Metabolic Rate Responses Research Articles

Fasting time after feeding affects the evaluation of metabolic response in abalone Haliotis discus hannai to nutrients using dietary methionine as an example

As one of the essential amino acid, methionine (Met) is the initiating amino acid for proteins synthesis, and it can also act as a molecular signal regulating various metabolic processes. Meanwhile, the postprandial metabolic responses varied greatly among different species, nutrients and fasting time. In the present study, postprandial metabolic responses of abalone Haliotis discus hannai fed with different levels of dietary methionine (0.46%, 1.19% and 2.07%, respectively) for 84 days were investigated. Compared with the group with 0.46% of dietary methionine, 2.07% of dietary methionine significantly increased the concentration of glucose in CFH at 0 h, 12 h, 24 h, 36 h, 60 h and 84 h, while the concentrations of ammonia were significantly decreased by 2.07% of dietary methionine at each time point after feeding (P < 0.05). The 1.19% of dietary methionine significantly increased the activity of trypsin at 0 h, 24 h 60 h and 84 h after feeding (P < 0.05). The phosphorylation levels of protein kinase B (AKT), mechanistic target of rapamycin (mTOR) and ribosomal s6 protein (S6) peaked at 12 h and then dropped to base level at 36–84 h. Compared with the group with 0.46% of dietary methionine, 1.19% of dietary methionine significantly increased the phosphorylation levels of AKT at 12 h and 24 h, and extended the phosphorylation time of AKT (P < 0.05). And the phosphorylation level of mTOR was significantly increased by 1.19% of dietary methionine at 12 h, 24 h and 36 h after feeding (P < 0.05). Significant activation or repression of the mRNA levels related to glucose and lipid metabolism were observed at 12–24 h after feeding, and most of which were remain stable at 36–84 h (P < 0.05). The expressions of genes related of insulin signaling pathway (phosphoinositide 3-kinase and protein kinase B), glycolysis (hexokinase) and transport of lipid (fatty acid transport protein) were significantly increased by 1.19% of dietary methionine, while the key gene of gluconeogenesis (glucose-6-phosphatase) were decreased. In summary, 1.19% of dietary methionine could enhance digestive and absorptive capacity, protein synthesis, glucose metabolism and fatty acid transportation of abalone. Take long-term feeding trial with dietary methionine as an example and combine the results of data analysis, it is suggested to analyze the protein level of mTOR signaling pathway within 36 h after feeding, assess the biochemical parameters in CFH and the mRNA levels of nutrient metabolism related genes within 36–84 h, and detect the activities of digestive and absorptive enzymes within 60–84 h.

Impact of definitive radiotherapy on metabolic response measured with 68Ga-PSMA-PET/CT in patients with intermediate-risk prostate cancer.

To assess the early metabolic response of the primary tumor using Gallium-68 (68Ga)-labeled-prostate-specific membrane antigen positron emission tomography (68Ga-PSMA-PET/CT), as well as the relationship between PSMA change in the primary tumor and PSA response after definitive radiotherapy (RT), either alone or in combination with androgen deprivation therapy (ADT) in intermediate risk prostate cancer (IR-PCa) patients. The clinical data of 71 IR-PCa patients treated with RT alone (36 patients, 50.7%) or RT and ADT (35 patients, 49.3%) were retrospectively analyzed. The difference between pre- and Posttreatment primary tumor PSMA expression and serum PSA values measured 4 months after completion of treatment were compared between treatment arms. Correlation between primary tumor metabolic response and serum PSA changes was analyzed. The median duration between pre- and Posttreatment 68Ga-PSMA-PET/CT for the entire patient population was 6.9 months (range, 5.6-8.4 months), and it was similar in both treatment arms. A decrease in primary tumor maximum standardized uptake value (SUVmax) was seen in 66 patients (93.0%), with a median value of 61.2%, which is significantly lower in patients undergoing RT alone than those undergoing RT and ADT (45.1 ± 30.6% vs. 59.1 ± 24.7%; p = 0.004). The complete metabolic response rate was significantly higher in patients undergoing RT and ADT than those treated with RT alone (40% vs. 0%; p < 0.001). Although moderate and positive correlation between pretreatment SUVmax and oosttreatment SUVmax was observed, there was no significant correlation between SUV change and PSA change. For patients treated with RT and ADT, posttreatment SUVmax was significantly lower and SUV change was significantly higher in patients with PSA nadir than in those without. Our preliminary results show that RT, with or without ADT, significantly reduces primary tumor SUVmax and serum PSA levels. Nonetheless, our findings indicate that early treatment response using 68Ga-PSMA-PET/CT is not feasible for those treated with RT alone, and it may only be useful in better distinguishing patients with and without PSA nadir for those who received both RT and ADT.

