Lugano Criteria Research Articles

Évaluation de la réponse des lymphomes en TDM : de CHESON à RECIL

In oncology, the use of standardized criteria to assess tumor response is crucial in clinical trials and routine care. Before 1999, criteria for malignant lymphomas were highly variable, complicating comparisons and assessment of treatment efficacy. This need for standardization to improve the reliability of results, particularly regarding normal lymph node size and how response is measured and assessed, led to the development of the Response Evaluation Criteria in Solid Tumors (RECIST) and Cheson criteria for lymphomas. The recent Response Evaluation Criteria in Lymphoma (RECIL), were specifically developed for the assessment of response to treatment in lymphomas, but these criteria are imperfect and the trend is to use the Lugano criteria instead.

Abstract PO-003: Peripheral blood and tumor tissue biomarkers associated with epcoritamab response in patients with relapsed or refractory diffuse large B-cell lymphoma: Data from the dose-expansion cohort of the phase 1/2 EPCORE NHL-1 trial (NCT03625037)

Abstract Introduction: Epcoritamab, a CD3xCD20 bispecific antibody, demonstrated deep and durable clinical responses in patients (pts) with relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL). We evaluated the correlation of peripheral blood (PB) and tumor tissue biomarkers with clinical response to epcoritamab. Methods: Pts received priming (0.16 mg), intermediate (0.8 mg) and full epcoritamab doses (48 mg). Absolute lymphocyte count (ALC) was analyzed locally. Blood immunophenotyping was assessed by flow cytometry, plasma cytokines by MSD assay, and %CD20+ in tumors by immunohistochemistry (n=117). Gene expression in baseline tumor biopsies was evaluated using HTG EdgeSeq (n=70). Microenvironment scores were estimated from gene expression as a sum of immune (B/T, NK, dendritic, and myeloid cells) and stromal scores (adipocytes, fibroblasts, and endothelial cells). Best overall response as of April 21, 2023 was assessed by independent review committee using Lugano criteria. P values were based on Wilcoxon rank-sum test. Results: In PB at baseline, significantly higher ALC (P=0.031), CD4+ (P=0.0038), and CD8+ (P=0.043) T-cell levels were observed in responders (R) vs nonresponders (NR). Similarly, CD4+ (P=0.02) and CD8+ (P=0.03) signatures and immune and microenvironment scores were higher in baseline tumor tissue in R vs NR. In PB CD8+ T cells, NR showed higher %PD1+ (P=0.016), %TIM3+ (P=0.048), and %TIM3+TIGIT+ (P=0.045). High tumor %CD20+ (≥90%) was observed in most pts (n=97/117); lower %CD20+ (<50%) was observed only in 6 NRs and 1 R. Epcoritamab treatment caused a rapid decline in circulating B cells irrespective of clinical response. Transient reductions in PB CD4+ and CD8+ T cells (ie, margination) were observed within 24 hours (H) after each dose during cycle (C) 1 and were more pronounced in R vs NR. Magnitude of margination for CD8+ T cells after the priming and intermediate doses was significantly lower in NR (reduced by median 22 & 41%) vs R (57 & 70%), while the difference in CD4+ T cells was not as pronounced in NR vs R, resulting in a substantially lower CD4+/CD8+ ratio in NR vs R. In C1, epcoritamab led to an increase of PB CD4+ and CD8+ T cells expressing activation/proliferation markers, with significantly higher fold change from baseline in R vs NR, especially within 24H post-priming dose. Early cytokine peaks of IFNy and IL-10 were more pronounced 6–24H post-priming dose and 6–14H post-first full dose in complete R vs pts with progressive disease. Epcoritamab also appeared to modulate NK cell numbers (under further investigation). Conclusions: In pts with R/R DLBCL, T-cell abundance and increased margination, activation, proliferation, and modulation of cytokines differed in R vs NR. These findings are consistent with epcoritamab’s mechanism of action and demonstrate the dependency on proper T-cell engagement for clinical benefit. Our findings also revealed differences in the dynamics of CD4+ and CD8+ T-cell margination in R vs NR, warranting further investigation. Previously submitted in part to EHA 2024. Citation Format: Monica Wielgos-Bonvallet, Jimin Zhang, Han Si, Kubra Karagoz, Melih Acar, Yasmin Karimi, Herve Ghesquieres, Michael Roost Clausen, Iş?l Alt?ntaş, Binhuan Wang, Wissam Assaily, Matthew Loya, Gregg Masters, Anantharaman Muthuswamy, Brandon Higgs, Mariana Sacchi, Tahi Ahmadi, Mark Fereshteh, Edith Szafer-Glusman, David Soong, Maria Jure-Kunkel, Andrew J Steele. Peripheral blood and tumor tissue biomarkers associated with epcoritamab response in patients with relapsed or refractory diffuse large B-cell lymphoma: Data from the dose-expansion cohort of the phase 1/2 EPCORE NHL-1 trial (NCT03625037) [abstract]. In: Proceedings of the Fourth AACR International Meeting on Advances in Malignant Lymphoma: Maximizing the Basic-Translational Interface for Clinical Application; 2024 Jun 19-22; Philadelphia, PA. Philadelphia (PA): AACR; Blood Cancer Discov 2024;5(3_Suppl):Abstract nr PO-003.

Epcoritamab + R-DHAX/C in transplant-eligible patients (pts) with high-risk relapsed or refractory (R/R) diffuse large B-cell lymphoma (DLBCL).

7032 Background: While high-dose therapy (HDT)–autologous stem cell transplant (ASCT) is potentially curative for pts with R/R DLBCL, many do not receive this treatment (tx) due to insufficient response to salvage chemoimmunotherapy; better options are needed. Epcoritamab is a CD3xCD20 bispecific antibody with efficacy and safety in R/R DLBCL as a single agent and in combination. We report updated data from epcoritamab in combination with rituximab, dexamethasone, cytarabine, and oxaliplatin or carboplatin (R-DHAX/C) in pts with R/R DLBCL eligible for HDT-ASCT, including high-risk pts (progressed within 12 mo of initial tx or primary refractory), from EPCORE™ NHL-2 (phase 1/2; NCT04663347). Methods: Adults with R/R CD20+ DLBCL eligible for HDT-ASCT received R-DHAX/C and epcoritamab (2 step-up doses, then 24- or 48-mg full doses) in 21-d cycles (Cs): QW, C1–3. If HDT-ASCT was deferred, pts could continue epcoritamab (21-d C: QW, C4; 28-d Cs: Q2W, C5–9; Q4W, C≥10) until disease progression. Primary endpoint was overall response rate (ORR; Lugano criteria). Results: As of Dec 15, 2023, 29 pts (median age, 58 y) received epcoritamab (24 mg, n=3; 48 mg, n=26) + R-DHAX/C. At baseline, 24 pts (83%) had progressed within 12 mo of initial tx, 19 (66%) had primary refractory disease (no response or relapse within 6 mo of initial tx), and 3 (10%) had prior CAR T. At 27.5 mo median follow-up, 16 (55%) pts had proceeded to HDT-ASCT and 2 (7%) remained on tx. ORR was 76% and complete response (CR) rate was 69% (Table). Median time to response was 1.4 mo (CR, 1.5 mo). At 24 mo, per Kaplan–Meier estimates, 60% of pts remained progression free, while 90% of pts who proceeded to ASCT (n=16) and 60% of pts who continued epcoritamab without ASCT (n=5) remained progression free; additionally, 90% of pts with CR who received ASCT (n=15) and 100% of high-risk pts with CR who received ASCT (n=12) remained in response. An estimated 86% of pts remained alive at 24 mo. The most common tx-emergent AEs (TEAEs) of any grade (G) were thrombocytopenia (76%), anemia (59%), nausea (48%), and neutropenia (48%; febrile neutropenia, 17%). CRS was low grade (38% G1, 7% G2), resolved, and did not lead to tx discontinuation. ICANS (G2) occurred in 1 pt and led to tx discontinuation. There were no fatal TEAEs. Conclusions: Longer follow-up reaffirms the efficacy and feasibility of epcoritamab + R-DHAX/C in ASCT-eligible DLBCL. Response rates were high and most pts proceeded to ASCT. Safety was manageable and consistent with prior data. These results, including new high-risk subgroup analyses, support future evaluation of epcoritamab + R-DHAX/C in ASCT-eligible DLBCL. Clinical trial information: NCT04663347 . [Table: see text]

