, open-label clinical trial has enrolled R/R CD20+ B-cell non-Hodgkin lymphoma subjects at 4 study sites in China. Objectives include safety, dose finding (RP2D), and antitumor activity. Eligible patients in each cohort received intravenous(iv) step-up doses of EX103 (with 1 priming dose and 2 intermediate doses followed by 1 target dose of EX103) administered in a 28-day dose limiting toxicity (DLT) observation period, and then received a target dose every 2 weeks for up to 12 cycles until disease progression or unacceptable toxicity. Response rates reported are based on the Lugano criteria (2014). Results As of June 2023, 5 cohorts (target dose from 1.2 to 18 mg) of the dose-escalation were completed. Among 13 evaluable patients , 9 of them are aggressive B-NHL (5 Diffuse large B-cell lymphoma (DLBCL), 3 Follicular lymphoma (FL) grade 3B, and 1 Mantle cell lymphoma (MCL)), 2 of them are indolent B-NHL (1 FL grade 1-3A, 1 Marginal zone lymphoma (MZL)), and 2 of them are Chronic lymphocytic leukemia (CLL). No DLT was observed, and the maximum tolerated dose (MTD) was not reached. The most common adverse events (AEs) were CRS, pyrexia, neutropenia, thrombocytopenia. All CRS were grade (Gr) 1-2, no Gr 3 or higher CRS. Most CRS events occurred in first or second treatment cycle, and all CRS related clinical symptoms were resolved within 48 hours. No Immune effector cell-associated neurotoxicity syndrome (ICANS) or other clinically significant neurologic AEs were reported. Among those patients, the median age was 51 years (range 43-66) and median number of prior lines of treatment was 5 (range 2-8). The preliminary Disease Control Rate (DCR) is 84.6% (11/13). Among 9 aggressive NHL patients, the overall response rate (ORR) was 67.7 % (6/9), including 3 DLBCL patients (1 each in 6 or 12 or 18 mg cohorts) and 1 MCL patient (in 3 mg cohort) achieving CR, and 2 grade 3B FL patients achieving PR (1 each in 6 or 18 mg cohorts). Both indolent NHL patients (1 FL (Grade 1-3A) and 1 MZL in 12 mg cohort) achieved PR and the preliminary ORR for indolent NHL was 100.0 % (2/2). Of 2 CLL patients, 1 achieved SD (3mg cohort). It is worth mentioning that two of the patients who failed prior CAR-T treatment had achieved PR after received 6-14 week treatment of EX103. Both patients are still under EX103 treatment. Conclusions Although this study has a limited number of subjects so far and the findings are preliminary, the available dose-escalation data demonstrate that single-agent EX103, even at low doses (3 or 6 mg), exhibits remarkable antitumor activity and favorable safety. Furthermore, EX103 demonstrates promising efficacy in heavily pretreated patients with R/R B-NHL, including some who have previously failed CAR-T treatment. The safety and efficacy of EX103 will be further evaluated in an ongoing clinical study.

Cerebrospinal Fluid IL-6 Plus IL-10 As Effective Diagnostic Biomarkers for Secondary Central Nervous System Lymphoma

