Grade Lymphoma Research Articles

In brief: Lisocabtagene maraleucel (Breyanzi) for large B-cell lymphoma.

The FDA has approved lisocabtagene maraleucel (Breyanzi – BMS) for treatment of adults with large B-cell lymphoma (LBCL), including diffuse large B-cell lymphoma (DLBCL) not otherwise specified, high-grade B-cell lymphoma, primary mediastinal large B-cell lymphoma, or follicular lymphoma grade 3B who have disease refractory to first-line chemoimmunotherapy, relapsed within 12 months of or after first-line chemoimmunotherapy, are not eligible for hematopoietic stem cell transplantation due to comorbidities or age, or have relapsed or refractory disease after ≥2 lines of systemic therapy.

17th International Conference on Malignant Lymphoma, Palazzo dei Congressi, Lugano, Switzerland, 13 - 17 June, 2023.

Introduction: High dose chemotherapy/autologous stem cell transplantation (ASCT) and CD19-directed chimeric antigen receptor-modified T cells (CART19) are potentially-curative treatment options for patients (pt) diagnosed with relapsed/refractory (R/R) diffuse large B cell lymphoma (DLBCL) and high grade B cell lymphoma (HGBL). Analysis of a large series of pt receiving ASCT and/or CART19 has not been performed and may reveal differences in treatment failure (TF) which could inform efforts to optimize pt selection for these therapies. Methods: Included pt were age ≤75 years who received ASCT and/or CART19 for R/R DLBCL/HGBL at the University of Pennsylvania between 3/1/13 and 3/1/21. All ASCT pt demonstrated either partial or complete metabolic response to salvage immunochemotherapy (IC). Freedom from TF (FFTF) was defined as the interval between receipt of cell infusion and proven/suspected relapse of lymphoma (DLBCL/HGBL for ASCT pt or any lymphoma for CART19 pt) or last follow-up (f/u) in remission. Data were censored on 3/1/23. Results: Characteristics at the time of relapse preceding ASCT or CART19 are listed in the Table. Minimum prior LOT was 1 for ASCT and 2 for CART19 pt. With a median length of f/u of 62.7 months (mo) for ASCT pt and 37.6 mo for CART19 pt, the estimated (est) rate of FFTF at 36 mo were 59% and 24%, respectively. Cox regression analysis of characteristics predictive of TF at 36 mo revealed history of tIL (hazard ratio [HR] 0.23, P = 0.016) for ASCT pt, and history of tIL (HR 0.48, P = 0.004) as well as IPI score ≥3 (HR 2.7, P < 0.001) for CART19 pt. As depicted in the Figure, ASCT pt experienced significantly higher est rates of FFTF at 36 mo if achieving actual FFTF at 3 mo (64% vs. 38%, P = 0.002), 6 mo (76% vs. 52%, P = 0.02), 12 mo (84% vs. 62%, P = 0.03) and 24 mo (95% vs. 78%, P = 0.03) post-infusion as compared to CART19 pt. For characteristics which predict for TF at 36 mo (no history of tIL and IPI score ≥3), the incidence was either similar or significantly lower for CART19 versus ASCT pt who achieved actual FFTF at 3, 6, 12 and 24 mo. Keyword: Aggressive B-cell non-Hodgkin lymphoma Conflicts of interests pertinent to the abstract. D. J. Landsburg Consultant or advisory role: Morphosys, Epizyme, Calithera, ADC Therapeutics, Karyopharm Research funding: Curis, Calithera, Epizyme Educational grants: Novartis S. D. Nasta Research funding: Pharmacyclics, Roche, Rafael, FortySeven J. Svoboda Consultant or advisory role: SEAGEN, Pharmacyclics, Incyte, Genmab, BMS, Atara, Astra Zeneca, Adaptive, ADCT Research funding: TG, SEAGEN, Pharmacyclics, Merck, Incyte, BMS, Astra Zeneca J. N. Gerson Consultant or advisory role: Genentech, Abbvie Research funding: Loxo S. J. Schuster Consultant or advisory role: Novartis, Regeneron, Nordic, Morphosys, MustangBio, Incyte, Genentech/Roche, Janssen, Legend Biotech, Loxo, Acerta, BiGene, Celgene, Nanovecter Research funding: Novartis, Pharmacyclics, Merck, DTRM, Juno Therapeutics, Abbvie, Adaptive Biotechnologies, Incyte, Genentech/Roche, Celgene, TG Therapeutics S. K. Barta Consultant or advisory role: Daiichi Sankyo, Kyowa Kirin, Janssen, Affimed Honoraria: Acrotech, Seagen, Kyowa Kirin E. A. Chong Honoraria: Juno/BMS, Novartis, Beigene, KITE, Tessa A. L. Garfall Consultant or advisory role: Jannsen, GlaxoSmithKline, Bristol-Myers Squibb Research funding: Novartis, Tmunity Therapeutics, Janssen, Crispr Therapeutics E. A. Stadtmauer Research funding: BMS, Celgene, Abbvie, Sorrento N. V. Frey Consultant or advisory role: Sana Biotechnology, Kite Pharma, Syndax Pharmaceuticals Research funding: Research Funding D. L. Porter Consultant or advisory role: Novartis, Kite/Gilead, Incyte, Janssen, Jazz, DeCart, BMS, Bluebird Bio, Angiocrine, Mirror Biologics, Capstan Therapeutics, Instill Bio Research funding: Novartis

Follicular lymphoma grade 3B: low grade, high grade or should we skip the grade?

Not available.

A CORRELATIONAL STUDY OF HISTOPATHOLOGY AND FDG-PET/CT IN THE DIAGNOSIS OF VARIOUS GRADES OF NON-HODGKIN LYMPHOMAS.

Lymphomas are a heterogeneous group of disorders arising from constituent cells of the immune system. The SUVmax (standardised uptake value) on PET/CT reects the tumor's aggressiveness. In this study, we observe the SUVmax in FDG-PET/CT and correlate it with the histopathological diagnosis and proliferation index in various grades of non-Hodgkin lymphoma (NHL). 187 cases of NHLs received at the Department of Pathology during the years 2018–2020 were included in the study. The age, nal histopathological diagnosis, Ki67 index, and SUVmax for each case were collected. Statistical analysis was performed using SPSS 23 to establish a correlation between histopathological diagnosis, the Ki67 index, and the SUVmax. There was a signicant correlation between high-grade lymphomas and SUVmax (r = 0.416, P value 0.001) and also between SUV max and the KI67 proliferation index (r = 0.731, Pvalue 0.001). The sensitivity and specicity of SUVmax were 70% and 76%, respectively. There is an acceptable correlation between the nal histopathological diagnosis, SUVmax, and Ki67, thus suggesting that SUVmax can be used as an additional tool for the early detection of high-grade lymphomas, rapid transformation, and recurrence in a known case

Comparison of first-line treatment with bendamustine plus rituximab versus R-CHOP for patients with follicular lymphoma grade 3A: Results of a retrospective study from the Fondazione Italiana Linfomi.