Roginolisib, an oral, highly selective and allosteric modulator of phosphoinositide 3-kinase inhibitor delta (PI3Kδ) in patients with uveal melanoma and advanced cancers.

9597 Background: The highly selective, oral allosteric modulator of PI3Kδ, roginolisib (IOA-244), blocks the activity of PI3Kδ-dependent signaling, in both tumor cells and Tregs. Methods: Continuous daily dosing of roginolisib at 10, 20, 40 and 80 mg in patients (pts) with pretreated solid tumours and Follicular Lymphoma (FL) were evaluated (Part A). Part B consists of a dose confirmation cohort in uveal melanoma (UM) pts of 2 parts, B.1 and B.2. Primary objective: safety of the anticipated biologically effective dose (BED). Secondary objectives: PK; PD (e.g., inhibition of CD63 expression on basophils, changes in immune cell subsets in peripheral blood); RECIST 1.1 or Lugano-based responses; PFS and OS. Exploratory studies: phenotypic changes in circulating immune cells by mass cytometry (i.e., CyTOF); response assessments by radiomics; analysis of circulating protein signatures via Olink proteomics. Results: Part A Solid Tumour (completed): Sixteen pts were treated in 4 cohorts of 4 pts each. Pts characteristics: uveal melanoma (9/16; 56%), cutaneous melanoma (5/16; 31%) and pleural mesothelioma (2/16; 13%). Only Grade 1 and 2 AEs by CTCAE v.5 were observed, including 2 cases of transient (lasting < 24 hrs) diarrhoea and 2 of AST/ALT elevation. Part A FL Cohort (completed): 8 pts were treated at 20 mg (n=4) and 80 mg (n=4). Grade 3 toxicities were transient and observed in 2/8 (25%) pts. 2/4 pts (50%) at the 80 mg had PR as per Lugano criteria. Treatment-emergent adverse events (TEAEs) did not result in study drug discontinuation, immune-related toxicity, or dose-limiting toxicity in either the solid tumor or hematological patients. UM pts (Part A and Part B)>: 29 pts (Part A: 9 pts; Part B.1: 7 pts, Part B.2: 13 pts), of which 23 were treated at 80 mg QD (RP2D). Mean time on treatment: 10.7 mo (range: 1.5-39.6 mo). ORR (RECIST 1.1): PR: 1/29 (3%); SD: 21/29 (72%). Median OS for Part A: 20.8 mo (5/9 with 4 pts alive); Part B.1 20.1 (4/7 with 3 pts alive); Part B.2 not determined; 1-year OS rate: Part A 66.7%; Part B.1 71%; Part B.2 immature. Exploratory Investigations: At 3.7 mo (Cycle 5), there were 2 groups: one with SD (13/29; 45%) and the other with PD (16/29; 55%). At 6 mo, this split continued with 38% (11/29) showing SD and 62% having PD (18/29). Volumetric changes matched durable SDs while having higher sensitivity in the 15 analyzed patients. Interestingly, tumor burden reduction in mediastinal lymph nodes was indicative of SD and 70% of pts had volumetric spleen size reduction. Volumetric and radiomic changes were matched with peripheral changes in plasma proteins and immune cell changes. Conclusions: Roginolisib is well tolerated at 80 mg, demonstrates efficacy, and induces phenotypic changes in circulating immune cells. At the RP2D, the most robust anti-tumour activity was observed in FL (50% PR) and UM pts (3% PR; 72% SD). Clinical trial information: NCT04328844 .

First-line treatment of follicular lymphoma (FL) with golcadamide, rituximab +/- nivolumab: An umbrella randomised phase 2 investigator-led study.

TPS7092 Background: The most common therapy FL pts receive remains chemotherapy which yields high efficacy but also significant toxicity.(Marcus 2017, Rummel 2013). FL pts are largely aged over 65 and may require treatment multiple times over their disease course thus novel regimens which enhance efficacy and minimise toxicity are highly desirable. FL patient (pt) outcomes are influenced by tumor microenvironment composition and manipulation with immunotherapy. Ikaros and Aiolos, key cell development and homeostasis transcription factors are upregulated in FL. Cereblon-modulating compounds (CELMoDs) such as golcadomide (G) promote degradation of these with demonstrated efficacy alone or with rituximab (R) in FL (responses-ORR- upto 75% in heavily pre-treated FL pts) (Morschhauser 2018, Michot 2021). We reported favourable efficacy of nivolumab (N) a PD1 inhibitor plus R in 1L treatment of FL (ORR 92% complete response CR 54%). (Hawkes 2021).This study (‘TOP-FLOR’; NCT05788081) builds on these findings and potential immunomodulatory synergy to explore the efficacy and safety of R + G, a novel CELMoD +/- N in treatment-naïve advanced stage FL pts. Methods: This is an open label multicentre umbrella Bayesian Optimal randomised Phase 2 trial (n=40). Eligibility includes: age >18 years, treatment-naïve, stage II-IV, low grade FL, ECOG 0-2. Pts from 5 Australian sites are randomised 1:1 to receive 8 cycles of R-G +/-N 8 cycles of 28 days (D) each as follows: Arm A; R 375 mg/m2 IV D1 + G 0.4 mg orally D1- 14; Arm B; R-G as above +N 480mg IV D1. All pts in partial response (PR) or CR post cycle 8 receive 8 doses of 12-weekly R maintenance. The primary endpoint (EP) is CR rate post induction in the absence of prohibitive toxicity (CTCAE V5.0). Secondary EP are overall toxicity, ORR (as per Lugano criteria), time to treatment failure, progression free survival, overall survival. Exploratory EP include: pt reported outcomes, PET radiomics, laboratory biomarkers. Study assessments include safety assessments every cycle until D28 post final study drug delivery. Response assessments (PET/CT), pt reported outcomes & biomarker bloods are performed at baseline, post cycles 2, 5 & 8, then 6 monthly during R maintenance. Futility analysis occurs after 11 pts are recruited to each arm with < 7 pts achieve the primary EP. Treatment arms will not be formally compared. Kaplan-Meier analysis will be used to report survival probabilities. This trial received IRB approval on 14 July 2023 (HREC/88597/Austin-2023). To date 15 pts have been randomised. Clinical trial information: NCT05788081 .