The seasonal response of metabolic rate to projected climate change scenarios in aquatic amphipods

The responses of organisms to climate change are mediated primarily by its impact on their metabolic rates, which, in turn, drive various biological and ecological processes. Although there have been numerous seminal studies on the sensitivity of metabolic rate to temperature, little is empirically known about how this rate responds to seasonal temperature ranges and beyond under conservative IPCC climate change scenarios. Here, we measured the SMR of the aquatic amphipod, Gammarus insensibilis, which served as our subject species, with body masses ranging from 0.20 to 7.74 mg ash free weight. We assessed the response of the SMR across nine temperature levels ranging from 12 to 30.2 °C. These temperatures match seasonal temperature norms, with an incremental increase of 0.6–1.2 °C above each seasonal baseline, as projected for the years 2040 and 2100 under the modest climate change scenarios. Overall, our findings showed that the effect of temperature on SMR varies with body mass, as indicated by a negative size-temperature interaction, with larger conspecifics exhibiting less sensitivity to temperature changes than smaller ones. From the cold to warm season, the SMR increased by an average of 14% °C−1, with increases of 18.4% °C−1 in smaller individuals and 11.4% °C−1 in larger ones. The SMR of smaller individuals peaked at a 0.6 °C increase from the current summer baseline (15.08% °C−1, Q10 = 4.2), while in larger ones it peaked with a 1.2 °C increase beyond autumn temperatures (14.9% °C−1, Q10 = 3.9). However, at temperatures reflecting global warming that exceed summer temperatures, the SMR of larger individuals levelled off, while that of smaller ones continued to increase. Overall, our findings suggest that smaller-sized individuals have a broader thermal window for SMR performance, while the SMR of larger-sized ones will become increasingly constrained at summer temperatures as those summer temperatures become hotter.

A quasi-experimental study on the energy expenditure, exercise intensity, and rating of perceived exertion of a male bodybuilding posing training.

This study is novel in classifying bodybuilding posing training as vigorous intensity exercise using metabolic equivalents (METs) and heart rate (HR) responses. It provides empirical evidence showing that posing training meets the vigorous intensity benchmarks, with METs and %HRmax values comparable to established vigorous exercise standards. The research highlights the novel finding that stimulant usage and the peak week phase of preparation significantly influence physiological responses and perceived exertion in bodybuilders. Specifically, athletes using stimulants and those in peak week displayed higher ratings of perceived exertion (RPE) and maximum heart rates, indicating that these factors notably affect the intensity and perceived difficulty of posing training.

Brentuximab vedotin and chemotherapy in relapsed/refractory Hodgkin lymphoma: a propensity score–matched analysis

AbstractSeveral single-arm studies have explored the inclusion of brentuximab vedotin (BV) in salvage chemotherapy followed by autologous stem cell transplantation (ASCT) for relapsed/refractory (R/R) classical Hodgkin lymphoma (cHL). However, no head-to-head comparisons with standard salvage chemotherapy have been performed. This study presents a propensity score–matched analysis encompassing individual patient data from 10 clinical trials to evaluate the impact of BV in transplant-eligible patients with R/R cHL. We included 768 patients, of whom 386 were treated with BV with or without chemotherapy (BV cohort), whereas 382 received chemotherapy alone (chemotherapy cohort). Propensity score matching resulted in balanced cohorts of 240 patients each. No significant differences were observed in pre-ASCT complete metabolic response (CMR) rates (P = .69) or progression free survival (PFS; P = .14) between the BV and chemotherapy cohorts. However, in the BV vs chemotherapy cohort, patients with relapsed disease had a significantly better 3-year PFS of 80% vs 70%, respectively (P = .02), whereas there was no difference for patients with primary refractory disease (56% vs 62%, respectively; P = .67). Patients with stage IV disease achieved a significantly better 3-year PFS in the BV cohort (P = .015). Post-ASCT PFS was comparable for patients achieving a CMR after BV monotherapy and those receiving BV followed by sequential chemotherapy (P = .24). Although 3-year overall survival was higher in the BV cohort (92% vs 80%, respectively; P < .001), this is likely attributed to the use of other novel therapies in later lines for patients experiencing progression, given that studies in the BV cohort were conducted more recently. In conclusion, BV with or without salvage chemotherapy appears to enhance PFS in patients with relapsed disease but not in those with primary refractory cHL.

Thermodynamic limitations on brain oxygen metabolism: physiological implications.