Background : Secondary central nervous system lymphoma (SCNSL) characterized by the involvement of the CNS at initial diagnosis of systemic lymphoma or in the setting of relapse. Accurate diagnosis and therapeutic response of SCNSL are particular challenges, which need to be improved. We aimed to evaluate the diagnostic and the post-therapeutic prognostic value of cerebrospinal fluid (CSF) cytokine in patients with SCNSL. Methods: In this retrospective study involving 234 NHL patients and 53 other CNS patients, the NHL patients was divided into two sub-groups based on with and without CNS involvement: SCNSL (n=57) and non-SCNSL (n=177). The CSF cytokine profiles (interleukin (IL)-2, -4, -6, and -10, tumor necrosis factor-α, interferon-γ, and IL-17A) of these patients were measured by cytometric bead assay and evaluated the ability of CSF cytokine levels as diagnostic, therapeutic and prognostic biomarkers for SCNSL. Results: CSF IL-6 and IL-10 levels were significantly higher in SCNSL patients than non-SCNSL and other CNS patients. CSF levels of IL-6 and IL-10 were significantly higher in patients with an stage at Ⅲ and Ⅳ, CSF WBC counts&amp;gt;5/µL, CSF protein ≥0.45g/L.Using a CSF IL-6 cut-off value of 10.13 pg/ml yielded a diagnostic sensitivity and specificity was 62.34% and 87.57%, respectively (AUC, 0.7798; 95% CI, 0.7083 to 0.8514); For a CSF IL-10 cutoff value of 7.82, the sensitivity was 76.23%, and the specificity was 98.31% (AUC, 0.8164; 95% CI, 0.7466 to 0.8862). Combined CSF IL-6 and IL-10 significantly improved the diagnostic effect of SCNSL (AUC, 0.8959; 95% CI, 0.8371 to 0.9547). The levels of IL-6 and IL-10 in cerebrospinal fluid of SCNSL patients who responded to intrathecal chemotherapy were significantly decreased during follow-up, while the levels of these two cytokines showed fluctuating changes in patients with progressive SCNSL. Moreover, poor Progression free survival (PFS) for patients with SCNSL was associated with the increased CSF IL-10 level at diagnosis with CNS involvement (P=0.035), but not with the increased CSF IL-6 level. Conclusion: Our study confirmed CSF level of IL-6 and IL-10 were potentially effective diagnostic biomarkers for SCNSL, and poor progression free survival (PFS) for patients with SCNSL was associated with the increased CSF IL-10 level.

Safety and Efficacy of Autologous HSCT in Nine Patients with AIDS-Related Non-Hodgkin Lymphoma

Background：In recent years, with the application of HIV combined with resistance retroviral therapy, the number of AIDS-NHL patients has gradually increased, surpassing Kaposi's sarcoma and becoming the first AIDS-related tumor. The prognosis of AIDS-NHL patients is worse than that of ordinary NHL patients, and more powerful treatment is needed. To analyze the safety and efficacy of 9 AIDS-related non-Hodgkin lymphoma (AIDS-related non-Hodgkin lymphoma, AIDS-NHL) treated with autologous hematopoietic stem cell transplantation (auto-hematopoietic stem cell transplantation, ASCT). Methods: 9 patients with AIDS-NHL were prospectively treated for their safety and efficacy. Results: The male to female ratio of 9 AIDS-NHL patients was 8:1, and the median age was 38 years. The pathology types were 4 DLBCL, 2 PBL, 1 BL, 1 HGBL and 1 HL, including 3 patients with refractory relapse (1 each of DLBCL, HGBL and PBL). Except for three patients with refractory relapse, the remaining six patients underwent first-line autologous HSCT. One PBL stage was in stage I low-risk group and the remaining patients were in stage III - IV high-risk group. Before transplantation, one patient was progressive, one patient was in partial remission, and the other patients achieved complete remission after chemotherapy. All patients underwent autologous HSC mobilization using PEG-G-CSF, with all CD34 + cell numbers&amp;gt; 210 ^ 6 / Kg. Transplantation pretreatment was performed with the BeEAM protocol, with a median time to granulocyte engraftment of 11 days and a median time to platelet engraftment of 14 days, with no transplant-related death. Two patients who did not achieve CR before transplantation all died due to disease progression within 3 months after transplantation, and the remaining patients remained in complete disease remission through follow-up until February 28,2023. Conclusion: AIDS-NHL patients are aggressive and have a poor prognosis, and active treatment is needed to improve their long-term survival. Our center prospectively performed autologous HSCT in nine patients with AIDS-NHL, and the results showed that the time of granulocyte and platelet engraftment was consistent with that of ordinary NHL patients, with no transplant-related death and was well tolerated. Failure to achieve complete remission before transplantation may be one of the adverse factors for the early death of patients.