In the setting of follicular lymphoma (FL), frontline therapy with rituximab, cyclophosphamide, doxorubicin, and prednisone (R-CHOP) has represented for many years the standard of care for patients with symptomatic advanced disease. More recently, the combination of bendamustine plus rituximab (R-B) has emerged as an alternative therapeutic option. We present a retrospective, multicenter, observational study aimed at comparing outcomes and toxicities observed in 145 patients diagnosed with grade 3A FL treated with a first line therapy in 15 Italian Fondazione Italiana Linfomi centers between the 1st of January 2014 and the 30th of May 2018. Seventy patients were treated with R-B and 75 with R-CHOP. In the R-B group, the median age at the time of diagnosis was 67 years compared with 59 years in the R-CHOP group. Patients in R-B group achieved a similar overall response rate (96% vs. 99%) and a better complete remission rate (87% vs. 80%, p=0.035) compared with patients in R-CHOP group. Progression free survival (PFS) was similar between individual treated with R-CHOP and R-B (48- month PFS 77.7% vs. 76.6% respectively, p=0.745). The overall survival was significantly longer with R-CHOP treatment (HR=0.16; 95% IC, 0.04-0.74; p=0.007); however, no statistical significant difference was observed after adjustment for age. With the limitations of the study design, our results suggest that both R-B and R-CHOP seem to be valid first-line treatment options in FL3A.

Differences in clinical characteristics and outcomes between patients with grade 3a and grades 1–2 follicular lymphoma: a real-world multicenter study

BackgroundThe difference between clinical characteristics and outcomes between follicular lymphoma grade 1–2 (FL1-2) and FL3a defined pathologically remains unclear, resulting in uncertainty how to treat FL3a. However, it may be crucial for clinicians to discriminate grade 3a and grade 1–2 for predicting prognosis and thus making treatment decisions.MethodsWe compared 1403 patients with FL1-2 and 765 patients with FL3a diagnosed between January 2000 and December 2020 from fifteen centers nationwide in China to describe differences in clinical characteristics and outcomes.ResultsCompared with FL1-2 patients, FL3a subgroup had a higher percentage of elderly patients (P = 0.003), and relatively more FL3a patients presented with increased levels of LDH (P < 0.0001) and higher Ki-67 indexs greater than 30% (P < 0.001). More FL3a patients were treated with CHOP ± R (P < 0.0001), and fewer were treated with the watchful-waiting approach (P < 0.0001). The results showed a higher incidence of relapse among FL3a patients, in which more patients underwent histological transformation (HT) when compared to FL1-2 (P = 0.003). 1470 (76.2%) patients of the entire cohort received R-CHOP therapy; survival analysis revealed that FL3a patients had a worse progression-free survival (PFS) rate than FL1-2 patients. Survival of FL3a patients with respect to FLIPI showed an inferior PFS in the intermediate and high-risk groups than FL1-2 patients. FL3a patients had a much worse prognosis than FL1-2 with or without progression of disease within 24 months (POD24). FL3a patients had higher likelihood of lymphoma-related death (LRD, P < 0.05), whereas the rates for non-LRD were comparable.ConclusionIn conclusion, this study demonstrates a marked difference in clinical features and outcomes in FL3a patients compared with FL1-2 patients. The results highlight the need for applying therapeutic approaches distinct from FL1-2 when treating FL3a patients.

Whole-body diffusion-weighted imaging with background body signal suppression and quantitative apparent diffusion coefficient in the detection, staging, and grading of non-Hodgkin lymphoma.

Assess reproducibility of detection, staging, and grading of non-Hodgkin lymphoma (NHL) using whole-body diffusion-weighted imaging with background body signal suppression (WB-DWIBS). Thirty NHL patients underwent WB-DWIBS, divided into 2 groups according to staging and grading. Image analysis and apparent diffusion coefficient (ADC) measurement of the largest lymph node in each group were performed by 2 observers. Inter-observer agreement was performed. Overall inter-observer agreement for detection of NHL was excellent (k = 0.843; 92.05%) with excellent inter-observer agreement of nodal disease (cervical, thoracic and abdominal) (k = 0.783, 0.769, and 0.856; 96.67%, 90.0%, and 93.3% respectively), extra-nodal disease (k = 1; 100%), and splenic involvement (k = 0.67; 83.3%). The overall inter-observer agreement of DWIBS in staging of NHL was excellent (k = 0.90; 94.9%) with excellent inter-observer agreement for stage I (k = 0.93; 96.4%), stage II (k = 0.90; 94.8%), stage III (k = 0.89; 94.6%), and stage IV (k = 0.88; 94.0%). There was significant difference between ADC in stage I, II (0.77 ± 0.13, 0.85 ± 0.09 × 10-3 mm2/s), and stage III, IV (0.63 ± 0.08, 0.64 ± 0.11 × 10-3 mm2/s, p < 0.002, < 0.001). Interclass correlation showed almost perfect agreement for ADC measurement in staging and grading groups (r = 0.96 and r = 0.85, respectively, p < 0.001). There was significant difference between ADC in aggressive lymphoma (0.65 ± 0.1, 0.67 ± 0.13 × 10-3 mm2/s) and indolent lymphoma (0.76 ± 0.14, 0.84 ± 0.09 × 10-3 mm2/s, p < 0.028, < 0.001). DWIBS is reproducible for detection and staging of nodal and extra-nodal involvement in patients with NHL. ADC can quantitatively participate in the staging and grading of NHL.

Lisocabtagene maraleucel in the treatment of relapsed/refractory large B-cell lymphoma.

Lisocabtagene maraleucel (liso-cel) is one of the three US FDA-approved chimeric antigen receptor T-cell therapies for the treatment of relapsed/refractory (R/R) large B-cell lymphoma (LBCL). TRANSCEND is the landmark trial that led to the approval of liso-cel in the third-line setting for R/R diffuse LBCL, primary mediastinal B-cell lymphoma, follicular lymphoma grade 3B and transformed lymphoma. The TRANSFORM and PILOT studies evaluated the use of liso-cel in the second-line treatment of R/R LBCL. This review details the structure and manufacturing process of liso-cel that make it distinct from other approved chimeric antigen receptor constructs, outlines results from landmark trials of liso-cel in LBCL and discusses liso-cel toxicity.

