Outcome Of non-Hodgkin Lymphoma Research Articles

Treatment modalities of marginal zone lymphoma and overall survival, haematological response, and underlying Sjögren's disease activity: a multicentre, retrospective, observational study

Sjögren's disease is the autoimmune disease with the highest risk of lymphoma development. There is no consensus on the optimal way to manage Sjögren's disease complicated by lymphoma. We aimed to describe characteristics, therapeutic strategies, and outcomes of non-Hodgkin lymphoma associated with Sjögren's disease, and their effect on lymphoma and Sjögren's disease prognoses. We did a multicentre, retrospective, observational study including patients with Sjögren's disease according to the 2016 American College of Rheumatology-European League Against Rheumatism criteria who did not fulfil diagnostic criteria for other connective tissue diseases. We included patients with a lymphoma diagnosis made before Jan 1, 2020, from two expert centres in Paris (France); from the French, multicentre, prospective Assessment of Systemic Signs and Evolution of Sjögren's Syndrome cohort; and via practitioners registered with the Club Rhumatismes et Inflammation. Using inverse probability of treatment weighting, the effect of lymphoma treatment was compared in relation to three endpoints: lymphoma progression-free survival, new Sjögren's disease systemic activity, and overall survival. Exploratory analyses also aimed to identify factors associated with lymphoma relapse, new Sjögren's disease systemic activity, and overall survival. People with lived experience were not involved in this research. 106 patients with Sjögren's disease who developed lymphoma were included in the study. The most frequent histological subtype was mucosa-associated lymphoid tissue lymphoma (68 [64%] of 106 patients), followed by other marginal zone subtypes (14 [13%] of 106 patients) and diffuse large B-cell lymphoma (14 [13%] of 106 patients). Among the 82 patients with marginal zone lymphoma (72 [88%] women and ten (12%) men; mean age at lymphoma diagnosis 57·5 years [SD 14·8]), multivariable analysis showed that pulmonary localisation was associated with mortality (hazard ratio [HR] 7·92 [95% CI 1·70-37·0]). A watch and wait approach was proposed in 19 (23%) of 82 patients with marginal zone lymphoma, 13 (16%) had first-line localised treatment (surgery or radiotherapy), and 50 (61%) had first-line systemic treatment. After a median follow-up of 7 years, 26 patients (32%) had lymphoma relapse, nine (11%) died, and 27 (33%) had new Sjögren's disease systemic activity. After inverse probability of treatment weighting, patients with systemic treatment at lymphoma diagnosis had a reduced risk of new Sjögren's disease activity (HR 0·43 [95% CI 0·21-0·90]). When comparing patients treated with a combination of chemotherapy and anti-CD20 therapy (n=32) with patients treated with monotherapy (n=18) as a first-line therapy for lymphoma, lymphoma-progression-free survival was improved in patients treated with combination therapy (HR 0·36 [95% CI 0·14-0·94]). The were no differences in new Sjögren's disease systemic activity or overall survival according to combination therapy or monotherapy. A systemic treatment strategy for Sjögren's disease-associated lymphoma, rather than localised treatment or a watch and wait strategy, reduces the risk of new Sjögren's disease systemic activity and combination therapy is associated with decreased risk of lymphoma relapse. None.

The multifaceted roles of extracellular vesicles for therapeutic intervention with non-Hodgkin lymphoma

Extracellular vesicles (EVs) contribute to the development of cancer in various ways. Non-Hodgkin lymphoma (NHL) is a cancer of mature lymphocytes and the most common hematological malignancy globally. The most common form of NHL, diffuse large B-cell lymphoma (DLBCL), is primarily treated with chemotherapy, autologous stem cell transplantation (ASCT), and/or chimeric antigen receptor T-cell (CAR-T) therapy. With NHL disease progression and its treatment, extracellular vesicles play remarkable roles in influencing outcomes. This finding can be utilized for therapeutic intervention to improve patient outcomes for NHL. This review focuses on the multifaceted roles of EVs with NHL and its potential for guiding patient care.

Lymphocyte subsets and soluble forms of MIC-A and MIC-B are prognostic factors in non-Hodgkin lymphoma patients.

MIC-A and MIC-B are the natural ligands for NKG2D, an activator receptor expressed in NK cells. Soluble isoforms of MIC-A and MIC-B (sMICA, sMICB) have been identified in different malignancies, affecting NK cells' cytotoxicity. The study was performed to determine the levels of sMICA, sMICB, the expression of MIC-A, and MIC-B on tumor tissues, and lymphocyte subpopulations (CD4 + , CD8 + , NK, NKT, Tγδ cells, B cells, monocytes) in 94 patients with non-Hodgkin's lymphoma (NHL) and 72 healthy donors.The most frequent lymphoma was diffuse large B cell lymphoma (48%). Patients with NHL had decreased numbers of CD4 T cells, CD8 T cells, B cells, monocytes, NK cells, type 1 dendritic cells, γδ T cells, and increased iNKT cells. Patients showed higher levels of sMIC-A and similar serum levels of sMIC-B.Survival was poorer in patients having higher LDH values and lower numbers of CD4 T cells, type 1 dendritic cells, gamma-delta T cells, and high levels of sMIC-A.In conclusion, high levels of sMIC and decreased numbers in circulating lymphocyte subsets are related to poor outcomes in NHL.