Quantifying Challenges to Development of Generics and Biosimilars in Non-Hodgkin's Lymphoma Therapeutics: The Future of Low-Cost Alternatives from Monoclonal Antibodies to CAR-T

Background: There are numerous monotherapies and combination therapies available to treat Non-Hodgkin lymphoma's (NHL), however relatively few of these varied antineoplastics agents have commercially available, lower-cost generic forms in the United States. High cancer drug prices, in particular for socioeconomically vulnerable and underinsured patients, pose challenges to affordable cancer treatment in the United States. In 2017, FDA initiated the Drug Competition Action Plan (DCAP) that aimed to ensure timely market competition by enabling generic drug development, review, and approval, and streamlining regulatory complexities. This regulatory program was designed to limit so-called “gaming” recognized as a cause of delay to generic drug approvals, a phenomenon that has the further deleterious effect of extending brand monopolies beyond what Congress intended with Hatch-Waxman Amendments (1984) establishing modern generic drug regulatory processes. In 2018, FDA announced analogous Biosimilars Action Plan (BAP). However, to date the efficacy of these measures has not been comprehensively assessed in the NHL development landscape. Methods: A model was created by surveying the FDA Orange Book (drug approval database) and Purple Book (biologic product approval database) for initial approval of drugs/biologics with their initial generic/biosimilar approval. Approvals were classified by drug class and availability of generic/biosimilar for the innovator product with approval from 2002 to 2023 (Fig. 1) and t-test were used to determine significance. Results: Of small molecule drug NHL therapeutics approved in the last two decades, only 37% (19/52; Fig. 2) have available, lower-cost generics, with use in more than one indication and time on market both positively and significantly corresponding with availability of generics for the original innovator drug (P &amp;lt; 0.05). Notably, while generic drug approvals dropped during the 2020-2021 period (possibly due to impact of the COVID-19 pandemic), after 2017 implementation of DCAP more generics for common NHL antineoplastics were approved. Conversely, there are relatively few biologic drugs (total of 41 approvals; Fig. 2) with biosimilars, in part due to retained patents and exclusivity, and perhaps indicating a lack of efficacy in BAP among NHL antineoplastics therapies. For off-patent innovator monoclonal antibodies (mAbs), which make up the majority of these therapies, development of biosimilars is effectively blocked by secondary or “process-related” patents which effectively extend the period of non-competition for complex biologic therapies. It is expected that novel bispecific antibody (biAb) therapeutics and novel therapies, such as CD19 CAR-T will also have a delayed time to low-cost biosimilar availability following a similar trend. Conclusions: With drug price and ever-rising insurance and patient payments a critical area of public health, in particular in the United States, availability of lower cost generics and biosimilars is a critical issue for NHL patients. As we move into the maturation of gene therapies and CAR-T therapeutics, it merits consideration of that additional regulatory programs may be needed to incentivize the development of efficacious and lower cost biosimilars. However, it is critical that controlling competition be carefully balanced with investment in both biologic drug entity and process-related innovations among these relatively complex therapeutic entities.

A Prospective Observational Study Evaluating Extracellular Water to Total Body Water Ratio By Using the Bioelectrical Impedance Analysis in Elderly Patients with Hematologic Malignancies