Progression of follicular lymphoma grade I in the central nervous system

Progression of follicular lymphoma grade I in the central nervous system

Efficacy Analysis of Bendamustine-Based Combination Regimen in Treatment of Patients with Relapsed/Refractory Non-Hodgkin Lymphoma

To investigate the efficacy and safety of bendamustine combined with gemcitabine, vinorelbine，glucocorticoids (BeGEV)±X regimen in treatment of patients with relapsed/refractory non-Hodgkin lymphoma. A total of 18 relapsed/ refractory non-Hodgkin lymphoma patients at the age of 18 years or older hospitalized in the First People's Hospital of Changzhou from March 2020 to March 2021 were selected. They received two or more cycles of BeGEV±X regimen. X could be anti-CD20 monoclonal antibody, PD-1-blocking antibodies, lenalidomide, BTK inhibitor, Bcl-2 inhibitor and so on according to patients' disease feature. The clinical efficacy and adverse effects were observed. In total, 18 patients completed two or more cycles of BeGEV±X regimen, including 14 with diffuse large B-cell lymphoma, one with low-grade follicular lymphoma, one with follicular lymphoma grade 3b, one with angioimmunoblastic T-cell lymphoma and one with peripheral T-cell lymphoma, not otherwise specified. 11 patients were male. The median age of the patients was 64 years old. 17 patients had modified Ann Arbor stage Ⅲ/Ⅳ disease. 13 patients had high- intermediate risk or high risk IPI score, while 15 patients had high-intermediate high risk or high risk NCCN-IPI score. 14 cases had extranodal sites of disease. And 6 cases had bulky disease. 12 patients experienced refractory disease, while 8 patients had received 3 line or more prior treatment. After two or three cycles of chemotherapy, the complete response rate was 6/18, the partial response rate was 3/18, and the objective response rate was 9/18. From the beginning of salvage chemotherapy to the end of follow-up, the median progression-free survival time was 130 days, and the median overall survival was 152 days. The most common grade 3 to 4 adverse events were hematologic toxicities, infection and febrile neutropenia. BeGEV±X is an effective salvage regimen in treatment of patients with relapsed/refractory non-Hodgkin lymphoma, while adverse events such as hematologic toxicities and infection should be closely monitored.

Deriving Predictive Features of Severe CRS from Pre-Infusion Clinical Data in CAR T-Cell Therapies

Background Cytokine release syndrome (CRS) is a life-threatening toxicity of chimeric antigen receptor (CAR) T-cell therapy that limits the widespread use of this lifesaving therapy. While only a portion of CAR T-cell therapy patients experience CRS, there is a limited understanding of its risk factors (Fajgenbaum et al. NEJM 2020). Known markers of severe CRS lack specificity or require central lab facilities, making them unsuitable for safety surveillance during trials or real-time clinical decision making. Earlier work by the authors suggests that patterns in longitudinal measurements of common laboratory markers distinguish patients who develop severe CRS after CAR-T infusion from others(Strait et al. JCO 40, 2022). Using pre-infusion clinical data from anti-CD19 CAR-T trials from the Medidata Enterprise Data Store (MEDS), we derived features that capture longitudinal patterns in common laboratory markers and vitals before and after the start of lymphodepleting chemotherapy (LDC). We fit penalized logistic regression models to these derived features using the occurrence of severe CRS (grade 3 and higher) as a binary response variable. Below we describe these novel features and their importance in predicting severe CRS following CAR-T therapy. Method Subjects in the anti-CD19 CAR-T trials obtained from MEDS had relapsed or refractory disease in one of the following: B Acute Lymphoblastic Leukemia (B-ALL), Mantle Cell Lymphoma (MCL), Non-Hodgkin Lymphoma (NHL), or Diffuse Large B-cell Lymphoma (DLBCL). Laboratory markers with repeated measurements between screening and the start of LDC as well as between LDC start and CAR-T infusion that were present in all studies were used to compute the pre and post LDC features respectively. Only post LDC features were derived for heart rate, systolic blood pressure, weight and temperature (vitals) measured between LDC start and CAR-T infusion. Age, weight and ECOG at enrollment, race, number of prior therapies, response to last therapy and prior allogeneic or autologous hematopoietic stem cell transplant were included as baseline features. Since the prevalence of grade 3+ CRS varies between the studies, we split the data into training (80%) and test (20%) partitions by stratifying on grade 3+ CRS per each study. Penalized logistic regression models were fit on the training partition and evaluated on the test partition. Results The dataset consisted of 361 patients: 19.1% B-ALL, 39.9% DLBCL, 21.6% MCL and 19.4% comprising patients with Transformed Follicular Lymphoma, Primary Mediastinal B-cell Lymphoma and High Grade B-cell Lymphoma; mean age 55.8 (SD=14.1) years, 69.5% males. 25.2% had CRS 3+ with a median time-to-event of 4 days. At enrollment, all patients had an ECOG score ≤ 1 with 47.7% patients having an ECOG = 0. During their last therapy prior to CAR-T cell therapy, 51.5% patients had progressive disease and 23.3% patients had a response followed by relapse. Feature importance values in the pre and post LDC intervals are shown in Figure 1. Pre-LDC, the levels of leukocyte count, hemoglobin, aspartate aminotransferase and the change in alanine aminotransferase, albumin, and platelets were the strongest predictors of developing grade 3+ CRS. Post-LDC but pre-CAR-T therapy, the levels of alanine aminotransferase, alkaline phosphatase, hemoglobin, platelets and albumin and the change in platelets, albumin, and creatinine were the strongest predictors. High levels of Chloride, both pre and post LDC correlate with lower risk of grade 3+ CRS. Among vitals, heart rate, temperature and systolic blood pressure, as well as the rate of change in weight post LDC are the strongest predictors of grade 3+ CRS. While partial response or disease progression in prior therapy is correlated with grade 3+ CRS, the model with baseline features alone performed worst on the test partition. Adding predictors based on laboratory markers and vital signs, results in about 10% improvement in the AUROC over the baseline model (Table 1). Conclusions Absolute levels as well as the rate of change in laboratory markers and vitals may indicate immune pathway activity that correlates with a future grade 3+ CRS event. Modeling the pre and post LDC kinetics can yield novel predictors for grade 3+ CRS.The association between pre-infusion temporal patterns in clinical variables and grade 3+ CRS implies that dynamic tracking of patient status will be key to effective mitigation of grade 3+ CRS. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Clinical Laboratory Mutation Analysis Performed on Tumor Biopsies from Patients with Newly-Diagnosed Germinal Center Aggressive B Cell Lymphoma