Recent thermodynamic modelling indicates that maintaining the brain tissue ratio of O2 to CO2 (abbreviated tissue O2 /CO2 ) is critical for preserving the entropy increase available from oxidative metabolism of glucose, with a fall of that available entropy leading to a reduction of the phosphorylation potential and impairment of brain energy metabolism. This provides a novel perspective for understanding physiological responses under different conditions in terms of preserving tissue O2 /CO2 . To enable estimation of tissue O2 /CO2 in the human brain, a detailed mathematical model of O2 and CO2 transport was developed, and applied to reported physiological responses to different challenges, asking: how well is tissue O2 /CO2 preserved? Reported experimental results for increased neural activity, hypercapnia and hypoxia due to high altitude are consistent with preserving tissue O2 /CO2 . The results highlight two physiological mechanisms that control tissue O2 /CO2 : cerebral blood flow, which modulates tissue O2 ; and ventilation rate, which modulates tissue CO2 . The hypoxia modelling focused on humans at high altitude, including acclimatized lowlanders and Tibetan and Andean adapted populations, with a primary finding that decreasing CO2 by increasing ventilation rate is more effective for preserving tissue O2 /CO2 than increasing blood haemoglobin content to maintain O2 delivery to tissue. This work focused on the function served by particular physiological responses, and the underlying mechanisms require further investigation. The modelling provides a new framework and perspective for understanding how blood flow and other physiological factors support energy metabolism in the brain under a wide range of conditions. KEY POINTS: Thermodynamic modelling indicates that preserving the O2 /CO2 ratio in brain tissue is critical for preserving the entropy change available from oxidative metabolism of glucose and the phosphorylation potential underlying energy metabolism. A detailed model of O2 and CO2 transport was developed to allow estimation of the tissue O2 /CO2 ratio in the human brain in different physiological states. Reported experimental results during hypoxia, hypercapnia and increased oxygen metabolic rate in response to increased neural activity are consistent with maintaining brain tissue O2 /CO2 ratio. The hypoxia modelling of high-altitude acclimatization and adaptation in humans demonstrates the critical role of reducing CO2 with increased ventilation for preserving tissue O2 /CO2 . Preservation of tissue O2 /CO2 provides a novel perspective for understanding the function of observed physiological responses under different conditions in terms of preserving brain energy metabolism, although the mechanisms underlying these functions are not well understood.

High Complete Metabolic Response Rates with Epcoritamab SC + GemOx in Patients with Relapsed/Refractory Diffuse Large B-Cell Lymphoma Ineligible for Autologous Stem Cell Transplant: Updated Results from Epcore NHL-2

High Complete Metabolic Response Rates with Epcoritamab SC + GemOx in Patients with Relapsed/Refractory Diffuse Large B-Cell Lymphoma Ineligible for Autologous Stem Cell Transplant: Updated Results from Epcore NHL-2

Results from the Epcore NHL-2 Trial Arm 8: Epcoritamab SC + R-Mini-CHOP Leads to High Complete Metabolic Response Rates in Patients with Previously Untreated Diffuse Large B-Cell Lymphoma Ineligible for Full-Dose R-CHOP

Results from the Epcore NHL-2 Trial Arm 8: Epcoritamab SC + R-Mini-CHOP Leads to High Complete Metabolic Response Rates in Patients with Previously Untreated Diffuse Large B-Cell Lymphoma Ineligible for Full-Dose R-CHOP

Outcome on Mesenteric Mass Response of Small-Intestinal Neuroendocrine Tumors Treated by 177Lu-DOTATATE Peptide Receptor Radionuclide Therapy: The MesenLuth Study, a National Study from the French Group of Endocrine Tumors and Endocan-RENATEN Network.

A mesenteric mass (MM), characterized by fibrotic reaction, is present in most small-intestinal neuroendocrine tumors (SI-NETs). 177Lu-DOTATATE peptide receptor radionuclide therapy (PRRT) has shown its efficacy in patients with progressive SI-NETs. However, because of specific tissue characteristics of desmoplastic MMs, we hypothesize that these lesions may be refractory to 177Lu-DOTATATE PRRT. Methods: From the national French Groupe d'étude des Tumeurs Endocrines database, we identified patients with an advanced SI-NET and a MM (≥2 cm with a retractile aspect) of a SI-NET treated by at least 1 course of 177Lu-DOTATATE PRRT. The primary endpoint was a MM objective response rate (ORR) of less than 5%. Secondary endpoints were metabolic response, MM-related safety, and clinical response, as well as MM progression-free survival (PFS) and non-MM PFS. Results: In total, 52 patients were included. The MM ORR was 4% (n = 2), and the non-MM ORR was 8% (n = 4). No patient had a MM metabolic response, and the non-MM metabolic response rate was 12% (n = 6). Among the 26 patients with baseline MM-related symptoms, 46% had a clinical response. Four patients presented with gastrointestinal complications during PRRT. The median MM-related PFS was not reached, and the non-MM PFS was 50.3 mo (95% CI, 38.2-61.7 mo). Conclusion: This study confirms that 177Lu-DOTATATE PRRT does not lead to morphologic response on MMs (ORR < 5%). However, it allows MM stability, with few MM-related side effects, and has a relevant impact on MM-related symptoms.