Concordance between physician response assessment and a novel method per Lugano criteria in patients with lymphoma using real-world data.

e19082 Background: Clinical response assessment criteria, such as RECIST v1.1 and Lugano 2014, provide a standardized approach to assess treatment effectiveness in oncology clinical trials. Corresponding methodologies are needed for real-world data (RWD) to improve interpretability alongside clinical trial data and facilitate replication of results across RWD studies. We developed a RWD novel methodology, real-world Lugano (rwLugano), derived from Lugano 2014 criteria to classify lymphoma treatment response among patients with diffuse large B-cell lymphoma (DLBCL). Methods: A retrospective multisite RWD study identified adult patients with DLBCL treated with first line chemoimmunotherapy in US clinical practice (01JAN2015-31DEC2022). Participating sites abstracted clinical data via medical chart review and positron emission tomography-computed tomography (PET-CT) reports. Deidentified digital PET-CTs taken at treatment initiation and first response assessment were uploaded for BICR. Three distinct methods were used to assess treatment response: 1) physician-reported obtained from unstructured clinical notes in medical records, 2) rwLugano calculated using data (i.e., components of Lugano 2014) from PET-CT reports, and 3) BICR adjudication by two lymphoma radiologists using Lugano 2014 criteria. We compared the proportion of patients by response category: complete (CR), partial (PR), stable (SD) and progressive (PD) for each method. Analyses included agreement (%), concordance (Cohen’s kappa [κ]), and odds ratios with 95% confidence interval (OR; 95%CI) estimated using multivariable generalized linear mixed models (GLMM) adjusted for baseline characteristics. Results: The study identified 174 patients with DLBCL (female n=71 [41%]; white n=135 [78%]; Hispanic n=13 [7%]; mean age 66 years). Fewer patients were classified as CR at initial response via physician-reported response (n=111, 64%) compared to rwLugano (n=145, 83%), and BICR (n=142, 82%). Overall and CR agreement with BICR (see Table) was higher for rwLugano (overall: 83%, κ=0.49; CR: 86%, κ=0.50) than physician-charted response (overall: 72%, κ=0.45; CR: 76%, κ=0.43). In GLMM models, physician-charted response underestimated CR compared to BICR (OR=0.22, 95%CI:0.12-0.43), whereas rwLugano was statistically similar to BICR (OR=1.2, 95%CI:0.6-2.4). Conclusions: This study found that physician-reported response may underestimate CR at initial response, and rwLugano may be more consistent with BICR for treatment response assessment. Use of rwLugano warrants further evaluation as a methodology to assess treatment response in RWD lymphoma research. [Table: see text]

Development of a novel methodology to assess response to lymphoma treatment in real-world data.

e19081 Background: Innovation in the use of real-world data (RWD) for regulatory purposes is an important provision of 21st Century Cures Act. Numerous initiatives to enhance RWD methodologies in oncology drug development are ongoing, including evaluation of treatment response assessment to support effectiveness research. Blinded independent central review (BICR) standardizes response assessment in clinical trials, and corresponding RWD methodologies are needed. This study assess feasibility of BICR using RWD, and evaluates a novel, standardized treatment response methodology among patients with diffuse large B-cell lymphoma (DLBCL). Methods: A retrospective multisite chart review identified adult patients with DLBCL treated with first-line chemoimmunotherapy in US (01JAN2015-31DEC2022). Clinical data, including physician-reported response, were abstracted from medical charts and positron emission tomography-computed tomography (PET-CT) reports at treatment initiation and first response assessment. Lugano 2014 criteria, such as standardized uptake value (SUV) and Deauville score, were extracted and converted to an algorithm (rwLugano). Absence of normal tissue SUV in PET-CT reports was addressed using published values for background, mediastinum, and liver to facilitate a real-world Deauville (rwDeauville) score for rwLugano classification. PET-CTs underwent deidentified digital image transfer for BICR using Lugano 2014 criteria by two lymphoma radiologists. Descriptive analyses assessed BICR feasibility and completeness of rwLugano data elements. Results: Six oncology practices, comprising 77 physicians, abstracted medical records and PET-CT reports for 185 patients. PET-CT scans were available for BICR for 174/185 (94%) patients (41% female, mean age 66 years). BICR discordance for Deauville score at baseline and initial response occurred in 7% (12/174) and 29% (50/174), respectively. For response assessment per Lugano, BICR discordance occurred in 9% (16/174), and were further adjudicated by a third party. Lugano discordance was often related to interpretation of marrow activity and/or new disease sites, highlighting variability in lymphoma treatment response assessment. Medical record review found Deauville score charted for 97 (56%) patients at baseline and 145 (83%) at first response. Tumor SUV was complete (174/174, 100%) at baseline and for all patients (63/63, 100%) not charted as CR at first response. Thus, 29 patients (17%) required calculation of rwDeauville at first response, providing data to calculate rwLugano for all patients in the final cohort (174/174, 100%). Conclusions: This study suggests BICR, though resource intensive, can be performed, and the component measures necessary to assess response per Lugano criteria can be obtained using RWD. Accordingly, rwLugano warrants further analysis for concordance with BICR- and physician-reported response.

Subcutaneous epcoritamab + GemOx in patients with relapsed or refractory DLBCL: Updated results from EPCORE NHL-2.

7037 Background: Gemcitabine + oxaliplatin (GemOx) is commonly used with rituximab to treat relapsed or refractory (R/R) diffuse large B-cell lymphoma (DLBCL); however, outcomes are suboptimal: 33% complete response (CR) rate; 5 mo median progression-free survival (PFS); 10 mo median overall survival (OS; Cazelles et al, Leuk Lymphoma 2021). We report additional efficacy and safety results of epcoritamab + GemOx in difficult-to-treat R/R DLBCL (EPCORE™ NHL-2 phase 1/2 trial, NCT04663347). Methods: Adults with R/R CD20+ DLBCL who failed or were ineligible for autologous stem cell transplant (ASCT) enrolled to receive subcutaneous (SC) epcoritamab (2 step-up doses followed by 48-mg full doses) in 28-d cycles (C): QW, C1–3; Q2W, C4–9; Q4W, C≥10 until unacceptable toxicity or disease progression. GemOx was given Q2W in C1–4. The primary endpoint was overall response rate (ORR) per Lugano criteria. Subgroup analyses by prior treatment (tx) and response were performed. Results: As of Sept 1, 2023, 97 pts with ≥6 mo of follow-up had received epcoritamab 48 mg + GemOx (median follow-up, 9.7 mo). Pts had a median of 2 prior lines of tx (pLOT; range, 1–6); 55% had primary refractory disease, 38% had bulky disease (>6 cm), 30% had prior CAR T, and 9% had prior ASCT. Median age was 72 y, with 34% of pts ≥75 y. A median of 7 cycles of epcoritamab and 4 cycles of GemOx were initiated. At data cutoff, tx was ongoing in 46% of pts. ORR was 78% and CR rate was 55%. Median time to CR was 1.7 mo; median duration of CR was 13.3 mo. Additional efficacy outcomes are shown in the Table. Safety was consistent with previous reports. The most common tx-emergent AEs (TEAEs) of any grade (G) were hematologic AEs (68% thrombocytopenia; 59% neutropenia [6% febrile neutropenia]; 51% anemia) and CRS (51%). CRS was primarily low grade (27% G1, 23% G2), with only 1 pt experiencing G3 CRS; all events resolved and none led to tx discontinuation. ICANS was reported in 3 pts (G1, n=2; G3, n=1); all events resolved, but 1 pt discontinued tx. There were 13 fatal TEAEs; in 3 cases, the contribution of epcoritamab + GemOx could not be ruled out: COVID-19, multiple organ dysfunction syndrome, and small intestinal perforation. Conclusions: These long-term results continue to demonstrate that SC epcoritamab in combination with GemOx leads to deep, durable responses, which translate to high rates of PFS and OS in challenging-to-treat, high-risk pts with R/R DLBCL. CR rates were consistently high across prespecified subgroups. Higher CR rates in pts with 1 vs ≥2 pLOT indicate that earlier use may further improve outcomes. No new safety signals were identified. The benefit-risk profile of this combination supports the combinability of epcoritamab in R/R DLBCL. Clinical trial information: NCT04663347 . [Table: see text]

