Therapy For non-Hodgkin Lymphoma Research Articles

Comprehensive Bridging Radiotherapy for Limited Pre-CART Non-Hodgkin Lymphoma

This cohort study examines the role of comprehensive bridging radiotherapy in the setting of chimeric antigen receptor T-cell therapy for non-Hodgkin lymphoma.

Abstract CT164: Phase 1a/1b clinical trial of LP-284, a highly potent TP53 mutation agnostic DNA damaging agent, in patients with refractory or relapsed lymphomas and solid tumors (NCT06132503)

Abstract Background: Patients (pts) with relapsed or refractory (R/R) aggressive non-Hodgkin lymphoma (NHL) typically experience poor prognosis. In addition, despite advances in NHL therapies, TP53 mutations and double rearrangements of MYC and BCL2 have been associated with adverse clinical outcomes. LP-284, a DNA damaging agent with nanomolar potency in NHL cells, is agnostic of TP53 mutation status. In a TP53-mutated mantle cell lymphoma (MCL) xenograft model, LP-284 inhibited tumor growth at least 3-fold more than ibrutinib and bortezomib. Furthermore, LP-284 resulted in near complete tumor regression in a MCL model that is refractory to ibrutinib and bortezomib. In a high-grade B-cell lymphoma with MYC and BCL2 rearrangement xenograft model, LP-284 led to 99% tumor growth inhibition when used as a single agent and showed synergistic effect with rituximab. The above data strongly suggests that LP-284 is a promising therapy for aggressive R/R NHL, especially subgroups with TP53 mutation and/or MYC/BCL2 rearrangements. LP-284 also showed promise in the setting of solid tumors, as evidenced by strong anti-tumor potency in a spectrum of solid tumor cell lines and sarcoma xenograft models. Methods: This Phase 1, first-in-human, open-label, dose escalation study assesses the safety, tolerability, pharmacokinetics (PK) and clinical activity of LP-284 in adult pts with R/R lymphomas and solid tumors. Up to 30 adult pts will be enrolled in the Phase 1a dose escalation study. After completion of Phase 1a, up to 40 pts with R/R diffuse large B-cell lymphoma (DLBCL) and MCL, each, will be enrolled for a dose expansion Phase 1b study. The primary objectives of the Phase 1a study are to evaluate the safety and tolerability of escalating doses of LP-284 and to determine the MTD and RP2D. Participants will receive LP-284 via i.v. infusion on days 1, 8, and 15 of 28-day cycles. A Bayesian Optimal Interval (BOIN) design is being used to determine the MTD. Dose escalation involves single patient cohorts for the first 2 dose levels and at least 3 pts/cohort for subsequent dose levels. The secondary objectives are to characterize the PK and to assess the clinical activity of LP-284. The exploratory objectives are to evaluate the association between tumor response and changes in ctDNA and importantly to identify potential genomic features associated with LP-284 response, particularly those related to DNA damage response pathways. The primary objectives of Phase 1b are to obtain preliminary estimates of clinical activity in adult patients with R/R DLBCL and MCL, and to determine the dose of LP-284 for further development based on exposure-response/safety relationships derived from the totality of the data obtained from both Phase 1a and 1b. Trial (NCT06132503) is open to accrual. Citation Format: Jianli Zhou, Reginald Ewesuedo, Giulia Agnello, Aditya Kulkarni, Kishor Bhatia. Phase 1a/1b clinical trial of LP-284, a highly potent TP53 mutation agnostic DNA damaging agent, in patients with refractory or relapsed lymphomas and solid tumors (NCT06132503) [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 CT164.

Abstract 6327: Impact of G-CSF on safety and efficacy of CAR T-cell therapy in non-Hodgkin lymphoma