The Outcome of Tisagenlecleucel (Tisa-Cel) Vs Axicabtagene Ciloleucel (Axi-Cel) CD-19 CAR-T Cell Therapy in Relapsed/Refractory NHL, Real World Data, Single Institution Experience

ABSTRACT Background: In the Kingdom of Saudi Arabia, non-Hodgkin lymphoma (NHL) reported as 6.1%. The estimated age adjusted incidence is 6/100,000. The more advanced disease stage at presentation reaches up to 40% stage IV. The cure rate with first line of therapy (R-CHOP) reaches up to 70%. The CD 19 chimeric antigen receptor (CAR) T-cell therapy targets CD19-expressing B cells and shows efficacy against B-cell lymphomas. Objective: The registration of CAR-T therapy products at KSA was in 2020 for Tisa-Cel and 2022 for Axi-Cel. The objective is to describe the outcome of the more available CAR-T therapy products in relapsed or refractory NHL. Methods: Retrospective analysis of CAR-T therapy outcome in NHL and compare the outcome of the two products for the same patient's population, using patients' chart electronic file assessment in the tertiary institution treating over 500 new lymphoma per year. Patients: Between November 2020 and May 2023, 44 patients with relapsed or refractory NHL to ≥2 lines of therapy, Follicular lymphoma (FL) relapsed after three lines of therapy counted for four patients treated with Axi-Cel. All patients received an infusion were included in the analysis. Of the 44 patients, 54.5% were male (n=24), the median age was 51 (20-75), and ECOG was 0-3. NHL subtype includes germinal center B-cell (GCB) 52% (n=23) and activated B-cell (ABC) 38.6% (n=17); the disease stage by PET/CT scan was III (47.7%, n=21) and IV (47.7%, n=21). In Axi-Cel group, 9.1% (n=4) received CAR-T as second line for relapse refractory disease or relapse within 12 months of complete remission (CR) after 1 st line therapy. Other patients received at least two lines of therapy prior to CAR-T infusion; 65.9% received ≥ 3 lines of therapy. Seven patients (16%) relapsed after autologous stem cell transplantation (ASCT) have received CAR-T therapy Tica-Cel product (n=6). Four patients (9.1%) have controlled CNS involvement at the infusion time. All patients received lymphodepletion (LD) therapy with fludarabine and cyclophosphamide (Flu/Cy). 25% (n=11) needed bridging chemotherapy therapy before LD, radiation therapy (XRT) bridging was counted for 13 patients (29.5%). The patients' characteristics and disease in Table-1. Results: Overall response rate (ORR), complete responses (CR), partial responses (PR). The respective toxicities include cytokine release syndrome (CRS) and neurologic events namely ICANS. The best ORR was 68.2%; 43.2% of the patients had CR and 25% had PR. The disease progression (DP) was 29.5%. In Axi-Cel group, ORR, CR, PR, and DP was 84.2%, 52.6%, 31.6% and 10.5, respectively. In Tica-Cel group; ORR, CR, PR, and DP was 56%, 36%, 20% and 44%, respectively. The estimated 2 years overall survival was 75% in all patients; 89.5% and 64% in Axi-Cel and Tica-Cel, respectively (p=0.47), Figure1. The estimated overall progressive free survival (PFS) was 61.4% with 73.7% in Axi-Cel group and 52% in Tica-Cel group (p=0.2), Figure2, the best PFS was seen in GCB subtype 65.2% vs 47.1% in ABC, (p= 0.05), Figure4. In FL, PFS was 100%, the patient number is small. PFS was 62.5% in-patient with CRS compared with 50% on non-CRS patient, not statistically significant (p= 0.7), Figure3. The main toxicities post CAR-T cell infusion including cytokines release syndrome (CRS) was 90.9% with 9% grade ≥ 3. In Tica-Cel, grade CRS-IV was 9% while 0% in Axi-Cel. Neurotoxicity (NT)-ICANS was 27% with grade ≥ 3 of 13.6% in both groups (20% in Tica-Cel and 5.6% in Axi-Cel). Tocilizumab was used in 72.7% in all cohorts with higher number of patients in Axi-Cel 17/19 (98.5%). Dexamethasone (Dexa) was used in CRS in 36.4%, in Axi-Cel; 42% of patients received Dexa while 32% in Tica-Cel group. In addition, for treatment of ICANS; Dexa was needed in 31.6% of Axi-Cel patients and 20% in Tica-Cel group. Upon the latest patient's follow-up, two patients (10.5%) in Axi-Cel group and 36% (n=9) in Tica-Cel group died from DP. The outcome of both products is summarized in Table-2. Conclusions: In this single-center retrospective analysis of CAR T-cell therapy in relapsed or refractory NHL or FL in adults, the rates of durable responses were like the real-world data. The best response rate was higher in Axi-Cel group; however, the follow-up duration of disease response is shorter in Axi-Cel group. The toxicity profile is similar in both groups with a bit higher of Grade-III-IV ICANS in Tica-Cel group. Keywords NHL, FL, CAR-T, CRS, ICANS

The Impact of Pre-Existing Autoimmune Disease on the Safety and Efficacy of CAR T-Cell Therapy for Non-Hodgkin Lymphoma