Outcomes in patients (pts) with relapsed/refractory (R/R) diffuse large B cell lymphoma (DLBCL) treated with systemic therapy from real world experience (ORCHID) study.

e19067 Background: Odronextamab, an off-the-shelf CD20×CD3 bispecific antibody, has shown compelling efficacy (objective response rate [ORR] 52%, complete response [CR] rate 31.5%) and a generally manageable safety profile in pts with heavily pretreated R/R DLBCL in the single-arm ELM-2 trial (NCT03888105; Ayyappan et al. ASH 2023). We evaluated outcomes in pts with R/R DLBCL treated with currently available third-line or later (3L+) therapies in a real-world setting (ORCHID; NCT05338892) to better evaluate results from ELM-2 in the absence of a randomized control arm. Methods: ORCHID is a multicenter, retrospective, observational study, using electronic medical record or research databases, of pts with R/R DLBCL who have received ≥2 prior lines of therapy (LoTs; including an anti-CD20 and an alkylator) and initiated 3L+ systemic therapy for DLBCL between January 1, 2015 and June 30, 2021. After applying similar eligibility criteria to those in the ELM-2 trial, inverse-probability of treatment weighting (IPTW) was used to balance key prognostic variables between the trial and real-world cohorts. Pts were followed from the start of qualifying LoT until death, end of study period (December 31, 2021), or loss to follow up, whichever occurred first. The primary endpoint was ORR per Lugano criteria assessed by independent central review (ICR). Secondary endpoints included ICR-assessed CR rate, disease control rate (DCR), progression-free survival (PFS), duration of response (DOR), and overall survival (OS) (see Thieblemont et al. ASH 2022). Results: Pts in ORCHID (N=148) generally had less severe disease than trial pts prior to IPTW. The most commonly used regimens were anti-CD20 based therapies, CAR T, and chemotherapy alone. The IPTW cohort had a median age 65 y, 79% Ann Arbor stage III/IV, 66% primary refractory, 88% refractory to last LoT, and median (range) prior LoT: 2 (2–6). In the IPTW cohort, ORR was 44%, CR 18%, and DCR 50%. Median (m) PFS (mPFS), DOR (mDOR), and OS (mOS) were 7.2, 9.0, and 10.8 mo, respectively. Given the lack of regular scans in routine practice (47% of pts had only one ICR response assessment over the study period), sensitivity analysis that considered subsequent treatment as progression resulted in shorter mPFS (4.6 mo) and mDOR (6.1 mo). In the majority of LoTs initiating non-CAR T therapy (n=111), ORR was 33%, CR 15%, DCR 43%. The mOS in non-CAR T group was 7.5 mo and was not reached in those intended for CAR T. Conclusions: Pts in the ORCHID study, especially those who did not receive CAR Ts, had markedly lower response rates than those in the R/R DLBCL cohort of ELM-2. Despite prior failure, most pts still received an anti-CD20 based regimen in 3L+ setting in routine practice, highlighting the need for treatment options with different mechanisms of action that provide deep and durable responses and improve outcomes in this pt population. Clinical trial information: NCT05338892 .

Multicenter, randomized phase II study of epcoritamab for patients with large B-cell lymphomas achieving a partial response after CD19-directed CAR T-cell therapy (CAR-T).

TPS7100 Background: Despite the promising efficacy of CAR-T for patients with relapsed or refractory (R/R) large B-cell lymphomas (LBCL), more than 60% of patients will relapse, the majority of which occur in the first 6 months. Approximately 30% of patients with LBCL treated with CAR-T achieve a partial response (PR) on day 30 (D30) PET-CT assessment. Of patients in a D30 PR, 70% will eventually progress, yet the standard of care remains close observation. Early consolidative treatment strategies utilizing therapies with a different mechanism of action may improve outcomes, but there are currently no reliable biomarkers. Epcoritamab (Epco), a bispecific antibody directed against CD20 and CD3, has been approved by the FDA for LBCL patients who relapse after at least 2 lines of therapy. In the phase 2 study, Epco was associated with an overall response rate (ORR) of 63% and a complete response (CR) rate of 39%, including similar responses in a subset of patients who were relapsed 100 days post CAR-T. This study is a trial-in-progress that will evaluate the efficacy of epco compared to observation for patients with LBCLs achieving a PR on D30 post CAR-T PET-CT assessment. Methods: This is an investigator-initiated, randomized, phase II, multicenter, open-label study (NCT06238648) evaluating epco monotherapy for a fixed duration of 12 cycles compared to observation for LBCL patients with D30 PR after standard of care CAR-T. A maximum of 120 patients will be randomized 1:1 to epco or observation across 10 academic centers. Stratification factors include line of CAR-T (second vs third line) and costimulatory domain (CD28 vs 4-1BB). Key inclusion criteria include PET evidence of a D30 PR. non-bulky disease ( <7.5cm), ANC of >1000, hemoglobin >7 g/dL if asymptomatic or >8 if symptomatic, platelet count >50,000. G-CSF, pRBCs and platelet transfusions are allowed. Key exclusion criteria include prior anti CD20xCD3 bispecific antibody therapy, ongoing or uncontrolled CRS or ICANS, and active or symptomatic CNS disease. Epco is administered subcutaneously at a dose of 0.16mg on day 1, 0.8mg on day 8, prior to full dose of 48mg on day 15. Epco is administered weekly in 28 day cycles (C) for C1-3, on day 1 and 15 of C4-9 and on day 1 of C10-12. PET-CT response is assessed by the 2014 Lugano criteria after 2 cycles, and then every 3 months during active treatment. The primary objective is efficacy, measured as conversion from D30 PR to CR. The secondary endpoints include frequency and severity of treatment emergent adverse events, ORR, duration of response, duration of complete response, progression free survival, event free survival, and overall survival. Peripheral blood samples will be collected pre-treatment and during treatment to assess for biomarkers of response and resistance. The study was activated in January 2024 and recruitment is ongoing. Clinical trial information: NCT06238648 .