Abstract Introduction: Chimeric antigen receptor T-cell (CAR-T) therapy is an established treatment modality for the management of refractory and/or relapsed non-Hodgkin lymphoma (NHL). Despite restrictions on granulocyte colony-stimulating factor (G-CSF) use in registration clinical trials due to potential worsening of cytokine release syndrome (CRS), G-CSF is often prescribed for neutrophil recovery post-CAR-T in clinical practice. We conducted a retrospective study to assess the association between G-CSF use and the safety and efficacy of CAR-T. Methods: Following Institutional Review Board approval, we retrospectively analyzed NHL patients receiving commercial CD19-targeted CAR-T across Mayo Clinic sites (Arizona, Florida, and Minnesota) between October 2017 and May 2023. Demographics, labs, and post CAR-T events were collected. Electronic medical records were reviewed for G-CSF exposure within Day 1 - 100 post-CAR T. Differences by G-CSF status were examined using a Chi-square test and Kruskal Wallis tests. Hazard ratios (HR) and 95% confidence intervals (CI) for overall survival (OS) were calculated using Cox model. Results: Among 270 CAR-T patients; 106 received G-CSF within 30 days and 164 did not. Median age was 56.9 with G-CSF and 58.3 without G-CSF. Most were male (75.2% G-CSF, 62.6% no G-CSF). Diffuse large B cell lymphoma was the predominant NHL subtype (67.0% G-CSF, 65.2% no G-CSF). G-CSF within 30 days was not associated with reduced incidence of neutropenic fever (11.7% G-CSF vs 9.9% no G-CSF, p = 0.6593) or documented infection (22.1% vs 18.3%, p = 0.4439). G-CSF correlated with decreased profound neutropenia duration (ANC < 100 μL, 0 vs 2 days, p < 0.0001) and incidence within 30 days ( 31.7% vs 60.4%, p < 0.0001) as well as incidence of protracted profound neutropenia (> 7 days, 3.8% vs 22.8%, p < 0.0001). G-CSF was associated with a higher incidence of cytopenias between days 30 -100: severe neutropenia (ANC < 500/uL, 28.8% vs 15.2%, p = 0.0075), severe anemia (Hb < 8 g/dL, 21% vs 9.7%, p = 0.0114), and severe thrombocytopenia (Plt < 50 g/L, 35.2% vs 20.9%, p = 0.0099). Logistic regression analysis showed that none of the examined covariates, including prior autologous stem cell transplant, ECOG PS score, and receipt of bridging therapy, were associated with severe neutropenia likelihood. G-CSF was associated with a higher CRS incidence (89.6% vs 79.9%, p = 0.0343), but grade 3 CRS or higher (4.7% vs 3.7%, p = 0.6675) was no different. No difference in complete response rates (66% vs 61.1%, p = 0.4707) or 2-year OS (p = 0.523) was observed between the 2 groups. Conclusion: G-CSF within 30 days was associated with reduced duration and incidence of profound neutropenia without a significant impact on incidence of neutropenic fever or documented infections. There was a signal of association between G-CSF and increased incidence of low-grade CRS and delayed cytopenias (day 30-100) that warrants confirmation in larger studies. Citation Format: Lay She Ng, Claire I. Yee, Radhika Bansal, Mohamed A. Kharfan-Dabaja, Grzegorz S. Nowakowski, Allison C. Rosenthal, Javier Munoz, Januario Castro, Wern Lynn Ng, Hemant S. Murthy, Yi Lin, Matthew R. Buras, Madiha Iqbal, Yucai Wang, Talal Hilal. Impact of G-CSF on safety and efficacy of CAR T-cell therapy in non-Hodgkin lymphoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6327.

Chimeric Antigen Receptor (CAR)-T Cell Therapy for Non-Hodgkin's Lymphoma.

This review focuses on the use of chimeric antigen receptor (CAR)-T cell therapy to treat non-Hodgkin's lymphoma (NHL), a classification of heterogeneous malignant neoplasms of the lymphoid tissue. Despite various conventional and multidrug chemotherapies, the poor prognosis for NHL patients remains and has prompted the utilization of groundbreaking personalized therapies such as CAR-T cells. CAR-T cells are T cells engineered to express a CAR that enables T cells to specifically lyse tumor cells with extracellular expression of a tumor antigen of choice. A CAR is composed of an extracellular antibody fragment or target protein binding domain that is conjugated to activating intracellular signaling motifs common to T cells. In general, CAR-T cell therapies for NHL are designed to recognize cellular markers ubiquitously expressed on B cells such as CD19+, CD20+, and CD22+. Clinical trials using CAR-T cells such as ZUMA-7 and TRANSFORM demonstrated promising results compared to standard of care and ultimately led to FDA approval for the treatment of relapsed/refractory NHL. Despite the success of CAR-T therapy for NHL, challenges include adverse side effects as well as extrinsic and intrinsic mechanisms of tumor resistance that lead to suboptimal outcomes. Overall, CAR-T cell therapies have improved clinical outcomes in NHL patients and generated optimism around their future applications.

Outpatient Administration of Chimeric Antigen Receptor T-Cell (CAR-T) Therapy for Non-Hodgkin Lymphoma (NHL), in a Large Multi-Center Network

Outpatient Administration of Chimeric Antigen Receptor T-Cell (CAR-T) Therapy for Non-Hodgkin Lymphoma (NHL), in a Large Multi-Center Network

Safety and Efficacy of Bridging Radiation Therapy in the Context of CD19 CART Therapy for Non-Hodgkin Lymphoma: Systematic Review and Meta-Analysis

Safety and Efficacy of Bridging Radiation Therapy in the Context of CD19 CART Therapy for Non-Hodgkin Lymphoma: Systematic Review and Meta-Analysis

Drug-Loaded Biomimetic Carriers for Non-Hodgkin's Lymphoma Therapy: Advances and Perspective.

Chemotherapy remains the mainstay of treatment for the lymphoma patient population, despite its relatively poor therapeutic results, high toxicity, and low specificity. With the advancement of biotechnology, the significance of drug-loading biomimetic materials in the medical field has become increasingly evident, attracting extensive attention from the scientific community and the pharmaceutical industry. Given that they can cater to the particular requirements of lymphoma patients, drug-loading biomimetic materials have recently become a potent and promising delivery approach for various applications. This review mainly reviews the recent advancements in the treatment of tumors with biological drug carrier-loaded drugs, outlines the mechanisms of lymphoma development and the diverse treatment modalities currently available, and discusses the merits and limitations of biological drug carriers. What is more, the practical application of biocarriers in tumors is explored by providing examples, and the possibility of loading such organisms with antilymphoma drugs for the treatment of lymphoma is conceived.