Background Comprehensive genomic analyses of tumor biopsies (bx) from patients (pts) with newly-diagnosed germinal center B cell (GCB) diffuse large B cell lymphoma (DLBCL) and high grade B cell lymphoma (HGBL) have identified molecular subtypes predictive of inferior survival outcomes following receipt of first-line immunochemotherapy (PMID: 29713087, 29641966, 30523719, 30523716). These experimentally-defined molecular subtypes are characterized by somatic mutations (mut), which can be detected through clinical laboratory mutation analysis (CLMA). We sought to identify the frequency and predictive value of these mut as detected by CLMA performed at our center on tumor bx from pts with newly-diagnosed GCB DLBCL/HGBL. Methods Pts diagnosed with de novo or previously-untreated transformed indolent GCB DLBCL/HGBL defined by Hans algorithm from 2015-21 who received R-CHOP or R-EPOCH in the first-line setting whose initial tumor bx underwent CLMA performed at the University of Pennsylvania with either the lymphoma sequencing panel (LSP) or PennSeq Lymphoma panel (PSLP) were retrospectively analyzed. Immunohistochemical staining (IHC) for MYC and BCL2 expression as well as fluorescence in situ hybridization (FISH) for MYC, BCL2 and BCL6 rearrangements were performed as per institutional standard. Therapy was given at the discretion of the treating physician. Disease free survival (DFS) was defined as the interval between diagnosis of DLBCL/HGBL to DLBCL/HGBL relapse or last follow-up in remission. Overall survival (OS) was defined as the interval between diagnosis and time of death or last follow-up while alive. Data were censored on 7/1/22. Results CLMA was performed on 59 pt tumor bx with 58 successful assays (98% success rate) and a median result turnaround time (TAT) of 16 days. 5 bx were excluded due to specific request for CLMA by treating clinician (3) or diagnosing pathologist (2) and 2 additional bx were excluded due to lack of clinical follow-up, resulting in analysis of 51 bx performed at random from pts evaluable for survival (n=32 LSP, n=19 PSLP). Baseline characteristics, including mut in genes of interest (GOI) identified in the above references, are listed in the Table. Of note, BCL2, MYC, DDX3X and PTEN mutations were not included the LSP and therefore not included in statistical analyses due to small sample size. R-EPOCH was received by 15 pts (29%) and R-CHOP by 36 pts (71%). With a median follow-up of 25.2 months, the Kaplan Meier estimate of 2 year (y) DFS was 60% (95% confidence interval [CI] 41-74%) and 2y OS 80% (95% CI 64-89%). As shown in the Figure, 2y DFS was significantly lower for pts with CREBBP mut vs not (45% [95% CI 18-68%] vs 67% [95% CI 44-83%], P=0.045), but not for pts based on other mut analyzed. All progression events for pts with CREBBP mut occurred ≤12 months (mo) from diagnosis. Of 16 bx with CREBBP mut, 15 mut were predicted to result in loss of function (LOF) (PMID: 28890946, 21390126). CREBBP mut were not significantly associated with baseline characteristics except for EZH2 mut (50% with CREBBP mut vs 11% no CREBBP mut, P=0.005 by Fisher's exact). Characteristics listed in the Table which were predictive of disease relapse by 2y with P<0.10 on univariate Cox regression analysis were International Prognostic Index Score ≥3 vs <3 (hazard ratio [HR] 2.3, 95% CI 0.86-6.5, P=0.098), HGBL vs DLBCL histology (HR 5.4, 95% CI 1.8-15.7, P=0.002), double hit lymphoma vs not (HR 9.0, 95% CI 2.6-30.8, P<0.001) and CREBBP mut vs not (HR 2.6, 95% CI 0.98-7.0, P=0.054). Conclusions In this cohort of pts with newly-diagnosed GCB DLBCL/HGBL treated with first-line immunochemotherapy whose tumor bx underwent CLMA at random, mut in CREBBP resulting in predicted LOF were frequently detected, not associated with routinely-analyzed baseline clinicopathologic characteristics and predicted for significantly lower 2y DFS with progression events occurring early. These findings may be of interest in light of availability of agents which may overcome loss of histone acetyltransferase function. Given the high success rate and rapid TAT of CLMA, results from this assay could inform the management of pts with newly-diagnosed DLBCL/HGBL in real-time, and additional efforts to incorporate findings from experimental molecular assays into CLMA-based studies as well as those to standardize CLMA gene panels may ultimately benefit this pt population. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Odronextamab in Patients with Relapsed/Refractory (R/R) Follicular Lymphoma (FL) Grade 1-3a: Results from a Prespecified Analysis of the Pivotal Phase II Study ELM-2

Background Odronextamab is a hinge-stabilized, human IgG4-based CD20×CD3 bispecific antibody that binds CD20 on B cells and CD3 on T cells, triggering T-cell-mediated cytotoxicity of malignant B cells. In ELM-1 (Ph1, NCT02290951), pts with FL Grade 1-3a receiving ≥2 prior lines of therapy and treated with odronextamab doses of ≥5 mg, had an ORR of 91% and CR rate of 72%. Responses were durable with a 4-y PFS rate of 54% (Bannerji R, et al. Lancet Haematol. 2022). The RP2D dose in R/R FL pts was determined as 80 mg weekly. Here, we present for the first time, results from a prespecified analysis of the FL Grade 1-3a cohort from the pivotal ELM-2 study (Ph2, NCT03888105), which incorporated an optimized step-up regimen designed to maintain efficacy while minimizing acute toxicity including cytokine release syndrome (CRS). Methods ELM-2 is a global, multicenter study enrolling pts at 91 sites in 13 countries. Adult pts with FL Grade 1-3a who had relapsed or were refractory to ≥2 prior lines of therapy including an anti-CD20 antibody and alkylator were enrolled. IV odronextamab was administered in 21-day cycles with steroid prophylaxis and weekly step-up dosing during Cycle (C) 1 to mitigate risk of acute toxicity. The initial step-up regimen consisted of 1 mg split over C1 Day (D) 1 and C1D2, and 20 mg split over C1D8 and C1D9, followed by the 80 mg full dose on C1D15 (1/20 regimen). The 1/20 regimen was revised during the study to further mitigate CRS risk by adding an intermediary step-up dose. The modified regimen consisted of 0.7 mg split over C1D1 (0.2 mg) and C1D2 (0.5 mg), 4 mg split over C1D8 and C1D9, and 20 mg split over C1D15 and C1D16, followed by the 80 mg full dose on C2D1 (0.7/4/20 regimen). 80 mg weekly continued until the end of C4. After C4, maintenance treatment with 160 mg odronextamab occurred every 2 wks until disease progression or unacceptable toxicity. The primary endpoint was ORR assessed by independent central review (ICR) according to Lugano 2014 criteria. CRS was assessed using 2019 ASTCT criteria. Results As of April 20, 2022, 96 pts were evaluable for safety; 85 for efficacy. Median age 59 y (range 22-84), 52% male, 58% FLIPI 3-5, 15.6% had bulky disease, and median prior lines of therapy were 3 (range 2-13). 74% were refractory to their last therapy, 79% refractory to prior anti-CD20 therapy, and 48% had progression of disease within 2 y (POD24). Median duration of study follow-up was 17.3 mos. ORR and CR rate by ICR were 81% (69/85) and 75% (64/85), respectively. ORR and CR rate were consistent across high-risk subgroups, including pts aged ≥65 y, POD24, FLIPI 3-5, and pts refractory to their last line of therapy; ORR and CR rate were also consistent for the subgroup of pts treated with the 0.7/4/20 step-up regimen. Responses were durable with both a median duration of response and a median duration of CR of 18.2 mos. Median PFS was 20.2 mos (95% CI 14.8-not estimable [NE]) and median OS was not reached (95% CI 23.0 mos-NE). TEAEs occurred in 95 (99%) pts, considered treatment related in 86 (90%). In the overall safety evaluable population, the most common TEAEs (>30% all grades) were CRS (51%), pyrexia (32%), anemia (31%), and infusion-related reaction (31%). Following implementation of the 0.7/4/20 step-up regimen in C1, no Grade ≥2 CRS was observed; only Grade 1 CRS was reported in 39% of pts. All CRS events resolved and only 1 pt received tocilizumab for CRS management. No ICANS was reported in the 0.7/4/20 regimen compared with 3% in the 1/20 regimen. COVID-19 was reported (n=13,14%), including Grade ≥3 (n=5, 5%). Treatment-related Grade 5 AEs were reported for 2 pts; treatment-related AEs led to discontinuation in 6 pts. Conclusions Consistent with the ELM-1 Ph1 study, the ELM-2 pivotal Ph2 study of odronextamab demonstrated compelling efficacy in pts with FL Grade 1-3a receiving ≥2 prior lines of therapy, with 75% of pts achieving CR by ICR and an acceptable safety profile. Durability of responses and favorable survival outcomes are clinically important in the context of heavily pretreated, highly R/R FL, where prognosis is typically poor. The 0.7/4/20 step-up regimen compares favorably to other CD20×CD3 bispecifics, with no Grade 2 or higher CRS reported. Odronextamab may represent an important treatment option for R/R FL, providing a more accessible option with favorable benefit/risk compared with existing therapies including CAR T cell therapy. Updated safety and efficacy data will be presented.