Randomized phase II study of preoperative afatinib in untreated head and neck cancers: predictive and pharmacodynamic biomarkers of activity

There is no strong and reliable predictive biomarker in head and neck squamous cell carcinoma (HNSCC) for EGFR inhibitors. We aimed to identify predictive and pharmacodynamic biomarkers of efficacy of afatinib, a pan-HER tyrosine kinase inhibitor, in a window-of-opportunity trial (NCT01415674). Multi-omics analyses were carried out on pre-treatment biopsy and surgical specimen for biological assessment of afatinib activity. Sixty-one treatment-naïve and operable HNSCC patients were randomised to afatinib 40 mg/day for 21–28 days versus no treatment. Afatinib produced a high rate of metabolic response. Responders had a higher expression of pERK1/2 (P = 0.02) and lower expressions of pHER4 (P = 0.03) and pRB1 (P = 0.002) in pre-treatment biopsy compared to non-responders. At the cellular level, responders displayed an enrichment of tumor-infiltrating B cells under afatinib (P = 0.02). At the molecular level, NF-kappa B signaling was over-represented among upregulated genes in non-responders (P < 0.001; FDR = 0.01). Although exploratory, phosphoproteomics-based biomarkers deserve further investigations as predictors of afatinib efficacy.

A Phase Ib Study to Evaluate the Safety and Efficacy of Nivolumab in Combination with R-CHOP in High-Risk DLBCL

Introduction Chemoimmunotherapy with R-CHOP is an established standard of care for diffuse large B-cell lymphoma (DLBCL) but is not curative in all patients (pts). Approximately 20% of DLBCL have aberrations involving the PD-L1/PD-L2 locus. This justifies the investigation of PD-1 checkpoint inhibitors in pts with DLBCL. This Phase 1b study was conducted to determine the maximum tolerated dose (MTD) for nivolumab in combination with R-CHOP in pts with DLBCL and to evaluate the preliminary efficacy of the regimen. Methods Patients with newly diagnosed de novo DLBCL or transformed low-grade lymphoma (tLL) were enrolled from 2019-2022. Treatment comprised a lead-in phase (LIP) with nivolumab 240 mg x 1 followed 2 weeks later by combination nivolumab-R-CHOP given every 3 weeks for 6 cycles. For combination therapy, nivolumab was administered on Day 1 followed by R-CHOP on Days 1-5 (Days 2-6 for Cycle 1). To establish MTD with Phase 1, nivolumab dosing followed a modified 3+3 dose escalation, starting with 1 mg/kg (dose level 1), escalating to 240 mg (dose level 2). MTD was administered for the Phase Ib portion of the study. Primary endpoints were determination of MTD and rate of complete metabolic response (CMR) by PET/CT using Lugano 2014 as best response by completion of 6 cycles of combination therapy (EOT). Correlations of immune subsets with durability of response and toxicity were exploratory. Results Thirty-three patients were enrolled, of which 25 and 22 pts were evaluable for toxicity and efficacy, respectively. The majority were men (n=21, 64%), White (n=26, 79%) with ECOG performance status of 0-1 (n=30, 91%). Twenty-seven (82%) had advanced stage and/or intermediate/high risk IPI score and 20 (65%) had germinal center subtype. Fifteen (45%) and 16 (48.5%) had tLL (2 with prior therapy for LL prior to transformation) and MYC aberrancy (13 with gains; 2 with single-hit and 1 with double-hit rearrangements), respectively. A dose of 240 mg of nivolumab was established as MTD. Twenty of 22 (91%) achieved CMR and 2 partial metabolic response (PMR) by EOT with overall response in 100%. One pt died from COVID-19 after 4 cycles but was in CMR on interim imaging. With median follow-up of 12 months (mo), 4 pts had progression. Both pts with PMR by EOT have not relapsed. Estimated 18-mo OS &amp; PFS were 95.4% &amp; 71.6%, respectively. Correlation of PFS with PD-L1 expression is underway. Most common therapy-related adverse events (TRAEs) attributed to nivolumab-R-CHOP were fatigue in 22 (88%), HTN in 21 (84%), lymphopenia in 21 (84%), and neutropenia in 18 (72%). High-grade (grade 3/4) neutropenia occurred in 15 (60%) with growth factor use per discretion of treating physician. Fifteen (60%) pts had infections, 47% high-grade. Immunotoxicities (IT) were the most common TRAEs attributed to nivolumab in 18 pts (72%), including thyroiditis (n=5, 20%), dermatitis (n=4, 16%), hepatitis (n=3, 12%), and infusion reactions (n=3, 12%). Most common high-grade IT: 1 case each of colitis, hepatitis, myocarditis (discontinued nivolumab), and dermatitis (discontinued nivolumab). For biologic correlates (Figures 1 &amp; 2): non-progressors (NP) were enriched for T regulatory cell (e.g., IFN-γ producing CD4+Foxp3+ phenotype) fragility while progressors (PD) were enriched for exhausted T cell immunophenotype (CD4+PD-1+CD39+) prior to both LIP and initiation of combination therapy (C1D1). Furthermore, exhausted-like T cell levels were significantly reduced at C1D1 in comparison to LIP in NP but not PD. Toxicities correlated to less exhausted-like effector T cell phenotype, decreased CD4+ naïve and central memory T cells, and increased circulating B cells and myeloid-derived suppressor cells. Conclusions This study demonstrates promising efficacy of frontline combination nivolumab-R-CHOP for high-risk DLBCL including pts with intermediate/high risk IPI, tLL, and MYC aberrancy. While limited by small sample size, this regimen resulted in response, PFS, and OS rates above historical rates reported in high-risk pts and provides basis for further evaluation of nivolumab-based therapies in such pts. We found correlations between progression, toxicity and specific immune subset populations. Attention to these biologic correlates as predictors of durable response and toxicity may allow for better patient selection to optimize benefits of therapeutic effect and risks of increased toxicity with nivolumab-based therapies in DLBCL.