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

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

Perceptions and Practices of Clinical Trial Enrollment Among Patients with Non-Hodgkin Lymphoma, Caregivers, and Providers

BACKGROUND : Clinical trials are critical to evaluate new therapies in non-Hodgkin lymphoma (NHL) and to enhance patient outcomes; however, accrual to these studies remain low. 1 Multiple patient- and healthcare provider (HCP)-related barriers contribute to the persistently low rates of trial participation. 2 Low enrollment in cancer clinical trials result in delays in the advancement of cancer research, as well as an escalation in the cost of developing and disseminating effective treatments. 2 HCPs play a critical role in advising, motivating, and recruiting patients to clinical trials. We designed a patient-provider tethered educational initiative in collaboration with the Leukemia and Lymphoma Society and BlackDoctors.org that examined real-world experiences and perceptions of clinical trials among HCPs, patients with NHL, and their caregivers. METHODS : Two educational activities were designed: The 1-hour patient/caregiver activity was broadcasted on CancerCoachLive.com in February 2023 and featured a multidisciplinary NHL expert panel of two hematologists/oncologists and a nurse practitioner. This program addressed the value of clinical trials, diverse representation, novel therapies under investigation, and real-world experiences from a patient panel. The complementary 1-hour HCP program was hosted on OMedLive.com in March 2023 and featured the same multidisciplinary NHL expert faculty panel and included pre-recorded patient interviews and an interactive live Q&A. The online programs remain on-demand for one-year post-activity. Attitudes toward clinical trials were assessed in both activities (patient and HCP). Additionally, the HCP survey assessed barriers and challenges managing patients with NHL and intent to modify treatment plans post-program were also assessed. RESULTS : To date, 1,706 HCPs and 2,119 patients with NHL or their caregivers participated in this educational initiative. Of the HCPs, 78% were hematologists/oncologists, 15% practice at an academic medical center, 26% practice at a community hospital, and 65% manage an average of 15 patients with NHL per week. Of the patients/caregivers, 72% identified as White, 17% were Black/African American, 7% were Hispanic, 4% were Native Hawaiian/Pacific Islander, and 67% were ≥65 years old. Most of the participants (89%) in the patient/caregiver activity were ≥55 years old, 67% were >65 years. At the time of the assessment, 31% of patients were receiving watch and wait, 15% were in remission, 15% had recurrent/relapsed disease, and 12% reported having had newly diagnosed NHL. Most patients (93%) indicated that they have not participated in a clinical trial but were open to discussions with their HCPs. Patients and their caregivers expressed a high degree of interest in clinical trials. Specifically, 78% of respondents indicated that they would participate in a clinical trial if they were eligible. There were misalignments in patient-provider perceptions regarding the top patient concerns when considering participation in a clinical trial. Patients or their caregivers cited potential side effects (50%), associated costs of treatment (20%), and transportation/lack of time or resources (20%) as their top concerns related to clinical trial participation. HCPs cited fear of the unknown (34%), potential side effects (27%), and potential associated costs (15%) as their top concerns. Post-activity, 64% of patients or their caregivers indicated that they were confident in discussing clinical trials with their HCP. HCPs reported that the most common barrier to patient enrollment in clinical trials they were motivated to address at their institution post-activity were lack of clinical trials at their institution or geographic region (51%) and patient lack of interest (28%). CONCLUSIONS: These data from large groups of HCPs, patients, and caregivers provided valuable insights into patient, caregiver, and provider perceptions of clinical trials and strong willingness on the part of patients with NHL to participate in trials. Importantly, we found that targeted educational interventions can enable most patients and caregivers to feel confident in discussing clinical trials with their HCP and can motivate HCPs to increase clinical trial opportunities for diverse populations of patients with NHL. Unger JM, et al. Am Soc Clin Oncol Educ Book. 2016; 35:185-198.Ford JG et al. Cancer. 2008; 112:228-242.

Digital Health Literacy in Patients with Non-Hodgkin Lymphoma: Informing Intervention Approaches to Address Financial Toxicity