CD19/BCMA dual-targeting FasTCAR-T GC012F for patients with relapsed/refractory B-cell non-Hodgkin lymphoma: An update.

e19045 Background: CD19-directed CAR-T cell therapy has been demonstrated to be a valuable treatment option for relapsed/refractory B-cell non-Hodgkin’s lymphoma (r/r B-NHL). It has been shown that between 39% and 97% of clinical samples of B-NHL also express BCMA. To further improve safety and efficacy, we have developed GC012F, a CD19 and BCMA dual-targeting CAR-T, manufactured using the novel next-day FasT CAR-T process, for the treatment of r/r B-NHL. The data from an investigator-initiated trial of GC012F for r/r B-NHL were reported at ASCO 2023 (# 7562). Here, we present updated results of the trial, including more pts and a longer follow-up period. Methods: This is a single-arm, open label trial (ChiCTR2100047061). The patients (pts) were enrolled and treated with a single infusion of GC012F in escalating dosing cohorts after a standard lymphodepletion regimen. The primary objectives of this study were safety and tolerability; the secondary were pharmacokinetics and efficacy. Cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) were graded by ASBMT 2019, adverse effects were evaluated according to CTCAE 5.0. Efficacy assessment of GC012F was referred to the Lugano criteria. Results: As of data cut-off on January 30th, 2024, with a median of 410.5 days (range: 28 - 839) of follow-up, all pts received single GC012F infusions at dose levels ranging from 3.7×104 to 3×105 CAR-T/kg. The median age was 49.5 years (range: 18 - 67). Ten pts were Ann Arbor stage III/IV disease. All pts lymphoma samples expressed CD19, and 9 out of 11 expressed BCMA. Ptsreceived a median of 2 prior lines (range: 2 - 3) of therapy including rituximab and anthracyclines. Two ptsreceived the auto-HSCT previously. 91.7% (11/12) of the pts achieved ORR at month 3 post GC012F infusion; 66.7% (8/12) CR at month 6 and 60% (6/10) CR at month 12, respectively. To date, the longest duration of remission is 27.0 months. No dose-limiting toxicities were observed. One pt had grade 3 CRS and recovered within 2 days. No ICANS were observed. Grade ≥ 3 hematologic toxicities included lymphocytopenia (11/12), neutropenia (11/12) and leukopenia (10/12). All TEAEs were resolved after treatment with standard of care and supportive care. The median peak copy number of CAR-T cells in the peripheral blood was 70,083 copies/μg DNA (range: 6,876 - 185,039), and the median peak time was 14 days (range: 9 - 21). CAR-T cells were also detected in tumor biopsies from all six pts tested. In five pts at progressive disease, the primary or new lesions were CD19 positive, and no CAR-T cells were detected. Conclusions: This first-in-human trial of GC012F for the treatment of r/r DLBCL showed a manageable safety profile and promising clinical responses and a long-lasting duration of a remission. Overall, CD19-BCMA dual targeting CAR-T product GC012F is a promising therapy for r/r DLBCL pts and longer follow-up is ongoing. Clinical trial information: ChiCTR2100047061 .

Acalabrutinib plus venetoclax and rituximab in treatment-naive mantle cell lymphoma: 2-year safety and efficacy analysis

AbstractThis phase 1b study evaluated safety and efficacy of acalabrutinib, venetoclax, and rituximab (AVR) in treatment-naive mantle cell lymphoma (TN MCL). Patients received acalabrutinib from cycle 1 until progressive disease (PD) or undue toxicity, rituximab for 6 cycles with maintenance every other cycle through cycle 24 or until PD, and venetoclax, beginning at cycle 2, for 24 cycles. Twenty-one patients were enrolled; 95.2% completed induction (6 AVR cycles) and 47.6% continued acalabrutinib maintenance. Thirteen (61.9%) patients had grade 3-4 adverse events (AEs), most commonly neutropenia (33.3%). Seven (33.3%) patients had COVID-19 infection (6 [28.6%] serious AEs and 5 [23.8%] deaths, all among unvaccinated patients). There was no grade ≥3 atrial fibrillation, ventricular tachyarrhythmias, major hemorrhages, or tumor lysis syndrome. Overall response rate (ORR) was 100% (95% CI, 83.9-100.0) with 71.4% complete response. With median follow-up of 27.8 months, median progression-free survival (PFS) and overall survival (OS) were not reached. PFS rates at 1 and 2 years were 90.5% (95% CI, 67.0-97.5) and 63.2% (95% CI, 34.7-82.0), respectively; both were 95% after censoring COVID-19 deaths. OS rates at 1 and 2 years were 95.2% (95% CI, 70.7-99.3) and 75.2% (95% CI, 50.3-88.9), respectively; both were 100% after censoring COVID-19 deaths. Overall, 87.5% of patients with available minimal residual disease (MRD) data achieved MRD negativity (10–6; next-generation sequencing) during treatment. AVR represents a chemotherapy-free regimen for TN MCL and resulted in high ORR and high rates of MRD negativity. The trial was registered at www.ClinicalTrials.gov as #NCT02717624.

Abstract CT243: Primary analysis of the Phase 2 ELM-2 study: Odronextamab in patients (pts) with relapsed/refractory follicular lymphoma (R/R FL)

Abstract Background: R/R FL is an incurable disease and outcomes worsen with successive relapses. A high unmet need remains for therapies that improve tumor control and extend survival after relapse. Odronextamab, an off-the-shelf CD20×CD3 bispecific antibody, demonstrated compelling efficacy, generally manageable safety, and maintenance of pt-reported overall quality of life scores from baseline in an interim analysis of the ELM-2 study (NCT03888105) in heavily pretreated pts with R/R FL (Villasboas et al. ASH 2023). Here, for the first time, we present the primary analysis of R/R FL in ELM-2. Methods: IV odronextamab was administered in 21-day cycles (C) until disease progression/unacceptable toxicity. Steroid prophylaxis and step-up dosing (0.7/4/20 mg) were used in C1 to mitigate the risk of cytokine release syndrome (CRS), followed by 80 mg on Days (D) 1, 8, and 15 of C2-4. Maintenance dosing continued at 160 mg Q2W, or Q4W if complete response (CR) was durable for 9 months (mo). Primary endpoint was objective response rate (ORR) per Lugano criteria by independent central review (ICR). Secondary endpoints included CR rate, duration of response (DOR), progression-free survival (PFS), and overall survival (OS). Primary analysis was performed when 128 pts had ≥52 weeks’ follow-up. Results: At data cutoff (Oct 20, 2023), 128 pts with FL Grade (Gr) 1-3a were evaluable for efficacy and safety: median age 61 yrs (range 22-84); FLIPI risk score 3-5 57.8%; POD24 49.2%; median 3 prior lines of therapy (2-13); 71.9% refractory to last treatment (Tx); 74.2% refractory to an anti-CD20 antibody. The median no. of Tx cycles was 19.4 (0.1-95.9); 95.3% and 85.2% of pts completed C1 and C4, respectively.Median efficacy follow-up was 20.1 mo; ORR was 80.5% and CR rate was 73.4% confirmed by ICR. Responses were durable (median DOR 22.6 mo; median DOCR 25.1 mo). Median PFS was 20.7 mo and 24-mo PFS was 46.1%. Median OS was not reached and 24-mo OS was 70.1%.The odronextamab safety profile was generally manageable and consistent with previous reports. Tx-emergent adverse events (AEs) occurred in all pts (Gr ≥3 85.9%); 15.6% had AEs leading to Tx discontinuation. With 0.7/4/20 mg step up (n=60), CRS events were mostly low grade (Gr 1 45.0%; Gr 2 10.0%; Gr 3 in 1 pt), occurred mostly in C1, and resolved in a median of 2 days; ICANS was reported in 1 pt (Gr 2). Infection rates were consistent with heavily pretreated, immunosuppressed pts (Leonard et al. JCO 2019; Hayne et al. BBMT 2020), occurring in 79.7% (102/128) of pts (Gr 4/5 14.0%; COVID-19 36.7% [Gr 5 6.3%]).Conclusion: Odronextamab demonstrated deep and durable responses in heavily pretreated pts with R/R FL; 91% of responders achieved CR, correlating with favorable PFS and OS at 24 mo. Odronextamab had a generally manageable safety profile and a low incidence of Gr 3 CRS/ICANS. Odronextamab could offer an important off-the-shelf Tx option for pts with heavily pretreated R/R FL. Citation Format: Geoffrey Chong, Michal Taszner, Silvana Novelli, Seok-Goo Cho, Jose C. Villasboas, Ana Jiménez Ubieto, Benoît Tessoulin, Michelle Poon, David Tucker, Jan Walewski, Yuqin Song, Emmanuel Bachy, Stephanie Guidez, Aranzazu Alonso, Deepa Jagadeesh, Stefano Luminari, Laura Magnano Mayer, Elżbieta Iskierka-Jażdżewska, Monica Tani, Jingxian Cai, Amulya Uppala, Saleem Shariff, Jurriaan Brouwer-Visser, Aafia Chaudhry, Hesham Mohamed, Srikanth Ambati, Tae Min Kim. Primary analysis of the Phase 2 ELM-2 study: Odronextamab in patients (pts) with relapsed/refractory follicular lymphoma (R/R FL) [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 CT243.