Management and Outcomes for Primary Mediastinal B-Cell Lymphoma Patients with Partial Metabolic Response

Background: The optimal management of patients with primary mediastinal B-cell lymphoma (PMBCL) who experience a partial metabolic response (PMR) on FDG-PET after initial systemic therapy is unclear. This study aimed to investigate different management strategies and outcomes for PMBCL patients who achieved PMR following primary systemic therapy, utilizing a single-center retrospective design. Methods: We reviewed the electronic medical records of 121 PMBCL patients who underwent post-chemotherapy PET scans at the Princess Margaret Cancer Center, Toronto, from January 2009 to September 2021. Using Modified Lugano criteria (2014), post-chemotherapy PET scan results were evaluated, with Deauville score (DS) 0-3 considered a complete metabolic response. Demographic, clinical, and imaging characteristics of the PMBCL population were analyzed. The Kaplan-Meier method was used to estimate progression-free survival (PFS), measured from the time of the post-systemic therapy PET. Results: A total of 121 patients with PMBCL underwent post-chemotherapy PET scans. Among them, 49 patients (40%) demonstrated incomplete metabolic response (DS4-5) Among these 49 patients, 12 showed primary refractory disease, while 37 demonstrated a partial metabolic response (PMR, DS4). The median age at diagnosis of the 37 patients with PMR was 30.8 years (range:18.4 - 52.8 years), and 20 (54%) were female. The median length of follow-up for these patients was 3.7 years (range: 0.4 to 9.2 years). Most PMR patients were stage I/II (26 patients, 70.3%), while the remaining were stage III (2 patients, 5.4%), or stage IV (8 patients, 21.6%), and 26 (70.3%) had a large mediastinal mass (maximum diameter exceeding 10cm). Initial systemic treatment was R-CHOP-21 (34 patients, 91.9%), R-CHOP combined with dose-adjusted R-EPOCH (2 patients, 5.4%), and dose-adjusted EPOCH (1 patient, 2.7%). Thirty one patients (83.8%) received 6 cycles. Following treatment strategies were employed to manage PMR: 1) radiation therapy (RT) only with or without biopsy in 30 patients (80.1%); 2) an observational approach (repeating PET scans without immediate treatment) in 3 patients (8.1%); 3) salvage chemotherapy in 3 patients (8.1%) and other approach in 1(2.7%) patient. The 2-year progression-free survival (PFS) rate for all patients with incomplete metabolic response (n=49) was 74.5% (95% CI = 62.5% to 88.9%). For patients with primary progression on post-chemotherapy PET scans the 2-year PFS (ie free of 2nd progression) was 40% (18.7% to 85.5%), while the 2-year PFS for patients with PMR was 85.4% (74.3% to 98.1%). PMR patients who underwent radiotherapy (RT) had the 2-year PFS rate of 92.7% (95% CI: 83.5% to 100.0%). No progression or relapsed occurred among the 3 patients with PMR who were managed with repeating PET scans without immediate further treatment. Conclusion: This study replicates prior work demonstrating a higher rate of incomplete metabolic response for PMBCL patients following R-CHOP-21 than typically reported for DLBCL. RT to persistent PET-avid sites is associated with excellent PFS. The favorable outcome of PMR patients without any additional treatment illustrates the non-trivial risk of false-positive PET scans following systemic therapy, and the need to identify criteria that can distinguish those who need additional treatment from those who can be safely observed.

A Phase I Study of Copanlisib and Venetoclax in Patients with Relapsed or Refractory Diffuse Large B-Cell Lymphoma