Introduction: Financial toxicity is the harmful effect of treatment costs on a patient's quality of life. Financial toxicity is common among cancer patients, and patients with hematologic malignancies often report worse financial toxicity than patients with other cancers. Thus, interventions to address financial toxicity in patients with hematologic cancers are urgently needed. Promising approaches include the use of digital media such as websites and educational videos. However, digital interventions may not be accessible for patients with low digital health literacy (DHL; the capacity to find and understand health-related information using electronic media). Information about DHL in patients with blood cancers is needed to inform future interventions addressing financial toxicity and other quality-of-life related issues. Here, we present a mixed-methods study describing DHL and its correlates among patients with non-Hodgkin lymphoma (NHL) who participated in a larger study about financial toxicity. Methods: Patients who received systemic therapy for NHL within the last year (N=50) participated in a cross-sectional study about the financial impact of cancer. Participants self-reported financial toxicity (Comprehensive Score for Financial Toxicity; COST) and digital health literacy (electronic Health Literacy Scale; eHEALS). They also rated whether they would consider using online tools to manage cancer-related expenses or communicate with their team about financial concerns, if offered in the future (yes, maybe, no). A subset of survey participants (n=13) completed a follow-up qualitative interview. Survey participants were purposively selected for interviews based on self-reported financial toxicity. Independent-samples t-tests, ANOVA, and correlations were used to test relationships between financial toxicity, DHL, sociodemographic factors, and patient preferences for intervention modalities/approaches. Rapid qualitative analysis was used to summarize participants' suggested modalities for financial toxicity interventions. Results: In this convenience sample of participants with NHL, participants were primarily older adults (median age 66, IQR 58-72.5), male (62%), and white/Caucasian (80%), with some college or more education completed (76%). The mean COST score was 28.0 (SD= 11.6, range: 0-44), with 32% reporting significant financial toxicity (COST score < 17.5). The mean eHEALS score was 24.6 (SD= 8.10, range: 8-40), and DHL did not vary significantly by age, gender, race/ethnicity, or household income (all p-values > 0.05). There was not a statistically-significant association between financial toxicity and DHL (r=0.028, p=0.849). However, DHL varied according to participants' preferences for online tools (Figure 1). Those who were interested in using online tools to manage cancer-related expenses reported higher DHL than those who were not interested(F(2,47)=5.43, p=0.007); there was a similar pattern for those interested in an online tool to communicate with their care teams (F(2,47)=5.73, p=0.006). Qualitative interviews (n=13) provided additional context for preferred formats for financial toxicity intervention preferences. For example, when asked about the best format for financial toxicity interventions, participants with higher levels of DHL suggested websites and phone applications, whereas participants with lower DHL levels suggested non-electronic modalities. Comfort level and barriers for utilizing technology-based interventions were also explored. Conclusions: A subset of NHL patients experiences financial toxicity, which does not appear to be directly related to DHL. Because DHL varies among patients with NHL, it may be important to risk stratify populations by DHL to appropriately focus and design tools for addressing financial toxicity. Patients with lower DHL may prefer other intervention modalities (e.g., written materials) and/or may benefit from additional support to access digital media interventions. Inclusion of participants with lower DHL levels in the early stages of intervention development may help to ensure that the most appropriate and usable tools for supporting patients with NHL are developed. Additional research is needed to better understand influences and correlates of DHL in patients with hematologic malignancies as well as the best approaches to financial toxicity interventions.

Duvelisib for Cytokine Release Syndrome Prophylaxis during CD19-Targeted CAR T Cell Therapy

Chimeric antigen receptor (CAR) T-cell therapy has transformed the treatment of patients with advanced non-Hodgkin lymphoma (NHL). However, treatment toxicity, including cytokine release syndrome (CRS) and immune cell-associated neurotoxicity syndrome (ICANS), can be significant. Effective prophylactic strategies may reduce the frequency and/or severity of CAR T cell therapy while also expanding the pool of patients eligible for such therapy. Duvelisib is an oral inhibitor of the gamma and delta isoforms of phosphoinositide 3-kinases (PI3K), which is an active therapy for CLL/NHL with an established safety profile. In addition, prior work from our group and others has demonstrated that PI3K inhibition can prevent CRS in an in vitro model (Amatya et al. ASH 2022) and can enhance antitumor cytotoxicity of CAR-T cells. Consequently, we performed a trial of duvelisib for CRS prophylaxis in patients undergoing standard-of-care (SoC) CAR T-cell therapy for NHL (NCT05044039). This was a phase I trial with a 3 + 3 dose escalation and two-arm dose expansion phase. The trial enrolled patients with NHL eligible for SoC CAR T-cell therapy and adequate organ function. Herein, we report data from the dose escalation cohort and the first dose expansion cohort, treated with duvelisib BID from day -2 to +28. The primary outcome was safety and tolerability. Secondary outcomes included the incidence and severity of CRS and ICANS, overall response rate (ORR), and progression-free survival (PFS). 17 patients are included in this analysis, including 6 patients in dose escalation and 11 of 14 planned patients in dose expansion cohort A, with full enrollment of cohort A expected prior to presentation. Median age was 68 years (range: 28 - 79) and 53% were male. Diagnoses included DLBCL (n = 13), MCL (2), FL (1) and PBMCL (1). For CAR-T cell therapy, patients received axi-cel (10), liso-cel (4), brexu-cel (2) and tisa-cel (1). 3 patients were enrolled on dose level 1 (15 mg BID) and 3 patients were enrolled on dose level 2 (25 mg BID). No patients experienced a dose-limiting toxicity (DLT) during dose escalation and consequently, 25 mg BID was selected as the recommended dose for expansion. 75 adverse events (AEs) were considered possibly (73) or probably (2) related to duvelisib by study investigators, including 14 severe (grade ≥3) AEs. The most common AEs were blood count abnormalities (41), liver function test abnormalities (12), fatigue (8) and nausea (6). The majority of severe AEs were cytopenias (13) and one patient had grade 3 hypokalemia. 13 patients (77%) had AEs attributed to duvelisib, including 6 patients (35%) with severe AEs. 76% of patients (13/17) experienced CRS at a median of 5 days following cell infusion (range 2 - 9) (Figure 1A). In 71% of patients (12/17), the onset of CRS was after day 3. Most were grade 1 (65%) and no patients experienced severe (grade 3 - 4) CRS. The median duration of CRS was 1 day (range: 1 - 7). ICANS occurred in 41% of patients (7/17) at a median of 7 days (range 4 - 10) and 12% of patients experienced severe (grade 3-4) ICANS. The median duration of ICANS was 5.5 days (range: 4 - 11 days). Toclizumab was given to 65% of patients for treatment of CRS and 53% received steroids for CRS and/or ICANS. All 17 patients were evaluable for disease response. At day +30, the overall response rate (ORR) was 71% (12/17) with 47% achieving complete response (CR) rate. At day +100, the ORR was 64% (9/14) with 50% CR. Best response was CR in 71% of patients and stable disease in 18% of patients. No patients had progressive disease (PD) as best response. CAR T cell expansion by flow cytometry was robust at all dose levels, consistent with prior reports (Figure 1B). With a median follow up of 93 days (range: 28 - 406), 53% of patients were alive and in remission. PD occurred in 6/17 (35%) patients with a median time to progression of 89 days (range: 28 - 182). Three patients enrolled on the study have died. One died from disease progression on day +266. Two died in remission from neutropenic sepsis (day +50) and vaping-induced lung injury (day +144). Data from this ongoing phase I study suggests that duvelisib with SoC CAR T-cell therapy is safe and tolerable. Preliminary data from this study suggest that the addition of duvelisib to CAR T-cell therapy may prevent grade 3-4 CRS and also delay the onset of CRS. Although limited follow-up is available, the depth and duration of response is similar to published data for CAR T-cells in this setting.