Introduction: Chimeric antigen receptor T-cell therapy (CAR-T) has revolutionized the treatment of non-Hodgkin lymphoma (NHL). Despite having an increased risk of NHL, patients with pre-existing autoimmune disease (AID) were excluded from pivotal CAR-T trials due to concerns that CAR-T may exacerbate AID. As a result, there are limited data on the safety and efficacy of CAR-T for NHL in patients with AID. Interestingly, there is also growing evidence that CAR-T can be therapeutically effective for AID, such as in the treatment of systemic lupus erythematosus (SLE). As CAR-T utilization for NHL increases, it is essential to characterize the safety and efficacy of this potentially curative therapy in patients with AID. This study aimed to evaluate the impact of AID on outcomes in patients treated with commercial CD19-targeted CAR-T for NHL. Methods: Following Institutional Review Board approval, we conducted a retrospective analysis of all patients who were treated with commercial CD19-targeted CAR-T for NHL and had a pre-existing AID across the Mayo Clinic Enterprise (Arizona, Florida, and Minnesota) between January 2018 and May 2023. Variables collected included age, gender, NHL type, AID type, and CAR-T product. Efficacy outcomes, including response rates at 6 and 12 months after CAR-T, were collected. Toxicities, including cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS), were collected and analyzed. Our chart review for AID included SLE, sarcoidosis, ulcerative colitis, celiac disease, pernicious anemia, Crohn's disease, psoriasis, Sjogren's syndrome, hypothyroidism (Hashimoto's disease), hyperthyroidism (Graves' disease), rheumatoid arthritis (RA), vasculitis, scleroderma, and mixed connective tissue disease (MCTD). Results: A total of 235 patients who received commercial CD19-targeted CAR-T for NHL across the Mayo Clinic Enterprise were identified (Table 1). Of these 235 patients, 27 had a pre-existing AID and 208 did not. The median age was 66 years (range 39-81) for patients with AID and 59 years (range 18-88) for patients without AID. Over half of the patients were male (59% of patients with AID and 51% of patients without AID). The most common NHL type was diffuse large B cell lymphoma (41% of patients with AID and 56% of patients without AID). Most patients received axicabtagene ciloleucel (85% of patients with AID and 84% of patients without AID). The most common AID was hypothyroidism (81%, n=22), although other conditions were also identified, including RA (11%, n=3), SLE (4%, n=1), pulmonary sarcoidosis (4%, n=1), psoriasis (4%, n=1), and MCTD (4%, n=1). Two patients had more than one AID. Median follow-up was 18 months (range 1-36) for patients with AID and 14 months (range 2-49) for patients without AID. Six months after CAR-T, the complete response (CR) rate was 77.2% and 45.1% in patients with AID and without AID, respectively (p=0.0042). Twelve months after CAR-T, the CR rate was 50% and 31.4% in patients with AID and without AID, respectively (p=0.0801). CRS of any grade occurred in 78% and 88% of patients with and without AID, respectively. ICANS of any grade occurred in 41% and 54% of patients with and without AID, respectively. Conclusion: AID did not appear to adversely impact the safety or efficacy of CAR-T for NHL. Limitations of our study include the small number of patients with AID and the fact that the most common AID was hypothyroidism. Larger studies are warranted to confirm these findings. Additional data are needed to characterize the impact of CAR-T for NHL on AID outcomes and to describe the effect of disease-modifying antirheumatic drugs on NHL outcomes after CAR-T.

Evaluation of the cachexia index using a bioelectrical impedance analysis in elderly patients with non-Hodgkin's lymphoma: A single-center prospective study.

Cancer cachexia is a disorder that affects patient outcomes. The present study prospectively evaluated the prognostic value of the cachexia index (CXI) in elderly patients with non-Hodgkin's lymphoma (NHL). We prospectively analyzed 51 elderly patients who were diagnosed with NHL at our institution. CXI was calculated as follows: CXI = SMI × Alb/NLR (SMI: skeletal muscle index, Alb: serum albumin, NLR: neutrophil-to-lymphocyte ratio). SMI was measured by a bioelectrical impedance analysis (BIA) using the InBody 720. We determined the sex-specific cutoff values of the CXI by a receiver operating characteristic curve analysis and divided all patients into low- and high-CXI groups. The median age at the diagnosis was 78years (60-93years), and 28 (55%) were male. The histologic subtypes were B-cell lymphoma in 49 patients and T-cell lymphoma in 2. Twenty-eight (55%) patients were categorized into the high-CXI group, and 23 (45%) were categorized into the low-CXI group. The overall survival (OS) in the low-CXI group was significantly shorter than that in the high-CXI group (3-year OS, 70.4% vs. 95.7%, p = 0.007). Among 23 patients with DLBCL, patients with low-CXI had shorter OS than those with high-CXI (3-year OS, 55.6% vs. 92.9%, p = 0.008). On the other hand, sarcopenia had less impact on the clinical outcome of DLBCL patients. Low-CXI was associated with poor outcomes in elderly NHL and the CXI may be a clinical useful index for predicting prognosis. Further large prospective studies are needed to verify this conclusion.

Abstract 6497: Availability of healthcare providers and its association with survival outcomes in non-Hodgkin lymphoma in the United States

Abstract Background: Survival outcome in Non-Hodgkin lymphoma (NHL) is significantly better in earlier stages, compared to advanced stages. Early identification of signs and symptoms, and prompt specialist availability and referral, are crucial for diagnosis and treatment at earlier stages. Mounting physician shortages are a growing concern, and we sought to analyze their effect on NHL mortality rates. Methods: We extracted data on the age-adjusted mortality rate (AAMR) and crude incidence rate (CIR) of NHL for all U.S. states and the District of Columbia from the Center for Disease Control (CDC) Wide-ranging Online Data for Epidemiologic Research (WONDER) database (2017-2019). Nevada was excluded due to missing information. Data on the state-wise number of primary care physicians (PCPs) was obtained from the Association of American Medical Colleges (AAMC) state physician workforce data report (2020), and of Hematology/Oncology specialists (HOs) was gathered from the National Provider Identifier (NPI) registry (2020). The number of PCPs and HOs per each NHL incidence (PCP/CIR, HO/CIR respectively) was then calculated. Correlations were analyzed using Pearson’s coefficient. Statistical analysis was performed using VassarStats. Results: Median AAMR for NHL in the US was 5.15 (IQR 4.35, 5.95) per 100, 000 population. The median number of PCP and HO per each case of NHL incidence was 4.32 (IQR 3.43, 5.21), and 0.28 (IQR 0.1, 0.37) respectively. States with fewer PCPs per each NHL incidence had higher AAMR (r=-0.37, p=0.007). States with a lower number of HOs per each NHL incidence had higher AAMR (r=-0.41, p=0.003) Conclusions: Based on the analysis, the availability of a lower number of PCPs and HOs per each NHL incidence is associated with increased AAMR of the disease. This data may strengthen the need for intensification of focus on decreasing the soaring physician shortages in the states, in order to help decrease the overall mortality associated with NHL. Citation Format: Shiva Jashwanth Gaddam, Udhayvir Singh Grewal, Zara Hassan, Poornima Ramadas. Availability of healthcare providers and its association with survival outcomes in non-Hodgkin lymphoma in the United States [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6497.