457 A Phase I Trial of Tazemetostat and Venetoclax in Relapsed and Refractory non-Hodgkin Lymphoma

OBJECTIVES/GOALS: Primary Objective: To evaluate the safety of venetoclax plus tazemetostat in patients with relapsed and refractory (R/R) Follicular lymphoma (FL) or Diffuse large B-cell lymphoma (DLBCL) Secondary Objectives: 1. To evaluate the tolerability of the combination of T+V using patient reported outcomes (PROs) 2. To evaluate the efficacy of T+V METHODS/STUDY POPULATION: Study design: A phase I trial in two parts: Part 1: a single-arm, open-label sequential dose escalation (3+3) of venetoclax in combination with tazemetostat, given at its recommended phase II dose (RP2D) of 800mg BID, to determine the maximum tolerated dose (MTD) of venetoclax. Part 2: two expansion cohorts (R/R DLBCL and R/R FL) to further characterize the safety and tolerability of the combination, and to estimate the preliminary efficacy. We will perform additional exploratory studies to determine if there are biologic features that correlate with responses. Eligibility: up to 38 patients aged >/=18 years old with histologically confirmed diagnosis of FL or DLBCL who have received at least 2 prior lines of therapy for lymphoma with evidence of disease progression and meet inclusion criteria RESULTS/ANTICIPATED RESULTS: Primary Endpoints: 1. Incidence and severity of adverse events as per CTCAEv5 2. Dose-limiting toxicity (DLT) of T+V, and to establish the maximum tolerated dose (MTD) of V plus fixed dose T Secondary Endpoints: 1. Incidence and Severity of toxicity and quality of life as per PRO-CTCAE and FACT-Lym 2. Overall response rate (ORR), complete response (CR) rate, partial response (PR) rate, as per Lugano criteria 3. Duration of response (DOR), progression-free survival (PFS), overall survival (OS)Exploratory Endpoints: 1. Characterization of tumor cells pre-treatment (including EZH2 mutations and BCL2 translocations) 2. Phenotypic analysis (including BCL2 expression) and quantification of the tumor microenvironment in pre-treatment samples (using image mass cytometry)Explorato DISCUSSION/SIGNIFICANCE: There is a need for novel therapeutic approaches to improve the prognosis for patients with R/R NHL. Preclinical data suggests synergism between the pair.5 Importantly, this represents a chemotherapy-free, oral regimen. If well tolerated, this could present an alternative therapeutic option for patients ineligible for more intensive therapies.

Abstract 5071: Minimal residual disease (MRD) status by peripheral blood mononuclear cells (PBMCs) and circulating tumor DNA (ctDNA) demonstrates rapid, deep, and sustained response in patients (Pts) with relapsed/refractory follicular lymphoma (R/R FL) treated with subcutaneous (SC) epcoritamab monotherapy in the pivotal phase 1/2 EPCORE™ NHL-1 trial

Abstract Introduction: Outcomes in high-risk R/R FL are poor. Epcoritamab SC, a CD3xCD20 bispecific antibody, demonstrated promising efficacy with a manageable safety profile in pts with R/R FL after ≥2 prior lines of therapy (phase 1/2 EPCORE NHL-1; NCT03625037). Here we evaluated MRD with PBMCs and ctDNA in pts with R/R FL and correlated the results with clinical findings. Methods: Adults with R/R FL 1-3A enrolled in EPCORE NHL-1 received epcoritamab SC in 28-day cycles. MRD analysis was performed on longitudinal plasma and PBMC samples collected at prespecified timepoints (clonoSEQ assay, Adaptive Biotechnologies). Screening tumor biopsies were used to identify trackable tumor clones; samples were quantified as tumor clones detected per mL plasma for ctDNA and per one million nucleated cells for PBMC. Overall response and progression-free survival (PFS) were assessed using Lugano criteria by independent review committee. Results: Of 128 pts in the R/R FL 1-3A cohort, 91 with PBMC data and 100 with ctDNA data were MRD evaluable. Overall MRD negativity was achieved in 67.0% [95% CI: 56.4-76.5] of pts per PBMC and 68.0% [95% CI: 57.9-77.0] of pts per ctDNA. Concordance of subject-level MRD status was high (79 of 89 with PBMC and ctDNA data; 88.8%). In most pts, MRD negativity was reached prior to radiographic complete response (PBMC, 76.4%; ctDNA 58.5%). MRD negativity by PBMC preceded ctDNA (median days to MRD negativity, 28 [PBMC] vs 57 [ctDNA]), suggesting a difference in methodology in detecting tumor DNA. Pts who became MRD negative had prolonged PFS (median not reached). Baseline MRD levels were not associated with clinical outcomes (PBMC; Wilcoxon P=0.59, ctDNA P=0.39). PFS was similar in pts achieving MRD negative status (median not reached, PBMC and ctDNA), independent of high-risk/difficult-to-treat disease (≥4 prior lines, Ann Arbor stage III-IV, bulky disease, double refractory, FLIPI 3-5, and POD24). The overall MRD negativity rate was also similar in high-risk pts, except those with ≥4 prior lines of therapy. Conclusions: Based on the EPCORE-NHL-1 study, one of the first pivotal studies to report MRD in pts with R/R FL, epcoritamab drives rapid, deep, and sustained responses as supported by MRD assessment by both PBMC and ctDNA. MRD results correlate with clinical outcome, and achieving MRD negativity is associated with longer PFS. PFS was similar among all pts who achieved MRD negativity, including those with high-risk disease. Citation Format: David Soong, Işıl Altıntaş, John Karavitis, Kim M. Linton, Wojciech Jurczak, Catherine Thieblemont, Kevin Zhao, Edith Szafer-Glusman, Daniela Hoehn, Elena Favaro, Mariana Sacchi, Maria Jure-Kunkel. Minimal residual disease (MRD) status by peripheral blood mononuclear cells (PBMCs) and circulating tumor DNA (ctDNA) demonstrates rapid, deep, and sustained response in patients (Pts) with relapsed/refractory follicular lymphoma (R/R FL) treated with subcutaneous (SC) epcoritamab monotherapy in the pivotal phase 1/2 EPCORE™ NHL-1 trial [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 5071.