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.

To Investigate the Efficacy of Long-Term Step-Reduction Methylprednisolone in the Treatment of Severe Persistent Thrombocytopenia after CAR-T Cell Therapy

We collected patients with thrombocytopenia after chimeric antigen receptor (CAR)T cell therapy for non-Hodgkin lymphoma in our center, and retrospectively analyzed the clinical characteristics of methylprednisolone for the treatment of thrombocytopenia after (CAR)T cell therapy .The primary objective was to evaluate the efficacy and safety of long-term step-reduced methylprednisolone in patients with severe persistent thrombocytopenia(Thrombocytopenia ≥ grade 3, duration≥2 weeks) after CAR-T cell therapy. This study retrospectively analyzed patients with non-Hodgkin lymphoma who received chimeric antigen receptor (CAR) T cell therapy in Tongji Hospital Affiliated to Tongji University from November 2018 to July 2023. 34 patients developed thrombocytopenia during treatment and follow-up,5 patients lost to follow-up;1 patient died of COVID-19 pneumonia;10 patients with thrombocytopenia after CAR-T cell therapy had poor response to TPO-RA, blood transfusion, and methylprednisolone, all of them progressed rapidly due to poor efficacy of CAR T cell therapy. The other 18 (CAR) T cell therapy patients with thrombocytopenia were all CR(Complete remission) assessed after 3 months (Table 1). Further analysis of the 18 patients with thrombocytopenia after (CAR) T cell therapy. The median follow-up period was 11.29 months (range,2.7 to 25.4 months), the lowest platelet count occurred 27.3 days (range, 4-106 days) after (CAR) T cell therapy. The incidence of grade 3-4 thrombocytopenia was 100%, and the incidence of grade 4 thrombocytopenia was 66.7%. The incidence of thrombocytopenia before (CAR) T cell therapy was 55.6%, all of them were grade 1-2 thrombocytopenia. Among them,11 patients with grade 3-4 thrombocytopenia with a duration＜2 weeks were effective of TPO-RA and platelet transfusion(Figure 1).7 patients with grade 3-4 thrombocytopenia with a duration≥2 weeks did not respond to treatment with TPO-RA or platelet transfusion, but long-term step-reduction methylprednisolone was effective (Figure 2). 7patients with thrombocytopenia who did not respond to TPO-RA or platelet transfusion,and were finally effective in methylprednisolone were further analyzed. The initial prednisone dose of methylprednisone was 1mg/kg/ day for 5-7 days, The dose was reduced step by step until platelets recovered to grade 1(Figure 3A).the median response time of the treatment was 16.6 days (range,6-30 days). Among them, 3 patients treated with methylprednisolone at a dose of 1mg/kg/ day for 5 day and then stop,after the discontinuation of methylprednisolone, relapse of thrombocytopenia occurred and the symptoms were relieved again after long-term step-reduction methylprednisolone treatment (Figure 3B). Apart from drug-controlled hyperglycemia and hypertension, we observed no other side effects of prednisone. Further, we found the median OS of the 7 patients who were treated with methylprednisolone was 28 months, and the median OS of the 11 patients who responded to TPO-RA was undefined (95% confidence interval 0.5296 to 25.06), with no significant difference in OS between the two groups (P=0.1224)(Figure 4) .The median PFS of the patients who were treated with methylprednisolone was 16 months, and the median PFS of the 11 patients who responded to TPO-RA was undefined (95% confidence interval 1.253 to 34.54), with a significant differences in PFS between the two groups (P=0.0063) (Figure 4). Studies have shown that long-term step-reduction methylprednisolone is effective in severe persistent thrombocytopenia (Thrombocytopenia ≥ grade 3, duration≥2 weeks) .There was no significant difference in OS between the the patients who did not respond to TPO-RA, platelet transfusion,and were finally treated with methylprednisolone and the patients who responded to TPO-RA, platelet transfusion, but PFS of the patients were treated with methylprednisolone was shorter, suggesting that severe and persistent thrombocytopenia may be related to disease progression.