[Introduction] Body composition assessment is often used in clinical practice for evaluating and monitoring sarcopenia and nutritional status. Bioelectrical impedance analysis (BIA), which uses the conductivity of the body's intracellular and extracellular fluids to respond to cell and tissue functions, has gradually become widely used in clinical practice because of its non-invasiveness, convenience, and low cost. The ratio of extracellular water to total body water (ECW/TBW) measured by BIA has been found to be related to the prognosis of many diseases, but its application value for patients with hematologic malignancies still needs to be further explored. The purpose of this study was to further explore the application value of ECW/TBW measured by BIA in elderly patients with hematologic malignancies. [Patients and Methods] We prospectively analyzed 82 elderly patients aged≥60 years with hematologic malignancies diagnosed at our institution between 2015 and 2018. Appendicular skeletal muscle mass (ASM) and ECW/TBW ratio were measured by using multifrequency BIA (InBody 720). In this study, the ECW/TBW cut off value to predict survival was determined by a receiver operating characteristic (ROC) curve analysis. The ECW/TBW ratio cut offs was 0.397 (sensitivity 67.3% and specificity 54.5%, area under the curve (AUC) 0.586, [95% confidence interval (CI) 0.46-0.711]) for all 82 patients. Patients with ECW/TBW &amp;lt; 0.397 were sorted into the non-overhydrated group (NOH-group) and those with ECW/TBW &amp;gt; 0.397 into the overhydrated group (OH-group). Skeletal muscle index (SMI) was defined as the ratio of ASM divided by height in square centimeters. Sarcopenia was defined according to the AWGS2019 algorithm, in which the patient has low muscle mass, and low muscle strength or low physical performance. The study protocol was approved by the Institutional Review Board of Yokohama Municipal Citizen's Hospital, and it was carried out in accordance with the Declaration of Helsinki. This trial was registered in the UMIN clinical trial registry (UMIN000035834). [Results] Median age at diagnosis was 78 years (60-93 years), with 46 males and 36 females. The diagnosis included non-Hodgkin lymphoma (NHL, n=51), multiple myeloma (MM, n=11), myelodysplastic syndrome (MDS, n=12), and acute myeloid leukemia (AML, n=8). The mean ECW/TBW ratio of all 82 patients was 0.397±0.014. There was no significant difference in the mean ECW/TBW ratio between disease types. Thirty-four patients (41%) were classified as OH-group and 48 patients (59%) were classified as NOH-group. The median age in the OH- and NOH- groups was 83 and 74 years (p&amp;lt;0.001). The mean BMI did not differ between the two groups (22.17 vs. 22.16 kg/m2, respectively, p = 0.99). The prevalence of sarcopenia was 41.4% (34/82). There was no significant difference in overall survival (OS) between the sarcopenia and the non-sarcopenia group (3-year OS, 58.1% vs. 63.3%, p=0.96). On the other hand, patients with OH-group had shorter OS than those with NOH-group (3-year OS, 46.8% vs. 70.5%, p=0.03). We next performed a subgroup analysis of NHL patients. Among 51 NHL patients, 30 (59%) had aggressive lymphoma and 21 (41%) had indolent lymphoma. Twenty patients (39%) were classified as OH-group and 31 patients (61%) were classified as NOH-group. Patients with OH-group had shorter OS than those with NOH-group (3-year OS, 67.1% vs. 90.3%, p=0.02). The prevalence of sarcopenia was 37.3% (19/51) and sarcopenia was not correlated with survival in NHL patients. Among 30 aggressive lymphoma patients, the overhydrated status was closely associated with poor outcome (3-year OS was 57.1% in the OH-group and 88.9% in the NOH-group, p=0.01). On the other hand, there was no significant difference in OS between the OH- and NOH- groups among 21 indolent lymphoma patients. Multivariate analysis showed that the overhydrated status (high-ECW/TBW ratio) was an independent prognostic factor for OS in patients with aggressive lymphoma (HR, 5.30; 95%CI, 1.01-27.7, p=0.04). [Conclusion] The present study demonstrated that high-ECW/TBW ratio was associated with poor outcome in elderly patients with hematologic malignancies. Especially, the overhydrated status was closely associated with poor outcome in elderly aggressive lymphoma patients. Since our results are based on a small-sized analysis, further large prospective studies are warranted to verify this conclusion.

A Phase I Clinical Trial of Fully Human Anti-CD19 Chimeric Antigen Receptor T Cells for Relapsed or Refractory Lymphoid Malignancies