Impact of Preemptive Use of Tocilizumab on Chimeric Antigen Receptor T Cell Outcomes in Non-Hodgkin Lymphoma

Despite the impressive results of chimeric antigen receptor (CAR) T cell treatment for lymphomas, adverse events such as cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome (ICANS), and infections are major issues that can lead to intensive care unit (ICU) admission and death. Current guidelines recommend tocilizumab for treating patients with CRS grade (G) ≥2; however, the optimal timing of intervention has yet to be determined. Our institution adopted the preemptive use of tocilizumab in cases of persistent G1 CRS, defined as fever (≥38 °C) for >24 hours. This preemptive tocilizumab treatment aimed to reduce evolution to severe (G≥3) CRS, ICU admission, or death. We report on 48 prospectively collected consecutive patients with non-Hodgkin lymphoma treated with autologous CD19-targeted CAR T cells. In total, 39 patients (81%) developed CRS. CRS started as G1 in 28 patients, as G2 in patients, and as G3 in 1 patient. Tocilizumab was administered in 34 patients, including 23 patients who received "preemptive" tocilizumab and 11 patients who received tocilizumab for G2 or G3 CRS from the onset of symptoms. CRS resolved without worsening severity in 19 patients out of 23 (83%) who received preemptive tocilizumab; 4 patients (17%) progressed from G1 to G2 for the development of hypotension and quickly responded to the introduction of steroids. No patients treated with a preemptive approach developed G3 or G4 CRS. Ten out of 48 patients (21%) were diagnosed with ICANS, including 5 patients with G3 or G4. Six infectious events occurred. The overall ICU admission rate was 19%. ICANS management was the most relevant reason for ICU admission (7 patients), and no patient required ICU to manage CRS. No deaths from CAR-T toxicity were observed. Our data indicate that preemptive tocilizumab use is feasible and useful in reducing severe CRS and CRS-related ICU admission, with no impact on neurotoxicity or infection rate. Therefore, early use of tocilizumab can be considered, especially for patients at high risk of CRS.

Factors associated with long-term functional and psychosocial outcomes in patients with non-Hodgkin lymphoma.

To assess the long-term functional, psychosocial and participation outcomes in an Australian cohort of non-Hodgkin lymphoma (NHL) survivors. A cross-sectional sample of adult NHL survivors at the Peter MacCallum Cancer Centre (between 2015 and 2020), participated by completing validated questionnaires. A series of analyses described their current level of function, psychosocial well-being, and participation. Of 129 participants (mean (M) ± standard deviation (SD) age: 62.5 ± 8.8 years), the majority (58%) had aggressive NHL and grade III-IV (72%), with time since diagnosis of 4.6 ± 1.2 years. Participants reported ongoing issues after completion of treatment: fatigue (63%), bladder dysfunction (61%), cognitive impairment (53%), and NHL-related pain (46%). Most made good functional recovery (M ± SD) (Functional Independent Measure-Motor: 79.5 ± 8.2), reported minimal change in their negative emotional states, and NHL-specific quality of life (QoL) (Functional Assessment of Cancer Therapy-Lymphoma: 133.5 ± 22.1). Participants were "well" adjusted to community living (Community Integration Measure: 42.2 ± 7.4) and satisfied with their current life (Satisfaction with Life Scale: 26.3 ± 6.0). Factors significantly associated with the poorer current level of function were: age at diagnosis < 60 years, time since NHL diagnosis > 4.5 years, and aggressive NHL type. Despite good functional recovery and adjustment in the community, NHL survivors report the presence of ongoing residual impairments and cognitive issues, which requires long-term rehabilitation-inclusive management.

CRC-403: A Phase 1/2 Study of bbT369, a Dual CD79a and CD20 Targeting CAR T Cell Drug Product with a Gene Edit, in Relapsed and/or Refractory B Cell Non-Hodgkin's Lymphoma (NHL)

BACKGROUND: Currently approved CD19 directed CAR T cell therapies have improved outcomes for non-Hodgkin lymphoma (NHL) patients, however only 30-40% of patients treated at 2nd relapse or later obtain long term remission after this treatment (Neelapu et al. 2017; Schuster et al. 2019). A next generation autologous CAR T cell, bbT369, has been devised specifically to address and overcome hypothesized mechanisms of CD19 CAR T cell treatment failure including loss/downregulation of target antigen, loss of co-stimulation pathways on tumor cells, exhaustion of CAR T cells, and CAR T cell dysfunction due to an immunosuppressive microenvironment (Shah and Fry 2019). bbT369 is a dual targeting (CD79a/CD20) CAR T cell that uses an OR gated design (encounter with either antigen activates the CAR T cell) to limit antigen escape. The construct contains split costimulatory domains (CD28 and 41BB) to enhance T cell activation and a gene edit knocking-out CBLB function intended to enhance potency and reduce T cell exhaustion. Studies have demonstrated CD79a and CD20 may be ideal targets in B cell lymphoma, with high tissue restricted expression. In Daudi cell and mouse models, bbT369 outperformed CD19 directed CAR T cells demonstrating increased IL-2 secretion and longer durations of tumor control (Certo et al, 2022). METHODS: CRC-403 (NCT05169489) is a non-randomized, open label, multi-site Phase 1/2 study enrolling relapsed and/or refractory B Cell Non-Hodgkin's Lymphoma (NHL), including diffuse large B cell lymphoma (DLBCL), high-grade B cell lymphoma (HGBCL), primary mediastinal (thymic) large B cell lymphoma (PMBCL), follicular lymphoma (FL) 3b, and DLBCL transformed from FL (tFL). Patients must have relapsed after ASCT or after at least 2 prior lines of therapy, including an anti-CD20 monoclonal antibody and an anthracycline containing chemotherapy regimen. Patients with tFL must be relapsed after receipt of ASCT or at least 2 prior therapies after documentation of transformation. In addition to patients naïve to CAR T cell therapy, patients with prior exposure to non-investigational CD19 CAR T cell therapy are eligible for enrollment if they did not experience disease progression within 6 weeks of initial CAR T cell infusion. Approximately 50 patients will be enrolled during the dose escalation phase to ensure a maximum of 36 subjects will be treated with bbT369. The primary endpoint of the phase 1 portion of this study is incidence of safety events, including adverse event, adverse events of special interest and dose limiting toxicities. Secondary endpoints include investigator assessed overall response rate including complete response rate, time to response, time to complete response and time to next therapy for B-NHL. Exploratory endpoints include OS, DOR, PFS, bbT369 expansion kinetics including expansion and persistence, immunophenotype in peripheral blood and tumor biopsy tissue with the objective of correlating findings with clinical response. The starting dose of bbT369 is 50x106 CAR+ T cells and a BOIN design is being used for dose escalation/de-escalation decisions during the study. Upon establishment of the RP2D, the phase 2 portion will begin enrollment.