Access and Outcomes of Minority Health Populations Receiving Commercial Anti-CD19 CART Therapy for Non-Hodgkin Lymphoma

Background: Anti-CD19 chimeric antigen receptor T cell (CART19) immunotherapy is now standard treatment for large B cell lymphomas (LBCL), but its use is limited by high costs and requirement for access to specialized tertiary care centers. In this study, we sought to investigate whether minority health populations (MHP) have equal access to CART19 and similar outcomes compared to non-MHP patients (pts). Methods: MHP was defined as self-reported non-White groups (not accounting for Hispanic/Latino ethnicity). We retrospectively evaluated three cohorts of non-Hodgkin lymphoma (NHL) pts from two Institution's catchment areas (defined as the counties providing at least 80% of an institution's pts) characterized by different proportions of MHP: a metropolitan area with a proportion of MHP higher than the US average (Abramson Cancer Center, ACC - Philadelphia, Pennsylvania) and a more rural area with a lower proportion of MHP (Knight Cancer Institute, KCI - Portland, Oregon). The first cohort (catchment area NHL cohort) included pts diagnosed with NHL in the catchment area of each Institution between January 2015 and December 2019 (most recent cancer registry data available), accounting for 8,956 cases for ACC and 4,568 for KCI. The second cohort (total LBCL cohort) included LBCL pts treated with any therapy at each Institution during the same timeframe as the third cohort (January 2018, when the first patient was treated with commercial CART19, and December 2022). The total LBCL cohort included 1,492 LBCL pts from ACC (1,111 from ACC catchment area) and 396 pts from KCI (388 from KCI catchment area). LBCL diagnosis was searched in the Electronic Medical Records using the following International Classification of Diseases (ICD) 10 definition: Diffuse Large B-cell Lymphoma (ICD-10-CM: C83.30-39) and Mediastinal (thymic) large B-cell Lymphoma (ICD-10-CM: C85.20-29). The third cohort (CART19 LBCL cohort) included the subset of the pts in the total LBCL cohort treated with commercial CART19 at ACC (194 pts;132 from catchment area) and at KCI (47 pts; 45 from catchment area) between January 2018 and December 2022. The data collection cut-off date was March 31 st, 2023. Pts were evaluated for 3-month response (Lugano criteria), progression-free survival (PFS), overall survival (OS), and toxicities (ASTCT, CTCAE) in the 30 days after CART19 infusion. Results: In the ACC catchment area NHL cohort, the proportion of MHP was 17.9%. In the total LBCL cohort of pts treated at ACC, the proportion of MHP patients was similar to the catchment area NHL cohort (15.7%). However, in the ACC CART19 LBCL cohort, the proportion of MHP pts was 6.7%. By excluding patients from outside the catchment area, the proportion of MHP pts in the ACC total LBCL cohort was 18.0%, and 8.3% in the CART19 LBCL cohort (p=0.004). At KCI, the proportion of MHP in NHL catchment area cohort was, as expected, lower 4.2%. In the total LBCL KCI cohort, MHP was 6.6%and in the CART19 LBCL cohort was 4.2%, although the number of MHP pts in this cohort was very low (n=2). Most pts in the KCI group were from the catchment area ( Fig. 1A). We then studied pts outcomes based on MHP status in the combined ACC and KCI CART19 LBCL cohorts (total: 241; non-MHP: 226; MHP: 15). Pts characteristics according to MHP status were balanced except for age at CART19 infusion (median age: MHP 50 vs non-MHP 62 years). MHP pts had a complete response rate (CRR) of 66.7% vs. 42.0% for non-MHP pts (p=0.104). The 12-month PFS was 34.9% for MHP and 34.9% for non-MHP pts (p=0.982). Likewise, no difference in OS was observed between the two groups (p=0.354) ( Fig. 1B). No difference in terms of the incidence and any grade CRS (66.7% vs. 63.3%; p=0.792) and ICANS (13.3% vs. 22.1%; p=0.423) was observed in MHP and non-MHP pts. To exclude that the outcome analysis was affected by the different age distributions in the two groups, we performed efficacy and toxicity analysis only in the population younger than 60 years old (n=107, MHP=12, non-MHP=95). Pts characteristics were similar in the two groups. CRR, PFS, OS, and toxicities did not differ between the two groups. Conclusion: This study shows that MHP access to tertiary care for LBCL is equitable, but reduced for commercial CART19 immunotherapy. Nevertheless, when treated with CART19, MHP pts have similar survival and safety outcomes compared to non-MHP. This study supports further efforts to establish equitable access to CART19 immunotherapy for diverse populations.