Introduction: Diffuse large B-cell lymphoma (DLBCL) is a genomically heterogenous disease, which can be classified into distinct subgroups or clusters (Chapuy et al., Nat. Medicine, 2018, Wright et al., Cancer Cell, 2020). Leveraging knowledge of genetic alterations to design novel personalized treatment strategies may improve outcomes. Preclinical data suggest that the pan-phosphoinositide 3-kinase (PI3K) inhibitor, copanlisib, plus the BCL-2 inhibitor, venetoclax, are synergistic in genetically defined, high-risk, subtypes of DLBCL (Bojarczuk et al., Blood, 2019). We therefore hypothesized that copanlisib plus venetoclax would be an active treatment for patients with relapsed/refractory DLBCL, particularly in those with perturbed B-cell receptor (BCR)/PI3K signaling, which were predicted to be enriched in the relapsed setting. Here, we report the results of a phase I study of copanlisib plus venetoclax for patients (pts) with R/R DLBCL. Methods: This is an investigator-initiated, phase I, multicenter trial (NCT04572763) with the primary objective of determining the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) of copanlisib and venetoclax in pts with R/R DLBCL. A standard 3+3 dose escalation design was employed, in which pts were treated with 60 mg IV copanlisib on days 1, 8, and 15 in addition to escalating doses of daily venetoclax for each 28-day cycle. During cycle 1, a venetoclax dose ramp-up was performed in the outpatient setting to a target dose of 200 mg (dose level (DL) +1), 400 mg (DL +2) and 800 mg (DL +3). The DLT observation period was the first cycle. Patients with progressive disease prior to the end of the DLT window were replaced. Key eligibility criteria included a confirmed diagnosis of DLBCL or high-grade B-cell lymphoma (HGBCL), relapse after or not a candidate for autologous stem cell transplant or chimeric antigen receptor (CAR) T-cell therapy, and adequate hematologic and organ function. Key exclusion criteria were poorly controlled hypertension or diabetes. CTCAE v5 and Lugano criteria were used to evaluate toxicity and efficacy, respectively. Results: As of July 21, 2023, 12 pts were evaluable. Patients were treated in DL +1 (n=5), DL +2 (n=3), and DL +3 (n=4). The median age was 62 years (range 24-87). Eighty three percent were male. Median number of prior treatments was 6 (range 1-11) and 10 pts had received prior CAR T-cell therapy. No DLTs were observed, though 2 pts in DL +3 were not able to escalate to 800 mg due to recurrent neutropenia and noncompliance, respectively. The most common toxicities were neutropenia (50%, all gr3/4), thrombocytopenia (42%, 8% ≥ gr3), nausea (33%, 8% ≥ gr3), fatigue (25%, 8% ≥ gr3), and headache (25%, 8% ≥ gr3) (Figure). Hyperglycemia occurred in 2 pts (both gr1). Serious adverse events occurred in 50% of pts and included fracture (n=1), hypoxia (n=2), and death (n=3), which were not related to study treatment. The deaths were related to progressive disease. Fifty percent of pts required drug holds (n=5 for venetoclax, n=5 for copanlisib). Sixty percent required growth factor support. There were no cases of laboratory or clinical tumor lysis syndrome. Sponsor support was withdrawn prior to completion of enrollment to DL+3, but DL+2 (copanlisib plus 400 mg venetoclax) was safe and well tolerated. The overall response rate (ORR) and complete metabolic response (CMR) rate was 8% (90% CI: 0 - 34%), as 1 pt in DL +1, who had received &amp;gt;5 lines of prior therapy, achieved a CMR, with response lasting 3 months. The median follow-up was 9.1 months. The median overall survival (OS) and progression-free survival (PFS) were 3.5 and 1.8 months, respectively. Conclusions: Copanlisib plus venetoclax is feasible and safe in pts with R/R DLBCL, with no DLTs observed. While it is possible that copanlisib plus venetoclax is active in select genomic subgroups of DLBCL, there was limited activity in this unselected, heavily pre-treated patient population.

Results of the Phase II of Epirchop Study, Evaluating the Efficacy of Tazemetostat in Combination with R-CHOP in Elderly Newly Diagnosed Diffuse Large B Cell Lymphoma (DLBCL): A Lysa Study