Abstract 4001: Monocyte transcriptome profiles associated with clinical response in patients with B-cell non-Hodgkin’s lymphoma receiving CD19-directed CAR-T therapy

Abstract Background Although CAR T-cell therapy has achieved remarkable response in patients (pts) with B-cell non-Hodgkin’s lymphoma (NHL), 20-30% of pts still have primary refractory disease (PD1), and another 30-40% relapse (PD2). We and others have shown that monocytes can modulate T-cell functions and impact clinical response to chemoimmunotherapy in NHL. Given that monocytes nadir and recovery kinetics differ from lymphocytes post lymphodepletion chemotherapy, we hypothesize that monocyte phenotype at peak CAR-T expansion and in the early month post CAR-T can modulate immune responses. Methods scRNAseq were performed on peripheral blood mononuclear cells of NHL pts prior to lymphodepletion chemotherapy (pre), at peak CAR-T expansion (peak), and one month following CAR-T (M1). Seurat v4.3.0 was used for unsupervised hierarchical clustering analysis. Lugano criteria was used to determine clinical responses which were categorized as CR (complete remission), PD1, or PD2. Results We analyzed 129,981 monocytes from 77 samples of 32 pts (16 CR, 4 PD1, 12 PD2) and 5 healthy controls. Unsupervised hierarchical clustering analysis identified 13 monocyte clusters: 4 classical monocyte (CM) clusters with transcriptome profiles for enriched signaling in IL-6, TGFβ, EMT, and p53; 2 intermediate monocyte (IM) clusters enriched for IL-1 or CD38 signaling; 2 non-classical monocytes (NM), one with increased CD36 expression; 3 monocytic MDSC clusters with enrichment of TGFβ, SIRPα, and HIF1α signaling; and 2 lymphoma-associated monocytes, expressing CD163 or CD169. At Pre and Peak, the distribution of the monocyte clusters was similar in pts with CR, PD2, or PD1, with only a slight decrease in the percent of NM in the PD2 group at Pre and slight increase of CD36 NM in PD1 at Peak. Compared to Pre, all pts had increased percent of CD36 NM and IL-1 IM at Peak. Interestingly, while the distribution of monocyte clusters was similar at Pre and Peak across clinical responses, GSEA showed that monocytes in CR pts, compared to PD1 and PD2, had gene expression enrichment of MYC target V2 pathway at Pre and TGFβ pathway at Peak. At M1, pts in PD1 had increased percent of p53 and TGFβ CM and decreased percent of NM. In contrast, pts with CR had decreased percent of IL-6 CM, p53 CM, TGFβ CM, IL-1 IM and increased percent of NM. Notably, as pts with CR and PD2 may appear similar clinically at M1, pts with PD2, compared to CR, have increased IL-6 CM, IL-1 IM, and decreased NM. In addition, GSEA showed that PD2 pts had increased IFNα response. Our results demonstrate that monocyte phenotype differences at Pre and Peak could be associated with CAR-T clinical response, and that persistent inflammatory monocyte signaling at M1 in pts with clinical response is associated with relapse. These data suggest a role for development of monocyte biomarkers to predict response and therapeutic targeting. Citation Format: Andre de Menezes Silva Corraes, Panwen Wang, Radhika Bansal, Henan Zhang, Zuoyi Shao, Kevin Regan, Eider Moreno Cortes, Arushi Khurana, Nora Bennani, Yucai Wang, Paul Hampel, Jonas Paludo, Patrick Johnston, Hemant Murthy, Madiha Iqbal, Stephen Ansell, Javier Munoz, Allison Rosenthal, Mohamed Kharfan-Dabaja, Januario Castro, Saad Kenderian, Haidong Dong, Ying Li, Yi Lin. Monocyte transcriptome profiles associated with clinical response in patients with B-cell non-Hodgkin’s lymphoma receiving CD19-directed CAR-T therapy [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 4001.

Early evaluation of CAR-T cell therapy response in R/R DLBCL patients using 18F-FDG PET/CT.

CD19-targeted chimeric antigen receptor T (CAR-T) cell therapy provides a durable response in patients with relapsed/refractory diffuse large B-cell lymphoma (R/R DLBCL). The role of fluorine-18-fluorodeoxyglucose (18F-FDG) positron emission tomography/computed tomography (PET/CT) for early evaluation of response in patients with that immunotherapy was evaluated. Three separate 18F-FDG PET/CT examinations of 53 patients (29 males, 24 females; median 62 years old) with R/R DLBCL were conducted; before bridging therapy [time of decision (TD)], before CAR-T (tisagenlecleucel, n=37; lisocabtagenemaraleucel, n=16) infusion [time of CAR-T infusion (IT)], and one month (M1) after CAR-T infusion. Response was evaluated based on the Deauville 5-point scale and Lugano criteria. Among 21 patients (39.6%) with complete metabolic response (CMR) at IT-PET, 20 were able to continue CMR, while one showed progression at M1-PET. Among 32 patients (60.4%) with non-CMR at IT-PET, 12, 8, 4, and 8 showed CMR, partial metabolic response (PMR), (non-metabolic response (NMR), and progressive metabolic disease (PMD), respectively, at M1-PET as compared with IT-PET. Evaluations of M1-PET as compared with baseline TD-PET indicated 32, 7, 5, and 9 patients with CMR, PMR, NMR, and PMD, respectively. After a median 10.1 months, 26 patients showed progression and 13 had died from DLBCL. The 32 who achieved CMR showed significantly longer progression-free (P<0.0001) and overall survival (P<0.0001) periods as compared to the 21 non-CMR patients. Fluorine-18-FDG PET/CT findings obtained one month after CAR-T cell therapy showed accuracy for early response evaluation and prediction of progression in patients with R/R DLBCL.

Comparison of Lugano Criteria Versus RECIL and PERCIST as Prognostic Factors in Diffuse Large B-Cell Lymphoma.