A First-in-Human Phase 1 Study of ABBV-525, a Small-Molecule MALT1 Inhibitor, in Patients with Relapsed or Refractory B-Cell Non-Hodgkin Lymphoma

Background and Significance Many B-cell malignancies are characterized by chronic activation of the B-cell receptor (BCR) and nuclear factor kappa B (NF-κB) signaling pathways. In many non-Hodgkin lymphoma (NHL) subtypes, constitutive NF-κB activation results from genetic mutations and/or auto-antigen stimulation of the BCR pathway. While agents targeting the BCR pathway are effective treatments for many B-cell malignancies, patients (pts) often have progressive disease due to acquired resistance to BCR-targeted agents. Thus, there is an unmet medical need for novel therapeutic targets and treatment approaches. The mucosa-associated lymphoid tissue lymphoma translocation protein 1 (MALT1) is an enzymatic and scaffolding node in the BCR pathway and a key mediator of the BCR/NF-κB signal transduction pathway. Its action is downstream, or in some instances parallel to, resistance mechanisms to existing NHL therapies, including BTK C481S and PLCG2 mutations, which are known acquired mechanisms of resistance to covalent Bruton's tyrosine kinase (BTK) inhibitors in pts with chronic lymphocytic leukemia (CLL). MALT1 inhibition represents a novel therapeutic approach for malignancies with chronic activation of NF-κB, including those pts with acquired resistance to upstream targets. ABBV-MALT1 is a small-molecule, tool compound, MALT1 inhibitor. Preclinical studies of ABBV-MALT1 have demonstrated potent activity against MALT1-relevant biomarkers, including inhibition of BCR pathway signal transduction and reduced NF-κB gene activation in non-germinal center B-cell diffuse large B-cell lymphoma (non-GCB DLBCL) cell lines. ABBV-MALT1 has also shown activity in a range of preclinical lymphoma models as both monotherapy and in combination with venetoclax, including robust antitumor activity in malignant B-cell models that are resistant to BTK inhibitors. This phase 1 study evaluates the clinical candidate MALT1 inhibitor ABBV-525 as monotherapy in pts with relapsed or refractory (R/R) B-cell NHL. Study Design and Methods This is a first-in-human, phase 1, open-label, multicenter study of single-agent ABBV-525 in pts with R/R B-cell NHL (NCT05618028). Eligibility criteria are listed in Table 1. The primary objectives are to evaluate safety, tolerability, and pharmacokinetics (PK) of ABBV-525 and to determine the recommended phase 2 dose (RP2D). The secondary objective is to assess the preliminary efficacy of ABBV-525 in subsets of pts with R/R B-cell NHL. Exploratory objectives include evaluating biomarkers predictive of response and pharmacodynamic biomarkers, including the effects of ABBV-525 on BCR pathway signal transduction and NF-κB gene activation. This is a 3-part study (Figure 1): dose escalation (part 1), dose optimization (part 2), and dose expansion (part 3). Part 1 aims to establish the maximum administered dose/maximum tolerated dose of ABBV-525 and is primarily guided by a Bayesian optimal interval design. Part 2 aims to identify the RP2D of ABBV-525. Part 3 will further characterize the safety profile of ABBV-525 at the RP2D. Approximately 150 pts are planned for enrollment, including those with various R/R mature B-cell lymphomas in part 1, pts with documented diagnosis of R/R CLL in part 2, and pts with documented diagnosis of non-GCB DLBCL in part 3. ABBV-525 is orally administered until disease progression, intolerable toxicity, or other study discontinuation criteria are met. Safety assessments include dose-limiting toxicities, adverse events (per National Cancer Institute Common Terminology Criteria for Adverse Events v5.0), clinical laboratory parameters, vital signs, and electrocardiogram variables. PK parameters, including maximum observed plasma concentration (C max), time to C max, and area under the concentration-time curve will be analyzed using noncompartmental methods. Efficacy will be assessed through response per disease-specific criteria (including International Workshop on Chronic Lymphocytic Leukemia, International Workshop on Waldenstrom's Macroglobulinemia, and Lugano classification). Duration of response will be evaluated by Kaplan-Meier estimates. Biomarker data will be analyzed as change from baseline and summarized for each scheduled postbaseline visit. Pts are being enrolled in 25 sites across the USA, Australia, Belgium, France, Germany, Israel, Spain, and UK. As of August 1, 2023, 2 pts had been treated.