CNCT19 CAR T-Cell Therapy in Relapsed or Refractory B-Cell Lymphoma: Long-Term Results of a Pilot Prospective Clinical Study

Background: Chimeric antigen receptor (CAR) T-cell targeting tumor cells depends on the single chain variable fragment (scFv) against the specific tumor antigen. Most anti-CD19 CAR-T products have the scFv deriving from hybridoma clone FMC63. We developed a new hybridoma clone HI19α which binds to distinct CD19 episodes. CNCT19 was a second-generation CAR T-cell with scFv derived from clone HI19α and 4-1BB/CD3-ζ costimulatory domain. The results of CNCT19 in pediatric and adult patients with relapsed or refractory (R/R) B-cell acute lymphoblastic leukemia had previously been reported [Runxia Gu et al. J Hematol Oncol. 2020 Sep 7;13(1):122]. Herein, we reported the outcome and long-term follow-up of a pilot study administrating CNCT19 in relapsed or refractory B-cell lymphoma. This trial was registered at www.clinicaltrials.gov as NCT03029338. Methods: Patients with R/R CD19-positive B-cell lymphoma were eligible for this study. Subjects with active central nervous system involvement were excluded. Lymphodepleting chemotherapy comprising fludarabine (25~30mg/m2, day -4,-3,-2) and cyclophosphamide (350mg/m2 day -4, -2) was administrated once the CNCT19 product was available. We infused CNCT19 cells in three regimens: three-day split dose (10%-30%-60%, patient (P)1-P10), two-day split dose (40%-60%, P11-P17), and single dose (P18-20). Results: From May 2017 through March 2019, 20 patients were enrolled. Diagnosis of histological subtypes included diffuse large B-cell lymphoma not otherwise specified (DLBCL, NOS) in 14 (70%) patients, DLBCL transformed from chronic lymphocytic leukemia in 1 (5%) patient, follicular lymphoma (FL) grade 3b in 1 (5%) patient, and mantle cell lymphoma (MCL) in 4 (20%) patients. Considering the differences in efficacy and survival between the population with MCL and those with LBCL, we here reported the results of 16 patients who had diseases of DLBCL or FL 3b. The median age was 51 (range 16 to 69), and 62.5% were male. The majority (87.5%) of patients had advanced stage disease, and 11 (68.8%) had non-GCB immunophenotype. Double expressor lymphoma (DEL, cut-off for MYC, >=40%, BCL2, >=50%) was identified in 11 (68.8%) patients, with one of them having MYC and BCL2 rearrangement. TP53 mutation and/or deletion were detected in 5 of 6 (83.3%) patients. The patients had received a median of 3 (range 2 to 7) lines of prior therapy. Thirteen (81.3%) patients had diseases refractory to last-line therapy. The median dose of infused CNCT19 cells was 2.48×106 (range 1.87 to 5.06×106) per kilogram of body weight. Cytokine release syndrome (CRS) occurred in 11 (68.8%) patients, all of whom were grade 1. Only one patient experienced CAR-T-cell-related encephalopathy syndrome (CRES), manifesting as distal muscle weakness of the bilateral upper limb, and he recovered completely after corticosteroids treatment. Twelve (75.0%) patients achieved a response after CNCT19 infusion, with a complete response (CR) rate of 37.5%. The ORR and CR rate at 3 months was 62.5% and 31.3%, respectively. Two patients with ongoing partial remission underwent allogeneic hematopoietic stem-cell transplantation, and both of them died of progressive disease at 6 months and 11 months post CNCT19 infusion, respectively. As of July 5, 2022, the median follow-up from CNCT19 infusion to the data-cutoff date was 44.5 months. The median progression-free survival and overall survival were 6.5 (95% CI 1.0 to NA) months and 12.7 (95% CI 2.9 to NA) months, respectively. Six (37.5%) patients remained alive by data cut-off. Conclusions: CNCT19 cells exhibited comparable efficacy and favorable safety in patients with R/R DLBCL and FL3b. A phase 2 clinical trial (NCT04586478) of administrating CNCT19 in R/R large B-cell lymphoma and high-grade B-cell lymphoma is underway.