High Grade B Cell NHL Outcomes: Real World Experience from the UK

Incidence of non-Hodgkin lymphoma (NHL) is increasing; it is already the sixth most common malignancy in UK (Cancer Research UK NHL incidence statistics 2022). It can present in aggressive or indolent form. Whilst for those with chemo-sensitive disease prognosis is good, with 5 year overall survival (OS) >50%, those with relapsing/refractory (R/R) forms have consistently poor outlook. Historically only 30-40% of these tolerate/respond to salvage therapy with <30% of those who respond able to proceed to consolidation with autologous stem cell transplant (ASCT). Despite this ~50% will relapse (Crump et al, Blood 2017 doi: 10.1182/blood-2017-03-769620). Recent treatment advances seek to address this area of unmet need. CAR-T cell therapy is presented as a highly effective solution for this cohort of patients. The pivotal studies leading to licensing and widespread adoption of these therapies drew comparison from SCHOLAR-1 which pooled data from 2 phase 3 clinical trials and 2 observational cohorts enabling data on 636 patients with refractory NHL to be analysed. There are challenges with this dataset and notably it does not include UK patients. We analysed patient level data for a UK NHL cohort and compare these to other, more historical data sets. 165 patients were identified. Diagnoses included primary DLBCL, DLBCL-transformed follicular lymphoma and PMBCL. Demographics: 92 male, 73 female; median age 64 (24-86yrs). Stage at diagnosis: I 10.3%, II 13.3%, III 21.2%, IV 54.5%, unknown <1%. IPI: 0- 2.4%, 1 - 13.3%, 2 - 27.3%, 3 - 26.7%, 4 - 18.8%, 5 - 3.6%, unknown 7.8%. C-MYC present in 20.7% of those where evaluated (24/116); of those 41.7% (10) double hit, 12.5% (3) triple hit. Cell of origin available for 54.5% (ACB 36.7%, GCB 63.3%). >90% considered suitable for intensive therapy; PS: 0 - 43%, 1 - 33.9%, 2 - 12.7%, 3 - 9.1%, 4 - <1%, unknown 4.2%. Nearly 2 thirds required >1 line treatment: 1 - 37%, 2 - 33.3%, 3 - 20.6%, 4 - 6.1%, 5 or greater - 3%. First line: 57.6% (95/165) 6-8 cycles R-CHOP (22% also received CNS prophylaxis - HD or intrathecal methotrexate, 16.8% additional radiotherapy (IFRT)); 10.3% abbreviated R-CHOP +/- IFRT; 9.7% dose attenuated R-CHOP, 16.4% R-CODOX-M/R-IVAC, 4.8% R-mini-CHOP, 1.8% non-intensive regimes and <1% IFRT alone. Best response was CR 52.7%, PR 11.5%, SD 13.3%, PD 11.5%, not available 10.9%. 63% (104/165) required second line treatment; time to treatment ranged from <6 months (27.9%), 6-12 months (32.7%), >12 months (37.5%), unknown in 2 cases. PS at first relapse: PS 0 - 36.6%, 1 - 45.5%, 2 - 7.1%, 3 - 7.1%, 4 - <1%. 35.6% with refractory disease had improvement in PS with treatment despite suboptimal response. 7.1% were considered too frail for further treatment. Second line therapy was primarily platinum based +/- IFRT +/- HD Mtx 71.2%; other intensive regimes included R-IVE, R-DHAP, R-ESHAP, R-CHOP and MATRIX (11.5%), less intensive regimes included R-lenalidomide, R-BP, R-miniCHOP, R-CVP, IFRT and R-CEPP (17.3%). Best response was CR 24.0%, PR 18.3%, SD 7.7%, PD 44.2%, not evaluated 5.8%. 31.7% proceeded to ASCT, 6 required >1 line of salvage therapy prior to ASCT. Exclusion basis: refractory disease 26.3%, declining PS and suboptimal response 7.5%, age only (>72years) 8.75%, frailty (PS > 2 - treatment induced/ comorbidities) 16.25%, age and frailty 13.75%, failed harvest 6.25%, patient choice 6.3%. 22 (66.6%) achieved CR after ASCT. 45 had suboptimal response to ≥2 lines intensive therapy but maintained fitness and would have been eligible for CAR-T. 47% (49/104) of those requiring salvage therapy proceeded to third line, 38.8% had refractory disease requiring treatment within 12months of first salvage treatment. 14.3% (7/49) had received ASCT. 57.1% (28/49) received intensive therapy, 18.4% (9/49) proceeded to ASCT. 42.9% were treated non-intensively. This UK dataset, analysing real world experience, highlights the challenge of high grade NHL. Whilst OS is: 2 year 63%, 5 year 29.1% with an additional 4.2% and 27.9% alive but <2 and <5 years from diagnosis respectively, for those with R/R disease OS is significantly reduced: 2 year 35.8%, 5 year 21.8%. CR rate after first line is 53.9%. However, 63% of patients required second line treatment; 4.8% relapsed >12months, 33.3% refractory; objective response rate (ORR) 42.3% (CR 24.0%), 35.8% alive at 2 years, 21.8% at 5 years. This is comparable to results from the referenced SCHOLAR-1 study supporting it as a reference point for new therapies.