Introduction: Tazemetostat (TAZ) is a selective oral EZH2 inhibitor with a favorable safety profile and activity in pts with either EZH2wild type or mutant B-cell NHL. In the phase I part of Epi-RCHOP study, we reported that R-CHOP plus TAZ (Taz-RCHOP) was well tolerated with safety and PK results comparable to R-CHOP alone, and the RP2D of TAZ in combination with RCHOP was consistent with TAZ monotherapy (800mg BID). We report here the efficacy results of the phase II TAZ R-CHOP study (Epi-RCHOP, NCT02889523), in pts 60-80y with newly diagnosed DLBCL. Methods: Pts received 6 R-CHOP every 21 days in combination with continuous TAZ at 800 mg BID, plus 2 cycles of TAZ and R (cycle 7 and 8). Prophylaxis with G-CSF, valaciclovir and trimethoprim sulfamethoxazole were strongly recommended. Primary endpoint was PET-based complete metabolic response rate (CR, Lugano 2014) at end of study treatment (EOT, i.e 8 cycles or at time of permanent treatment discontinuation) (data cut-off was January 30, 2023). Sample size calculation was made with the expectation of an increase of 10% in CR, with an H0 hypothesis of 70% and an H1 assumption of 80%, leading to a theorical sample size of 122 pts, assuming a drop out of 5%. The efficacy set correspond to pts who signed an informed consent and received at least one dose of TAZ. Pts without response assessment (no matter the reason) were considered non-responders. Key secondary objectives were progression free and overall survival. A sensitivity analysis was performed excluding pts who withdrawn their consent (N=112). Analyses were conducted using SAS® version 9.3. Results: From July 31, 2020 to July 18, 2022, 122 pts were enrolled in 27 LYSA centers. Median age was 70 years (60-80), 57% were female, 12% had an ECOG-PS2+, 70.5% a stage IV disease and 19.7% stage III, 66% elevated LDH, 73.8% an IPI of 3-5. Mutational profile was available for 76 pts, of whom 10 (13%) had an EZH2 mutations and 26 (34%) and EZB profile as assessed with LymphGen classifier. One hundred pts (82%) received 8 cycles and 22 had a premature treatment discontinuation (PTD), 12 (9.8%) during the first 2 cycles and 10 (8.2%) between cycle 3 and 8. Reasons for PTD were: consent withdrawal (N=10, including 7 during cycle 1 &amp; 2), adverse events (AE, N=6, including 2 treatment related), death (N=2, both due to septic shock), protocol deviation (N=2), progressive disease (N=1) or physician decision (N=1). Overall, the median percentage of TAZ dose received was 98.4% (mean 77.2%, Q1: 61%; Q3: 100%), and AE led to TAZ interruption in 4.1%, discontinuation in 2.8% and dose reduction in 2.4% of the cases. Mean time between cycles was 21.5 days. In oct 2020, after the inclusion of 22 pts, recommendation to cap vincristine at 1mg was done, due to an excess of constipation. At end of treatment or PTD, 92/122 pts (75.4%, IC95: 66.8-82.8%) achieved CR, 8 (6.6%) PR, 5 (4.1%) had a PD, 2 (1.6%) had died (septic shock) and 15 (12.3%) were not evaluated and considered as non-responders. The primary objective was not met in this efficacy set, with a CR of 75.4% (lower than the H1 at 80%). The sensitivity analysis, excluding the 10 pts that withdrawn their consent (all non-evaluated), showed a CR rate of 82.1% (92/112, IC95: 73.8-88.7%) and PR rate of 7.1%. After a median follow-up of 18.5 months (Range = [0.2; 28.1]), 17/122 pts had a relapse/progression (13.9%) and 12 had died: 4 due to lymphoma, 3 to COVID-19, 4 to AE (2 septic shock, 1 acute myeloid leukemia and 1 heart failure), 1 unknown cause (in CMR). The estimated 18m PFS and OS were 77.7% (IC95: 67.5-85.1%) and 88.8% (IC95: 79.9-93.9%) respectively. Most frequent AE were: neutropenia (53%), anemia (51%), nausea (47%), asthenia (42%), peripheral neuropathy (37%), gastro-intestinal hypomotility (35%), weight loss (28%), vomiting (24%), thrombocytopenia (24%). AE of grade 3 or more occurred in 73% of the pts and were mainly hematological AE with neutropenia (48%, including 6% of febrile neutropenia), anemia (23%), thrombocytopenia (17%) and gastro-intestinal disorder (overall 10.7%). Red blood cell and platelets transfusions were administered in 31% and 11.5% of the pts respectively. Conclusion: R-CHOP plus TAZ is doable. Efficacy results in this trial conducted during the COVID pandemic in a particularly challenging population, suggest that the combination warrant further investigation including correlative studies with molecular subclassification that will be presented.

The phase 2 LYSA study of prednisone, vinblastine, doxorubicin, and bendamustine for untreated Hodgkin lymphoma in older patients

AbstractOlder patients with classical Hodgkin lymphoma (cHL) require more effective and less toxic therapies than younger patients. In this multicenter, prospective, phase 2 study, we investigated a new firstline therapy regimen comprising 6 cycles of prednisone (40 mg/m2, days 1-5), vinblastine (6 mg/m2, day 1), doxorubicin (40 mg/m2, day 1), and bendamustine (120 mg/m2, day 1) (PVAB regimen) every 21 days for patients with newly diagnosed cHL aged ≥61 years with an advanced Ann Arbor stage. A Mini Nutritional Assessment score ≥17 was the cutoff value for patients aged ≥70 years. The primary end point was the complete metabolic response (CMR) rate after 6 cycles. The median age of the 89 included patients was 68 years (range, 61-88 years), with 35 patients (39%) aged ≥70 years. Seventy-eight patients (88%) completed the 6 cycles. The toxicity rate was acceptable, with a 20% rate of related serious adverse events. CMR was achieved by 69 patients (77.5%; 95% confidence interval [CI], 67-86). After a median follow-up of 42 months, 31 patients progressed or relapsed (35%), and 24 died (27%) from HL (n = 11), toxicity during treatment (n = 4), secondary cancers (n = 6), or other causes (n = 3). The 4-year progression-free survival (PFS) and overall survival rates were 50% and 69%, respectively. Multivariate analysis showed that liver involvement (P = .001), lymphopenia (P = .001), CRP (P = .0005), and comedications (P = .003) were independently associated with PFS. The PVAB regimen yielded a high CMR rate with acceptable toxicity. Over long-term follow-up, survival end points were influenced by unrelated lymphoma events. This trial was registered at www.clinicaltrials.gov as #NCT02414568 and at EudraCT as 2014-001002-17.