CAR T-Cell Therapy Remain Effective in Patients with Relapse/Refractory B-Cell Non-Hodgkin Lymphoma after Bispecific Antibodies Exposure: Results of a Lysa Study Based on the Descar-T Registry

Background Anti-CD19 Chimeric antigen receptor (CAR) T-cells and anti-CD3/CD20 bispecific antibodies (BA) have emerged as the most promising agents for the treatment of relapsed or refractory (R/R) B-cell lymphomas (B-NHL). Optimal sequencing of both treatment options is a matter of debate. Complete response around 30% have been reported with BA treatment of patients (pts) failing CAR T-cells. Given their promising efficacy and accessibility, BA may be given earlier in future therapeutic strategy, even before CAR T-cells. To date, there is no data regarding the outcome of pts treated with CAR T-cells after prior exposure to BA. Methods We retrospectively analyzed adult patients with R/R B-NHL treated with approved CAR T-cells (axi-cel, tisa-cel or brexu-cel) after prior exposure to BA. Patients’ data were collected through the French DESCAR-T registry and medical records. Results As of May 2nd 2022, we identified 32 pts in the DESCAR-T registry. Among those, 28 pts were evaluable for this analysis including 23 pts with large B-cell lymphoma (LBCL) (21 Diffuse large B-cell lymphoma, 1 Follicular lymphoma (FL) grade 3b and 1 High grade B-cell lymphoma), 3 Mantle cell lymphoma (MCL) and 2 FL. Patients had received a median of 4 (range: 2‒9) prior treatment lines before CAR-T cells therapy and 96.9% had refractory disease. Prior BA therapy were as follows: CD20/CD3 BA (n=26; 92.9% - mainly Glofitamab (n=18; 64.3%)), CD19/CD3 BA (n=1) and CD22/CD3 BA (n=1). BA were given as single agent for all pts but one who received a combination with lenalidomide. The best objective response rate (ORR) and complete response (CR) rates after BA were 53.6% and 25.0%, respectively. The median time to next treatment (TTNT) from BA initiation was 142 days (range : 37-482). In the LBCL subgroup, the 6-months (mo) PFS was 17.4% with a median PFS of 3.1 mo. In this subgroup, the median duration of response (DOR) was 2.7 mo. The reason for BA discontinuation was disease progression in all pts (missing information for 1 patient). The CAR T-cell type was axi-cel (n=16; 57.1%), tisa-cel (n=9; 32.1%) and brexu-cel (n=3; 10.7%). Twenty-three pts (82.1%) received bridging therapy. After CAR-T cell infusion, best ORR and CR rates were 92.9% and 50.0%, respectively. In the LBCL subgroup (Table 1), 72% received axi-cel and 28% received tisa-cel. Best ORR and CR rates after CAR T-cell infusion were 91.6% and 45.8%, respectively. After a median follow-up (FU) of 12.3 mo, the 1-year PFS (Figure 1) and OS were 37.2% and 53.5%, respectively. In this subgroup, the 1-year DOR was 40.7%. Among the 3 MCL and 2 FL, all pts responded and were progression free at the time of data cut-off. Cytokine release syndrome (CRS) occurred in 92.7% of pts, including 10.3% of grade 3 CRS (no grade 4). Immune effector cell-associated neurotoxicity syndrome (ICANS) occurred in 32.3% of pts, including 3.6% of grade 3 ICANS (no grade 4). During the FU (median FU of 8.4 mo), 7 pts (25.0%) died: 3 from toxicity and 4 from lymphoma progression. Conclusion In this series, the efficacy of CART appears preserved in B-NHL patients whose disease progressed after prior treatment with bispecific antibodies. No new toxicity signals have been identified. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Trial-in-Progress: AMC 112: Axicabtagene Ciloleucel in Relapsed or Refractory HIV-Associated Aggressive B-Cell Non-Hodgkin Lymphoma (NCT05077527)

Background: Persons living with HIV (PLWH) have an increased risk of B-cell malignancies, including diffuse large B-cell lymphoma (DLBCL), even with well-controlled HIV. The lifetime cancer risk in PLWH is 25% to 40%1-3, and cancer is the leading cause of death in PLWH in economically advanced countries. Non-Hodgkin lymphoma (NHL) is the most common cancer in PLWH in the United States. Despite aggressive frontline treatments, about 20-30% of patients with HIV-associated B-NHL will not be cured with current therapies4, comparable to the non-PLWH B-NHL population. Axicabtagene ciloleucel (axi-cel) is an FDA-approved CD19-directed CAR-T cell product for the treatment of patients with relapsed or refractory (R/R) DLBCL based on the ZUMA-1 (>2 prior lines of therapy5) and ZUMA-7 (primary refractory or relapse within 12 months of initial therapy6) trials. As patients with HIV were excluded from registrational studies, only sparse case reports or small case series7 exist to guide treatment in this context. With regards to safety concerns, a study of CD4 cell count trends in a subset of HIV-negative patients receiving axi-cel demonstrated low CD4 cell counts (median baseline 220/μL) that decreased over time and remained persistently low after lymphodepletion and axi-cel therapy (median CD4 cell count 155/μL at 1 year post treatment).8 This critical gap in evidence can potentially lead to lives lost in patients with HIV, typically aged 25 to 65 years. We hypothesize that axi-cel will be safe and feasible in treating R/R HIV-associated DLBCL. Study Design and Methods: This is a multicenter phase I study to define the safety and feasibility of axi-cel in R/R HIV-associated DLBCL (NCT05077527). Concurrent correlative studies will investigate immune reconstitution and HIV virologic response. All participants will receive the standard dose of axi-cel at AMC sites following conditioning chemotherapy; bridging therapy may be given at the discretion of the treating physician (Figure 1). Key eligibility criteria include HIV positivity with viral load <50 copies/mL; diagnosis of R/R DLBCL, high-grade B-cell lymphoma, primary mediastinal B-cell lymphoma, or follicular lymphoma grade 3B; either post 2 prior lines of therapy or refractory/relapsed within 12 months of frontline treatment; evaluable disease; adequate organ/marrow function; and CD19 positivity confirmed if previously received CD19-directed therapy. The study will enroll 20 participants, including at least 6 participants with a CD4 cell count <100/μL. A safety assessment of participants with CD4 cell count <100/μL will be done after 6 participants in that cohort have been enrolled in this study (Figure 2). If >2/6 participants experience dose-limiting toxicity, the study will halt recruitment of participants with CD4 cell count <100/μL and continue to recruit participants with CD4 cell count of ≥100/μL. The primary endpoint of the study is safety and feasibility. Safety is defined by blood count recovery of neutrophils to grade ≤2, and platelets to grade ≤2 within 6 weeks of axi-cel infusion, incidence/severity of infection, and incidence/severity CRS/ICANS9 among patients who receive axi-cel. The incidence of toxicity will be summarized using frequency and percentage and presented overall and for each CD4 cell count cohort (<100 versus ≥100/μL). The feasibility assessment will be evaluated as the proportion of participants who receive axi-cel among all enrolled participants who undergo leukapheresis. Based on published data10 from patients without HIV (success rate ~85%) and anticipating potential difficulties in clinical progression, leukapheresis, and manufacture, we assigned >50% as the acceptable feasibility cutoff for our study population. Key secondary endpoints include 1) complete response (CR) rate per Lugano criteria,11 2) event-free survival (time from enrollment to earliest of disease progression; commencement of new anti-lymphoma therapy; or death), and 3) response duration (time from date when response criteria are met to relapse or progression). Key exploratory endpoints include 1) differences in cytokine profiles between patients who achieve CR and those achieving <CR per Lugano criteria (tested for statistical significance using Wilcoxon rank sum test) and 2) associations between cytokine profile and CRS and ICANS severity (≥ grade 3 vs < grade 3, tested for statistical significance using Wilcoxon rank sum test). Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Mosunetuzumab with Polatuzumab Vedotin Is Effective and Has a Manageable Safety Profile in Patients Aged