This study aimed to compare the criteria of the Lugano, RECIL, and PERCIST for prognosis in patients with diffuse large B-cell lymphoma. We retrospectively evaluated 335 patients with diffuse large B-cell lymphoma. All patients underwent baseline 18 F-FDG PET/CT. Among them, 252 and 213 patients underwent interim PET/CT (I-PET/CT) and end-of-treatment PET/CT (EoT-PET/CT), respectively. Scans were interpreted by 2 nuclear medicine physicians using Lugano, RECIL, and PERCIST. RECIL and PERCIST were compared with Lugano for predicting progression-free survival (PFS) and overall survival (OS). All 3 response criteria could be used to predict PFS and OS. In I-PET/CT, the concordance index of Lugano in predicting PFS and OS was higher than that of RECIL (both P = 0.043) or PERCIST ( P = 0.008 and P = 0.034, respectively). In EoT-PET/CT, the concordance index of Lugano for predicting PFS and OS was similar to RECIL and not significantly different from PERCIST ( P = 0.597 and P = 0.231, respectively). For I-PET/CT, using the Lugano criteria is more accurate than RECIL or PERCIST in predicting PFS and OS. However, for EoT-PET/CT, the PERCIST criteria are minimally better.

Lisocabtagene Maraleucel in Relapsed/Refractory Mantle Cell Lymphoma: Primary Analysis of the Mantle Cell Lymphoma Cohort From TRANSCEND NHL 001, a Phase I Multicenter Seamless Design Study.

To report the primary analysis results from the mantle cell lymphoma (MCL) cohort of the phase I seamless design TRANSCEND NHL 001 (ClinicalTrials.gov identifier: NCT02631044) study. Patients with relapsed/refractory (R/R) MCL after ≥two lines of previous therapy, including a Bruton tyrosine kinase inhibitor (BTKi), an alkylating agent, and a CD20-targeted agent, received lisocabtagene maraleucel (liso-cel) at a target dose level (DL) of 50 × 106 (DL1) or 100 × 106 (DL2) chimeric antigen receptor-positive T cells. Primary end points were adverse events (AEs), dose-limiting toxicities, and objective response rate (ORR) by independent review committee per Lugano criteria. Of 104 leukapheresed patients, liso-cel was infused into 88. Median (range) number of previous lines of therapy was three (1-11) with 30% receiving ≥five previous lines of therapy, 73% of patients were age 65 years and older, 69% had refractory disease, 53% had BTKi refractory disease, 23% had TP53 mutation, and 8% had secondary CNS lymphoma. Median (range) on-study follow-up was 16.1 months (0.4-60.5). In the efficacy set (n = 83; DL1 + DL2), ORR was 83.1% (95% CI, 73.3 to 90.5) and complete response (CR) rate was 72.3% (95% CI, 61.4 to 81.6). Median duration of response was 15.7 months (95% CI, 6.2 to 24.0) and progression-free survival was 15.3 months (95% CI, 6.6 to 24.9). Most common grade ≥3 treatment-emergent AEs were neutropenia (56%), anemia (37.5%), and thrombocytopenia (25%). Cytokine release syndrome (CRS) was reported in 61% of patients (grade 3/4, 1%; grade 5, 0), neurologic events (NEs) in 31% (grade 3/4, 9%; grade 5, 0), grade ≥3 infections in 15%, and prolonged cytopenia in 40%. Liso-cel demonstrated high CR rate and deep, durable responses with low incidence of grade ≥3 CRS, NE, and infections in patients with heavily pretreated R/R MCL, including those with high-risk, aggressive disease.

Open-Label, Randomized, Phase 3 Study of Coformulated Favezelimab and Pembrolizumab Versus Chemotherapy in Patients with Relapsed or Refractory Classical Hodgkin Lymphoma Refractory to Anti-PD-1 Therapy: Keyform-008

Background: The importance of PD-1 therapy in relapsed or refractory (R/R) classical Hodgkin Lymphoma (cHL) is well established, with PD-1 inhibitors such as pembrolizumab being a standard of care option for patients. However, most patients eventually develop progressive disease and optimal therapy after anti-PD-1 failure has not been determined. The inhibitory checkpoint receptor, lymphocyte-activation gene 3 (LAG-3) is expressed in cHL tumor microenvironments and upregulation of LAG-3 is considered to play an important role in anti-PD-1 resistance. Favezelimab (MK-4280) is a humanized immunoglobulin G4 antibody that binds to LAG-3 and blocks interaction with major histocompatibility complex Class II ligands. Results from the ongoing phase 1/2 MK-4280-003 study of the combination of favezelimab and pembrolizumab demonstrated manageable safety and promising antitumor activity in patients with anti-PD-1-refractory R/R cHL. The randomized, open-label, parallel group, active-controlled, phase 3 KEYFORM-008 study (NCT05508867) is designed to evaluate efficacy and safety of the coformulation of favezelimab and pembrolizumab versus physician's choice of chemotherapy in patients with anti-PD-1-refractory R/R cHL. Study Design and Methods: Patients ≥18 years old, with histologically confirmed R/R cHL, an Eastern Cooperative Oncology Group performance status (ECOG PS) of 0-2, and adequate organ function are eligible. Patients must have exhausted all available treatment options with known clinical benefit, including having progressed on anti-PD-1-based therapy and being ineligible for or having failed autologous stem cell transplant (ASCT). In addition, patients should also have been ineligible for brentuximab vedotin (BV), relapsed or failed to respond to BV or discontinued BV due to toxicity. Patients with a history of central nervous system (CNS) metastases or active CNS involvement are excluded. Approximately 360 patients will be enrolled and randomly assigned 1:1 to receive coformulated favezelimab 800 mg and pembrolizumab 200 mg intravenously (IV) every 3 weeks (Q3W) or physician's choice of chemotherapy (gemcitabine 800-1200 mg/m 2 IV on days 1 and 8 of a 21-day cycle or bendamustine 90-120 mg/m 2 IV on days 1 and 2 of either a 21- or 28-day cycle). Randomization will be stratified by prior ASCT (yes vs no) and ECOG PS (0 or 1 vs 2). Treatment will continue for ≤35 cycles for the favezelimab/pembrolizumab coformulation or ≤6 cycles for chemotherapy or until disease progression, unacceptable toxicity, or withdrawal. Patients receiving physician's choice of chemotherapy with progressive disease confirmed by blinded independent central review (BICR) per Lugano criteria may be eligible to cross over to the favezelimab/pembrolizumab coformulation. Response assessments by positron emission tomography (PET) and computed tomography (CT) or magnetic resonance imaging (MRI) will be performed every 12 weeks (Q12W) until disease progression or trial discontinuation. Adverse events will be monitored throughout the study and graded per National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0. The primary end point is progression-free survival (PFS) per Lugano criteria by BICR. Overall survival (OS) is a key secondary end point. Other secondary end points are objective response rate (ORR), duration of response (DOR) per Lugano criteria by BICR, and safety. Exploratory end points include PFS on subsequent anticancer therapy and health-related quality of life. PFS, OS, and DOR rates in each treatment group will be estimated using the Kaplan-Meier method. The Clopper-Pearson method will be used to estimate ORR with 95% CI. Patient-reported outcomes will be assessed using EORTC Quality Of Life Questionnaire C30 and the EuroQuol 5-dimension, 5-level questionnaire. Enrollment for this study is open in sites in Australia, Belgium, Brazil, Canada, China, Czech Republic, France, Germany, Israel, Poland, Spain, South Korea, Sweden, Switzerland, Turkey, UK, and USA. ©2023 American Society of Clinical Oncology, Inc. Reused with permission. This abstract was accepted and previously presented at the 2023 ASCO Annual Meeting. All rights reserved.