Abstract 581: bbT369, a dual-targeted and CBLB gene-edited autologous CART product, demonstrates anti-lymphoma activity in preclinical mouse models

Abstract Anti-CD19 CAR T cell therapies have improved outcomes for non-Hodgkin lymphoma (NHL) patients. However, only 30-40% of patients treated with commercially available CART cell therapies obtain long term remission, highlighting the need for more efficacious and durable therapies. Emerging clinical data suggest several failure modes for CD19 CAR T cell therapies: including loss or downregulation of CD19 antigen, loss of co-stimulation pathways on tumor cells, exhaustion of CAR-T cells, and immunosuppressive microenvironments. To overcome these hurdles, we devised the next-generation autologous CAR-T cell therapy bbT369. bbT369 is dual targeted (CD79a/CD20) CAR T cell therapy that uses an OR gate design to limit antigen escape, has split 41BB and CD28 co-stimulatory domain architecture to augment T cell activation, and contains a knock-out of the CBLB gene to enhance potency and reduce T cell exhaustion. Here we report the first results with bbT369, demonstrating anti-lymphoma activity in in vitro assays and in vivo using xenograft mouse models. We demonstrate that CD79a and CD20 expression is B cell lineage restricted in normal human tissue and confirm that these proteins are co-expressed in diffuse large B cell samples. To target these antigens, we show a split dual-targeting CAR configuration is optimal for bbT369-directed tumor cell killing. Using an engineered megaTAL, we demonstrate high on-target activity of greater than 75% insertions and deletions (Indels) at the CBLB target site using clinical-scale manufacturing processes and low off-target activity (all off-targets less than 0.2%). In in vitro tumor co-culture assays, we show that inclusion of the CBLB gene edit in bbT369 increases Interleukin (IL)-2 production relative to an unedited anti-CD79a/CD20 CAR T cell control. Using various xenograft mouse models, we showed that bbT369 has similar or improved efficacy compared to anti-CD19 CAR drug product, including in low tumor-antigen models. In the Toledo subcutaneous xenograft model, bbT369 showed a 3-fold increase in T cell expansion compared with an unedited anti-CD79a/CD20 dual-targeting CAR T cell control. Furthermore, while a fraction of mice (3/5) receiving the unedited anti-CD79a/CD20 dual-targeting CAR T cells experienced late relapses (between 60-80 days following initial tumor clearance), all mice (n=5) receiving bbT369 were fully protected from late relapses (up to day 104 of follow-up). Collectively, the data support a first-in-human trial for bbT369 to evaluate initial safety and efficacy in NHL patients. Citation Format: Michael Certo, Christopher Baldeviano, Sharlene Adams, Martin Asimis, Alexander Astrakhan, Andy Chavkin, Maria L. Cabral, Jimmy Chu, Marie Debrue, Devina Desai, John Evans, Pinky Htun, Amanda Iniguez, Jordan Jarjour, Carl Johnson, Harini Kantamneni, Sema Kurtulus, Michael Magee, Unja Martin, Seamus McKenney, Sara Miller, Prashant Nambiar, Vinh Khang Nguyen, Mauris Nnamani, Jen Obrigewitch, Lisa Pechilis, Molly Perkins, Christopher Petersen, Jason Pinger, Cindy Rogers, Nick Rouillard, Kendal Sanson, Emily Thompson, Collin Walter, Roslyn Yi, Sarah Voytek, Philip Gregory. bbT369, a dual-targeted and CBLB gene-edited autologous CART product, demonstrates anti-lymphoma activity in preclinical mouse models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 581.

Clinical Outcomes of Patients With B-Cell Non-Hodgkin Lymphoma in Real-World Settings: Findings From the Hemato-Oncology Latin America Observational Registry Study.

PURPOSEReal-world evidence on non-Hodgkin lymphoma (NHL) management in Latin America is currently lacking. The objective of this study was to describe treatment characteristics and outcomes of NHL in Latin America.METHODSA total of 2,967 patients with NHL with aggressive and indolent subtypes, including diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), mantle-cell lymphoma (MCL), and mucosa-associated lymphoid tissue (MALT) lymphoma, with incident or prevalent diagnosis between 2006 and 2015, were retrospectively identified using clinical charts registered in the Hemato-Oncology Latin America Observational Registry. Associations between treatment regimen and age at diagnosis with clinical outcomes within each subtype were estimated using Cox proportional hazard regression.RESULTSMost patients with NHL received 1L chemoimmunotherapy, most commonly cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) with/without rituximab. Five-year survival rates were higher for MALT lymphoma (90.8%) and FL (87.6%) versus DLBCL (69.0%) and MCL (57.1%), with variations between countries. The median overall survival from first relapse for patients with DLBCL was 6.6 years, with lower risk of death for those diagnosed at age < 65 years (hazard ratio = 0.732; P = .0161). Patients achieved a longer median progression-free survival with 1L rituximab-CHOP (R-CHOP) versus CHOP or rituximab, cyclophosphamide, vincristine, and prednisone (RCVP) (7.7 v 3.0 or 1.8 years, respectively). Use of regimens other than R-CHOP was associated with a higher risk of death/progression for patients with DLBCL (rituximab, ifosfamide, carboplatin, and etoposide/ifosfamide, carboplatin, and etoposide) and FL (CHOP). There was no relationship between treatment prescribed and age at diagnosis with outcomes from first/second relapse in DLBCL and FL.CONCLUSIONDifferences in treatment outcomes between NHL subtypes were observed, reflecting variations in NHL management and barriers to treatment access in Latin America. These data provide necessary evidence to understand NHL management in this region and highlight the need to improve treatment outcomes for these patients.