Background: Treatment decision-making for elderly DLBCL patients (pts) is challenging. Advancing age is associated with an increase in the incidence of comorbidity and vulnerability to treatment-related toxicities (Thieblemont & Coiffier. J Clin Oncol 2007). Mosunetuzumab (M) is a CD20xCD3 T-cell engaging bispecific monoclonal antibody (Ab) that redirects T cells to eliminate malignant B cells. The Phase Ib/II GO40516 study (NCT03671018) is evaluating M in combination with the anti-CD79b antibody-drug conjugate polatuzumab vedotin (Pola; M-Pola) in pts with B-cell non-Hodgkin lymphoma (B-NHL). In the ongoing Phase II part of the study, M-Pola showed an acceptable safety profile with promising activity in pts with R/R B-NHL (Budde et al. ASH 2021). Here, we present a subgroup analysis of the efficacy and safety of M-Pola in pts aged <65 and ≥65 years with R/R aggressive B-NHL from the Phase Ib dose-escalation and Phase II dose-expansion cohorts. Methods: All pts in this analysis had DLBCL (including transformed follicular lymphoma and follicular lymphoma grade [Gr] IIIB), an Eastern Cooperative Oncology Group performance status (ECOG PS) 0-2, and ≥1 prior line of therapy, including an anti-CD20 Ab. Treatment cycles were 21 days. Pola (1.8mg/kg intravenous [IV] infusion) was given on Day (D)1 of Cycle (C)1-6. M (IV infusion) was given with step-up dosing during C1 to mitigate cytokine release syndrome (CRS), and the recommended Phase II dose was used in the Phase II dose-expansion cohort (1mg on C1D1, 2mg on C1D8, 60mg on C1D15 and C2D1, and 30mg on D1 of C3-8). Pts with stable disease or a partial response at the end of C8 could continue M for a total of 17 cycles, while pts with a complete response (CR) discontinued M after C8. In the Phase II expansion cohort, mandatory hospitalization was not required for M administration. Response was assessed by investigators using Lugano 2014 criteria (Cheson et al. J Clin Oncol 2014). CRS events were reported using American Society for Transplantation and Cellular Therapy criteria (Lee et al. Biol Blood Marrow Transplant 2019). Results: As of March 15, 2021, with a median follow-up of 5.3 months (range: 0.7-23.7 months), 60 pts with R/R DLBCL had received M-Pola: 24 (40%) were aged <65 years and 36 (60%) were aged ≥65 years. At study entry, for pts aged ≥65 years, the median age was 73 years (range: 65-83), 53% had ECOG PS 1 and 8% had PS 2, 50% had International Prognostic Index 3-5, 81% had Ann Arbor stage III/IV disease, and 81% and 72% were refractory to a prior anti-CD20 Ab and to last prior therapy, respectively. There were more pts <65 years than pts ≥65 years with high lactate dehydrogenase (LDH; 63% vs 44%, respectively), with ≥3 prior lines of therapy (67% vs 56%), and refractory to CAR T-cell therapy (38% vs 25%; Table). Compared with younger pts, those aged ≥65 years had a numerically higher ORR (72% [95% CI: 55-86] vs 54% [95% CI: 33-75]) and CR rate (56% [95% CI: 38-72] vs 38% [95% CI: 19-59]). The rate of Gr 3-4 adverse events (AEs) was lower in pts ≥65 years than in those <65 years (39% vs 58%, respectively), with fewer neutropenia events occurring (14% vs 33%); the rate of serious AEs of any Gr was similar (39% vs 33%). Five pts ≥65 years discontinued M and/or Pola due to treatment-related AEs compared with one pt <65 years. The rate of CRS was comparable in pts aged ≥65 and <65 years (17% vs 21%), all CRS events were low-Gr (≥65 vs <65 years: Gr 1, 14% vs 21%; Gr 2, 3% vs 0%), and all CRS events resolved. Rates of serious AEs of infection were comparable in pts aged ≥65 and <65 years (11% vs 17%, respectively). Rates of peripheral neuropathy were 42% in pts aged ≥65 years vs 21% in pts aged <65 years, with most events Gr1-2 (≥65 vs <65 years: 1 vs 2 Gr 3 events). After the first M-Pola dose, pharmacodynamic changes in interferon-α and T-cell activation in peripheral blood were similar across age groups. Conclusions: M-Pola is effective and has a manageable safety profile in pts with heavily pretreated DLBCL, including older pts who may have more comorbidities and fewer treatment options, such as those who are poor candidates for CAR T-cell therapy. Numerically higher ORR and CR rates were seen in pts aged ≥65 years, although longer follow-up is required. Comparable rates of CRS and serious AEs were observed across age groups. Enrollment in the Phase II study with no mandatory hospitalization is ongoing. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Response Adapted Ultra Low Dose Radiation Therapy for the Definitive Management of Orbital Indolent B-Cell Lymphoma