Consolidative Radiotherapy for Residual PET-Avid Disease on Day +30 Post CAR T-Cell Therapy in Non-Hodgkin Lymphoma

Up to30% of non-Hodgkin lymphoma (NHL) patients achieve a partial response (PR) to anti-CD19 Chimeric Antigen Receptor T-cell Therapy (CART) on day +30. Most PR patients relapse and only 30% achieve spontaneous complete response (CR) without additional therapies. This study is the first to report on the role of consolidative radiotherapy (cRT) for PR PET-avid disease on day +30 post-CART in NHL. Aretrospective review across 3 institutions from 2018 to 2022 identified 60 patients with B-cell NHL who received CART and achieved PR (Deauville 4-5) with <5 PET-avid disease sites on day +30. Progression-free survival (PFS) was defined from CART infusion to any disease progression. Overall survival (OS) was defined from CART infusion to death. Local relapse-free survival (LRFS), calculated based on the total number of PR sites, was defined from CART infusion to local relapse (LR) in the PR site identified on day +30. cRT was defined as comprehensive (compRT) - treated all PR PET-avid sites - or focal (focRT). Followingday +30 PET scan, 45 PR patients were observed and 15 received cRT. Only one patient received consolidative systemic therapy and belonged to the cRT group. Prior to CART, bridging RT was given to 13 patients (9 in observation group and 4 in cRT group). There were no significant differences in the pre-CART and day +30 baseline characteristics, including the median size and SUVmax of the PR sites, between the two groups. However, the median number of PR sites on day +30 was higher in the cRT group (2 [range 1-3] vs 1 [range 1-3], p = 0.003). The median equivalent 2 Gy dose was 39.1 (Interquartile range 36.8-41) Gy, and the most common cRT regimen was 37.5 Gy in 15 fractions. The median follow-up was 21 months. Among the observed patients, 15 (33%) achieved spontaneous CR, and 27 (60%) experienced disease progression with all relapses involving the initial PR sites. Among patients who received cRT, 10 (67%) achieved CR, and 3 (20%) had disease progression with no relapses in the radiated PR sites. None of the 10 cRT patients achieving CR relapsed or required subsequent therapies. The 2-year PFS was 80% and 37% (p = 0.012) and the 2-year OS was 78% and 43% (p = 0.12) in the cRT and observation groups, respectively. Patients consolidated with compRT (n = 12) had superior 2-year PFS (92% vs 37%, p = 0.003) and 2-year OS (86% vs 43%, p = 0.048) compared to observed or focRT patients (n = 48). There were no grade 3+ RT-related toxicities. A total of 90 PR sites were identified; 64 were observed and 26 received cRT. Fourteen (22%) observed PR sites achieved spontaneous sustained CR and 42 (66%) experienced LR. Twenty-four (92%) PR sites consolidated with cRT achieved sustained CR and none experienced LR. The 2-year LRFS was 100% in the cRT sites and 31% in the observed sites (p<0.001). NHL patients who achieve PR by PET to CART are at high risk of local progression. cRT for residual PET-avid disease on day +30 post-CART appears to alter the pattern of relapse and improve LRFS and PFS.

Retraction: A deep insight into CAR-T cell therapy in non-Hodgkin lymphoma: application, opportunities, and future directions.

[This retracts the article DOI: 10.3389/fimmu.2021.681984.].

POSTER: CT-321 Safety and Efficacy of an Academic Anti-CD19 Chimeric Antigen Receptor (CAR) T-Cell Therapy for Non-Hodgkin Lymphoma and Acute Lymphoblastic Leukemia Developed in Brazil: Increasing Access in a Public Health System

POSTER: CT-321 Safety and Efficacy of an Academic Anti-CD19 Chimeric Antigen Receptor (CAR) T-Cell Therapy for Non-Hodgkin Lymphoma and Acute Lymphoblastic Leukemia Developed in Brazil: Increasing Access in a Public Health System

CT-321 Safety and Efficacy of an Academic Anti-CD19 Chimeric Antigen Receptor (CAR) T-Cell Therapy for Non-Hodgkin Lymphoma and Acute Lymphoblastic Leukemia Developed in Brazil: Increasing Access in a Public Health System

CT-321 Safety and Efficacy of an Academic Anti-CD19 Chimeric Antigen Receptor (CAR) T-Cell Therapy for Non-Hodgkin Lymphoma and Acute Lymphoblastic Leukemia Developed in Brazil: Increasing Access in a Public Health System

Chimeric antigen receptor T-cell therapy in hematologic malignancies: Successes, challenges, and opportunities.

The success of chimeric antigen receptor T-cell (CAR-T) therapy in hematologic malignancies has realized a longstanding effort toward harnessing the immune system to fight cancer in a truly personalized fashion. Second generation chimeric antigen receptors (CAR) incorporating co-stimulatory molecules like 4-1BB or CD28 were able to overcome some of the hindrances with initial CAR constructs resulting in efficacious products. Many second-generation CAR-T products have been approved in the treatment of relapsed/refractory hematologic malignancies including multiple myeloma (MM), non-Hodgkin lymphoma (NHL), and acute lymphoblastic leukemia. However, challenges remain in optimizing the manufacturing, timely access, limiting the toxicity from CAR-T infusions and improving sustainability of responses derived with CAR-T therapy. Here, we summarize the clinical trial data leading to approval CAR-T therapies in MM and NHL, discuss the limitations with current CAR-T therapy strategies and review emerging strategies for overcoming these limitations.