Background: Chimeric antigen receptor (CAR) T-cells have revolutionized the standard of care for numerous lymphoid malignancies but continue to present challenges related to toxicity, long-term efficacy, cost, and accessibility. Novel CAR-T cell constructs hold promise for improving desired outcomes. CD19 CAR-T cells with fully humanized chimeric antigen receptors have demonstrated excellent preclinical activity and the potential for lower rates of cytokine release syndrome (CRS) and severe immune effector associated neurotoxicity syndrome (ICANS). To evaluate safety, we conducted a phase 1 clinical trial evaluating fully human Hu19-CD841BBZ CAR-T cells with a 4-1BB costimulatory domain against relapsed or refractory (R/R) CD19-positive lymphoid malignancies, utilizing a single lymphodepletion regimen and local CAR-T cell manufacturing using the Prodigy® Device. Methods: We designed a parallel-group phase I trial with two clinical groups. Group A enrolled subjects with relapsed and refractory CD19+ lymphomas and chronic lymphocytic leukemia (CLL), while Group B comprised patients with acute lymphoblastic leukemia/lymphoma (ALL). The primary endpoint was safety and toxicity assessment, along with the identification of the recommended phase 2 dose in each clinical group. Secondary endpoints included efficacy evaluation. Dose escalation in each group followed a “3 + 3” phase I study design, with three dose levels: 5e5 CAR-T cells/kg, 1e6 CAR-T cells/kg, and 2e6 CAR-T cells/kg. Lymphodepletion consisted of cyclophosphamide 60mg/kg on day -6 and Fludarabine 25mg/m2/day on days -5 to -3. Dose-limiting toxicities included prolonged CRS grade 3 or higher, ICANS grade ≥ 3, and grade ≥ 3 non hematologic toxicities with the exception of self-limited (&amp;lt;7 days) laboratory abnormalities without associated symptoms or clinical consequences. Results: As of 7/1/2023, a total of 13 patients were enrolled in Group A (NHL), and two patients were enrolled in Group B (B-ALL). Three patients in Group A withdrew consent or were withdrawn at the investigator's discretion due to new comorbid conditions before cell collection. Additionally, three patients were unable to receive CAR-T cell infusions due to disease progression, including two with Burkitt lymphoma. Among the remaining patients, 7 in NHL and 2 in B-ALL, received CART cells. The average age was 59 (range: 40-73), and 2 patients were female. In the NHL group, diseases treated included CLL (3), mantle cell lymphoma (2), follicular lymphoma (1), and Waldenstrom's (1). The median number of prior treatments was 4 (range: 3-10). CAR-T cell product manufacturing was successful in all patients to achieve the target dose, with a mean transduction efficiency of 43.8% (29.7% - 54.6%). One potential dose-limiting toxicity, nodular regenerative hyperplasia of the liver, considered possibly related to CAR-T cells, was observed in the NHL group at the 1e6 cells/kg dose level, leading to an expansion of this dose level. Other observed toxicities were as expected and manageable. Six patients experienced CRS, with grades 1-2 in the NHL group. Both patients in the B-ALL arm experienced CRS, one grade 1 and one grade e, with observed severity congruent with known disease burden before receiving CAR-T cells. Two cases of CRS required no intervention, while the remaining cases received tocilizumab (n=4), steroids (n=2), and/or anakinra (n1). There were three occurrences of ICANS, two in Group A and one in Group B. Treatments included corticosteroids (n=3) and anakinra (n=2). Among the 7 NHL patients evaluable for response, 2 achieved complete remission (follicular, mantel cell), three had a partial response (CLL), and one exhibited stable disease (Waldenstrom's). Two NHL patients (CLL and Mantel Cell) had subsequent disease progression. One B-ALL patient evaluable for response achieved a CR but experienced disease progression at one year and subsequently died. Discussion: In this parallel-group phase 1 study, fully human Hu19-CD841BBZ CAR-T cells with a 4-1BB costimulatory domain were successfully manufactured in all patients undergoing leukapheresis. Human CAR-T cells demonstrated preliminary safety and clinical activity in the setting of heavily pre-treated patients with R/R B cell malignancies. A platform of point-of-care manufacture permits access to novel CAR-T cell products, and may facilitate the development of novel immune effector cell products.

Detection and Quantification of the Epstein-Barr Virus in Lymphoma Patients from Ethiopia: Molecular and Serological Approaches.

The Epstein-Barr virus (EBV) is a known oncogenic virus associated with various lymphoma subtypes throughout the world. However, there is a lack of information regarding EBV prevalence in lymphoma patients, specifically in Ethiopia. This study aimed to investigate the presence of the EBV and determine its viral load in lymphoma patients from Ethiopia using molecular and serological approaches. Lymphoma patient samples were collected from the Ethiopian population. DNA and serum samples were extracted and subjected to molecular detection methods, including quantitative polymerase chain reaction (qPCR) analysis targeting the EBNA1 gene. Serological analyses were performed using an enzyme-linked immunosorbent assay (ELISA) to detect EBV viral capsid antigen IgG antibodies. EBV DNA was detected in 99% of lymphoma patients using qPCR, and serological analyses showed EBV presence in 96% of cases. A high EBV viral load (>10,000 EBV copies/mL) was observed in 56.3% of patients. The presence of high EBV viral loads was observed in 59.3% of HL patients and 54.8% of NHL patients. This study provides important insights into the prevalence and viral load of the EBV among lymphoma patients in Ethiopia. The findings contribute to the limited knowledge in this area and can serve as a foundation for future research.