<h3>Purpose/Objective(s)</h3> Radiation therapy (RT) to doses of 24-30 Gy is used for the treatment of indolent B-cell lymphoma (BCL); however, significant acute and late ocular effects are common. We aimed to develop a response adapted (RA) strategy that maintains excellent disease outcomes but reduces orbital morbidity. <h3>Materials/Methods</h3> We performed a phase II prospective study of a RA strategy in 50 patients (pts) with stage I-IV orbital indolent BCL. Pts were treated with ultra-low dose (ULD) RT to 4 Gy in 2 fractions and assessed in 3-month intervals for response. Pts with persistent orbital lymphoma were offered an additional 20 Gy in 10 fractions. Pts that had a complete response (CR) to ULD RT were observed. We also evaluated this treatment strategy in a separate 55 pt retrospective cohort. <h3>Results</h3> From July 2015-January 2021 51 pts were enrolled. Fifty evaluable pts had follow-up for study inclusion. The median age was 63 years (29-88); 62% were female (n=31). Pts had MALT lymphoma (n=32, 64%), follicular lymphoma (FL, n=16, 32%) and low grade BCL (n=6, 12%). Most pts (62%, n=31) had stage I disease limited to one (n=28) or both (n=3) orbits. Pts had newly diagnosed (n=36, 72%); relapsed (n=9, 18%) and refractory lymphoma (n=5, 10%). At a median follow up of 35 months [95% CI 22.2 – 37.4], 90% of pts (n=45) experienced a CR to RA RT, including 44 pts that had a CR to ULD RT (median time to CR 3.4 months) and 1 pt that had a CR after an additional 20 Gy. No local recurrences were observed. Treatment was well tolerated with no grade ≥3 toxicity. Five pts did not have a CR to planned RA therapy including 1 pt that refused additional RT, one pt treated with rituximab, one pt that had a PR on initial evaluation but has not returned for subsequent in person evaluations due to COVID, one pt being observed with stable disease and a final pt that received an additional 20 Gy to the orbit that has a persistent stable mass after the 20 Gy. In a planned subset analysis of 26 pts with newly diagnosed stage 1 disease (MALT, n=22; FL, n=3; low grade BCL, n=1); 92.3% (n=24) had a CR to RA RT, with one pt requiring an additional 20 Gy. For all 26 pts with newly diagnosed stage 1 disease, the 3-year freedom from distant relapse rate was 90.4% with 3 distant relapses (contralateral orbit, n=2; paratracheal nodes, n=1). The median follow-up among the 55 pts (MALT, n=38; FL, n=13; low grade B-cell lymphoma, n=4) treated in the retrospective cohort between March 2013 and October 2021 was 28.7 months (95% CI 21.2 - 36.1); 98% (n=54) of pts had a CR with RA RT, including 2 pts with a CR after an additional 20 Gy. The remaining pt went on to receive systemic therapy in lieu of additional RT for persistent disease. Among the 54 pts that had a CR with RA RT there was one local relapse in a pt with conjunctival FL 27.8 months after experiencing a CR to ULD RT. This pt received 20 Gy with resolution of the locally relapsed disease. <h3>Conclusion</h3> We observed excellent disease control with negligible toxicity in the first prospective study assessing this novel approach of RA ULD RT for pts with indolent B-cell lymphoma.

IBCL-081 MAGNIFY Phase 3b Study of Lenalidomide + Rituximab (R2) Followed by Maintenance in Relapsed/Refractory Indolent Non-Hodgkin Lymphoma: Complete Induction Phase Analysis

Patients with relapsed indolent NHL (iNHL) have limited standard treatment options. Lenalidomide + rituximab (R2) has shown complimentary clinical activity and is tolerable in both untreated and relapsed/refractory (R/R) iNHL. MAGNIFY is a multicenter, phase 3b trial in R/R follicular lymphoma (FL) grades 1-3b, transformed FL (tFL), marginal zone lymphoma (MZL), or mantle cell lymphoma (MCL; NCT01996865). In the induction phase, lenalidomide 20mg PO d1-21 of a 28-d cycle + rituximab IV 375mg/m2/week cycle 1 and then q8w starting with cycle 3 (R2) are administered for 12 cycles. Patients with ≥SD were randomized 1:1 to R2 vs rituximab maintenance for 18 months. Data here are the complete induction phase analysis in efficacy-evaluable patients with FL grades 1-3a or MZL. The focus of this interim analysis was ORR by 1999 IWG criteria in the induction ITT population. As of March 5th, 2021, 394 patients (318 [81%] FL gr1-3a; 76 [19%] MZL) were enrolled. Median follow-up was 40.6 mo (range, 0.6-79.6). Median age was 66 y (range, 35-91), 328 (83%) had stage III/IV disease, with a median of 2 prior therapies (94% prior rituximab-containing). ORR was 71% with 42% CR/CRu. All patients have completed R2 induction (n=232, 59%) or discontinued study treatment (n=162, 41%); 141 patients (36%) prematurely discontinued both lenalidomide and rituximab, primarily due to AEs (n=54, 14%) or PD (n=42, 11%). The majority who have completed induction have been randomized and entered maintenance (n=217). Median DOR in the induction period was NR (95% CI, 43.9 mo-NR); median PFS in the induction safety population was 50.5 mo (95% CI, 39.5-NR). Most common all-grade TEAEs were 47% fatigue, 43% neutropenia, 37% diarrhea. Grade 3/4 AEs occurring in ≥5% of patients included 37% neutropenia (10 patients [3%] had febrile neutropenia), 8% leukopenia, 6% thrombocytopenia, 5% anemia, 5% fatigue. These data represent a complete analysis of all patients in the induction phase of MAGNIFY that continue to support that R2 is active with a tolerable safety profile in patients with R/R FL grade 1-3a and MZL, including rituximab-refractory, double-refractory, and early relapse patients.

ABCL-422 Subcutaneous Epcoritamab in Patients With Relapsed or Refractory Large B-Cell Lymphoma (EPCORE NHL-1): Pivotal Results from a Phase 2 Study

Treatment options that are more tolerable, readily available, and capable of inducing deep and durable responses are needed in patients with relapsed or refractory (R/R) large B-cell lymphoma (LBCL). Epcoritamab is a novel, subcutaneous (SC) CD3xCD20 bispecific antibody with preliminary potent antitumor activity. Report primary results from the LBCL expansion cohort in the phase 2 study of SC epcoritamab in patients with R/R B-cell NHL (EPCORE NHL-1; NCT03625037). Adults with R/R CD20+ LBCL were included. Patients had DLBCL (including double/triple-hit and transformed), high-grade B-cell lymphoma (HGBCL), primary mediastinal LBCL (PMBCL), or follicular lymphoma (FL) grade (G) 3B. As of January 31, 2022, 157 patients were treated. Patients received epcoritamab (priming and intermediate doses followed by 48 mg) as 1-mL SC injections (QW, cycle [C] 1-3; Q2W, C4-9; Q4W, C≥10) until disease progression or unacceptable toxicity. The 157 patients had a median of 3 (range, 2-11) prior lines of therapy (LOT), 61 (38.9%) received prior CAR T, 61% had primary refractory disease, and 83% were refractory to the last LOT. With a median follow-up of 10.7 mo, the overall response rate (ORR) by IRC (Lugano/PET-CT) was 63% with 39% complete response (CR). ORR/CR rates were 69%/42% for CAR T-naive patients and 54%/34% for CAR T-exposed patients. Median duration of response was 12 mo overall and not reached among complete responders. ORR was similar across prespecified subgroups of age, prior LOT, and de novo or transformed disease. The most common treatment-emergent AEs were CRS (49.7%; 31.8% G1, 15.3% G2, 2.5% G3), pyrexia (23.6%), fatigue (22.9%), neutropenia (21.7%), and diarrhea (20.4%). Ten patients (6.4%) experienced ICANS; all but one event was G1-2, and the G5 ICANS was the only treatment-related death. Epcoritamab is a convenient, SC, off-the-shelf therapy that demonstrated clinically meaningful, compelling efficacy including deep and durable responses in a challenging-to-treat, highly refractory LBCL population. Efficacy was observed in both CAR T-exposed and CAR T-naive patients. The safety profile was manageable and consistent with previous findings. This study was funded by Genmab A/S and AbbVie.