Clinical relevance of serum-derived exosomal messenger RNA sequencing in patients with non-Hodgkin lymphoma.

Background: The clinical utility of mRNA cargo in exosomes is unclear, although exosomes have potential as non-invasive biomarkers. This study aimed to investigate the feasibility of exosomal mRNA sequencing for monitoring disease status and predicting outcomes in non-Hodgkin lymphoma (NHL) patients.Methods: Exosomes were isolated from archived serum samples of 33 patients with NHL who were registered into our prospective cohort: diffuse large B-cell lymphoma (DLBCL, n = 17), intravascular B-cell lymphoma (IVL, n = 1), primary mediastinal large B-cell lymphoma (PMBL, n = 4), follicular lymphoma (FL, n = 3), mantle cell lymphoma (MCL, n = 3), and extranodal NK/T-cell lymphoma (ENKTL, n = 5). Exosomal mRNA sequencing was performed, and its concordance with clinical course was analyzed and compared with those of circulating tumor DNA (ctDNA) mutations.Results: Exosomal mRNA sequencing was performed successfully in 26 cases (79%, 26/33), whereas the remaining seven cases were not completed due to their small amount of RNA. The exosomal mRNA sequencing of DLBCL showed gene expression profiles consistent with activated B-cell-like and germinal center type. The longitudinal assessment of exosomal mRNA sequencing results in accordance with the clinical course showed that the post-treatment changes of exosomal mRNA expression were more consistent with treatment outcome than were those of ctDNA mutations. In particular, the exosomal mRNA expression of genes such as BCL2 and BCL6 was increased at the time of disease progression in DLBCL and FL patients.Conclusions: This study demonstrated the feasibility of exosomal mRNA expression profiles as a biomarker for NHL patients. Our results might provide the rationale for studies to explore the potential of exosomal mRNA as a biomarker in NHL patients.

Soluble ICAM-1 As Effective Serologic Marker to Predict Clinical Outcome for Early -Stage I/II Nasal Natural Killer /T-Cell Lymphoma

Background: Extranodal Natural killer (NK) /T-cell lymphoma, nasal type (NNKTL), a unique and aggressive neoplasm, is commonly observed in East Asia and Latin America. Even at early stages, NNKTL has a poor clinical outcome because intrinsic chemotherapy resistance, rapid local disease progression and distant metastasis. Despite the use of high dose radiation therapy with or without multiagent chemotherapy regimens, NNKTL has a high rate of relapse (25-40%). Moreover, the estimated 5-year survival on relapsed NNKTL is 52.3%. The identification and validation of readily available biomarkers that predict treatment outcomes can aid in the use of consolidation cellular therapy (i.e. allogeneic bone marrow transplant) and tailored surveillance programs. Elevated serum levels of soluble intercellular adhesion molecule-1 (sICAM-1) had been associated with inferior outcomes in non-Hodgkin lymphoma, but their utility in NNKTL remains unidentified. Here, we examined sICAM-1 levels in patients of early-stage NNKTL and its correlation with clinical characteristics, response to the therapy and clinical outcomes.Material and Methods: This was a retrospective observation study conducted in patients diagnosed as Stage I/II NNKTL in the upper aerodigestive tract treated at Shanghai Cancer Hospital, Shanghai, China and for which biospecimens collected at diagnosis and at the end of therapy (EOT) (frozen serum) were available. The study was approved by the IRB (Protocol number). Baseline and EOT sICAM-1 levels were measured by ELISA (R&D systems, Minneapolis, MN, sensitivity =0.35ng/ml) according to the manufacture' s protocol. Differences of sICAM-1 expression between baseline and EOT were analyzed by paired t-test. Difference of sICAM-1 between complete response and non-complete response groups were determined by Mann-Whitney U-test. Comparing sICAM-1 among different clinical characteristics was determined by Chi square and Fisher's test. Differences in overall survival (OS) and progression-free survival (PFS) between patients with high and low sICAM-1 levels were analyzed by the Kaplan-Meier method.Results:A total of 74 patients were included in the study (18F/56M), the median age of the patients was 45.5 (19-73). Patients were treated with radiation therapy alone (N=34), or combined modality therapy (N=40). As previously noted in other studies, achievement of a complete response at the end of therapy was associated with a better PFS and OS (P<0.001). The median sICAM-1 at the EOT was higher (210.2+86.7ng/ml) when compared to baseline levels (166.2+70.5ng/ml, p<0.001). Of interest the sICAM-1 levels at baseline were higher among patients that failed to complete a complete response (CR) (241.2+58.7ng/ml vs 162.6+69.3ng/ml, p= 0.0265).The net change (EOT minus Baseline) of sICAM-1 levels (ΔsICAM-1) was significantly higher is patients with relapse disease (81.4+63.1 vs 33.5+81.2, p<0.023). Furthermore, higher ΔsICAM-1 was associated with shorter PFS (40m vs 56m, P=0.05) and a trend towards a poor overall survival although p value did not reach statistically difference.Conclusion: Higher sICAM-1 levels at diagnosis were associated with primary treatment failure in early stage NNKTL. In addition, an elevated ΔsICAM-1 in patients achieving a complete response to first like therapy were associated with relapse disease and shorter PFS. Together, our data suggests that sICAM-1 may be used as serological biomarker to monitor and predict clinical outcome of early stage NNKTL patients. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

A mass transfer model for computational prediction of proliferation and therapy outcome of non-Hodgkin lymphoma

Mathematical modeling constitutes an emerging area of oncological research aiming to predict spatial and temporal evolution of tumors, by describing many different phenomena, which occur at different scales. Among these, modeling at the macroscopic scale has an interesting potential of application, when applied in a framework where actual diagnostic imaging is used to identify the metabolic tumor volume undergoing proliferation.Diffuse large B-cell lymphoma (DLBCL) is a cancer of B cells, a type of lymphocyte that is responsible for producing antibodies. The most common form of Non-Hodgkin lymphoma among adults, DLBCL can arise in any part of the body and may play a very aggressive malignancy. This paper aims to enforce a mass transfer modeling approach in order to gain deeper insight into the dynamics of tumor growth at the tissue scale and to develop a predictive, quantitative method for each patient at hand. A cohort of 18 patients has been successfully enrolled to validate the model. Results confirm that tumor proliferation, at the macroscopic scale, scores many nonlinear features, and show that the proposed model could be used by oncologists as a decision support tool towards personalized treatment optimization of solid tumors.

The Influence of Interleukin-2 Gene Polymorphisms on the Risk and Clinical Outcome of Non-Hodgkin Lymphoma.

Polymorphisms in the IL-2 gene are associated with various diseases and cancers including non-Hodgkin lymphoma (NHL). The aim of the study is to assess the impact of IL-2 genetic polymorphisms [- 330T/G (rs2069762) and + 114T/G (rs2069763)] on the susceptibility and prognosis of NHL. Sixty patients with NHL as well as 60 age and sex matched healthy control subjects are included in this study. IL-2 genotypes were determined by Polymerase Chain Reaction-Restriction Fragment length Polymorphism assay (PCR-RFLP). Our study revealed that both IL-2 rs2069762 and rs2069763 gene polymorphisms are associated with increased risk of developing NHL; OR = 3.609 (95% CI = 1.527-8.417) and 4.142 (95% CI = 1.637-10.538) respectively. Moreover, the simultaneous presence of both polymorphisms is associated with about 6 fold increased risk of developing NHL. Also, IL-2 rs2069762 and rs2069763 gene polymorphisms increase the risk of unfavorable prognosis with OR = 17.300 (95% CI = 3.392-87.725) and 10.424(95% CI = 1.870-58.413) respectively. These findings suggest that IL-2 (rs2069762) and (rs2069763) gene polymorphisms could be involved in the development of NHL.

Clearance of Hepatitis C Virus (HCV) Is Associated With Improved Outcomes in HCV-Associated Lymphoma

BackgroundImproved hepatitis C virus (HCV) clearance due to directly acting antiviral agents has led to remarkably improved outcomes of indolent HCV-associated non-Hodgkin lymphoma (NHL). The impact of directly acting antivirals on the outcomes of aggressive NHL is still under investigation. Characteristics of HCV-associated NHL in black patients are not well characterized. We report outcomes of HCV-associated NHL compared to their HCV-negative counterparts in a predominantly black population. Patients and MethodsPatients with lymphoma between January 2007 and December 2017 were retrospectively studied. Depending on presence or absence of HCV RNA, patients were grouped into HCV positive (HCV+) and HCV negative (HCV−) cohorts. Depending on virologic clearance (VC), HCV+ were classified into HCV+ with VC and HCV+ without VC. Overall response rate (ORR), complete response, overall survival (OS), and progression-free survival (PFS) of HCV+ patients with and without VC were compared to HCV− patients. ResultsOf 397 patients with lymphoma, 40 had HCV. Black comprised 90% of HCV+ patients. Diffuse large B-cell lymphoma was most frequent (47%) in the HCV+ group. HCV+ patients without VC had significantly worse OS and PFS compared to HCV− patients. There were no differences in ORR, complete response, PFS, and OS of HCV+ patients with VC and HCV− patients. These results were consistent in subgroups of diffuse large B-cell lymphoma and aggressive lymphoma. ConclusionHCV clearance is positively associated with lymphoma outcomes in black patients. Patients who clear HCV have noninferior outcomes to HCV− patients, while those who fail to clear HCV have significantly worse outcomes.

Outcome of non Hodgkin lymphoma: A single center experience

Outcome of non Hodgkin lymphoma: A single center experience

18F-FDG PET/computed tomography may predict the outcome of newly diagnosed indolent non-Hodgkin lymphoma in patients managed with initial 'watch-and-wait' approach.

The aim of this study was to investigate the role of F-fluorodeoxyglucose (F-FDG) PET/computed tomography (CT) in the outcome of non-Hodgkin lymphoma (NHL) in patients managed with initial 'watch-and-wait' treatment. Sixteen patients with newly diagnosed NHL treated with initial watchful waiting were retrospectively recruited. They had a baseline F-FDG PET/CT and at least one follow-up PET/CT. The standard uptake values (SUV), metabolic tumor volume (MTV) and total lesions glycolysis (TLG) of lymphoma were measured in PET/CT. They were followed up for at least 2 years or until disease progression. The endpoint was the time to initiation of lymphoma treatment (TLT). Comparing the baseline and the follow-up PET/CT, four out of 16 patients showed spontaneous regression of lymphoma, three of the 16 patients had stable disease and the remaining nine of the 16 patients had progressive disease in the follow-up PET/CT. After a median follow-up of 32 months (range 14-90 months), 10/16 patients had progressive disease and chemotherapy was initiated. The median TLT was 21.0 months. In univariate analysis, MTV and TLG in baseline PET/CT were significant to predict TLT. Kaplan-Meier curves showed a statistical difference for TLT in the two groups of patients stratified by MTV or TLG at baseline (median TLT, 66.0 months vs. 12.0 months, P = 0.007). However, patients' age, Ann Arbor staging, International Prognostic Index and SUVmax were not significant. A proportion of patients with NHL might experience spontaneous regression of lymphoma. F-FDG PET/CT turned out as a prognostic factor for TLT in patients with NHL under watchful waiting.