Epcoritamab SC + R-Mini-CHOP Leads to High Complete Metabolic Response Rates in Patients with Previously Untreated Diffuse Large B-Cell Lymphoma Ineligible for Full-Dose R-CHOP: First Disclosure from Arm 8 of the Epcore NHL-2 Trial

Background: Rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) is a standard of care for previously untreated (1L) diffuse large B-cell lymphoma (DLBCL); however, some patients are not candidates for full-dose R-CHOP due to advanced age, frailty, or underlying comorbidities. For these patients, various attenuated treatment regimens have been evaluated, with low-dose R-CHOP (R-mini-CHOP) being widely adopted as a standard 1L regimen. However, outcomes are suboptimal, with overall response rates (ORRs) and complete metabolic response (CMR) rates around 70% and 40-60%, respectively, and a 2-y progression-free survival rate of only 47%, leaving substantial room for improvement. Epcoritamab, a subcutaneous (SC) CD3xCD20 bispecific antibody, was approved by the US FDA for the treatment of adults with relapsed or refractory DLBCL, not otherwise specified, including DLBCL arising from indolent lymphoma, and high-grade B-cell lymphoma after ≥2 lines of systemic therapy. In the 1L setting in patients with high-risk DLBCL, epcoritamab SC with full-dose R-CHOP had a favorable safety profile and showed promising efficacy, including an ORR of 100% (Falchi et al, ASCO 2023). Here we report initial data from arm 8 of the EPCORE™ NHL-2 study (NCT04663347; phase 1/2) evaluating epcoritamab SC + R-mini-CHOP in 1L DLBCL. Methods: Adults with 1L CD20 + DLBCL who were not considered candidates for full-dose R-CHOP due to age ≥75 y or age ≥65 y with comorbidities (reduced left ventricular ejection fraction, history of myocardial infarction [&amp;gt;6 mo prior to enrollment], exertional chest pain, arrhythmia [grade ≤2], hypertension requiring treatment, or diabetes) were enrolled. Patients received epcoritamab SC (QW, cycles 1-2 [21 d each]; Q3W, cycles 3-6 [21 d each]; Q4W, cycles 7-8 [28 d each]) with R-mini-CHOP in cycles 1-6 (Q3W). A safety run-in was conducted to confirm acceptability of the safety profile. The primary endpoint of arm 8 was ORR as assessed by PET-CT per Lugano criteria. Results: As of April 24, 2023, 28 patients had received epcoritamab SC 48 mg + R-mini-CHOP. The median age was 81 y, 14 patients (50%) had IPI 3-5, 10 patients (36%) had bulky disease (&amp;gt;6 cm), and 15 patients (54%) had stage IV disease. At the data cutoff, median follow-up was 6.2 mo (range, 2.5+ to 11.7), with 9 patients (32%) having completed treatment and 15 patients (54%) still on treatment. R-mini-CHOP median relative dose intensity was ≥94%. There were no dose-limiting toxicities. The most common treatment-emergent AEs (TEAEs) of any grade were cytokine release syndrome (CRS; 43%), neutropenia (32%), fatigue (25%), anemia (21%), constipation (21%), and hypokalemia (21%). TEAEs decreased over time; 3 patients (11%) discontinued epcoritamab SC due to TEAEs. One grade 5 TEAE (cytomegalovirus infection reactivation) was recorded. CRS events were primarily low grade (grade 1-2: 39%, grade 3: 4%, grade ≥4: 0%), timing was predictable, and a majority of events were observed after the first full dose (cycle 1, day 15); all events resolved, with a median time to resolution of 3 d (range, 1-7). No ICANS events were reported. All 20 efficacy-evaluable patients had a response (ORR, 100%), with 17 patients (85%) achieving CMR. Median time to response was 1.4 mo ( Figure). At both month 6 and month 9, most patients who achieved CMR remained in CMR, suggesting durability of response. The study is ongoing and updated results will be presented. Conclusions: Epcoritamab SC + R-mini-CHOP showed encouraging efficacy with high response rates in patients with 1L DLBCL who cannot tolerate full-dose R-CHOP, including elderly, frail, and high-risk patients. There were no new safety signals, and findings were consistent with previously reported data, supporting the feasibility of the combination. These results warrant further investigation of epcoritamab-based therapies in 1L DLBCL.

Glofitamab Plus R-CHOP Induces High Response Rates with a Manageable Safety Profile in Patients with Previously Untreated Diffuse Large B-Cell Lymphoma (DLBCL): A 12-Month Analysis from a Phase Ib Study

Background: Over a third of patients (pts) with DLBCL do not respond or relapse after first-line (1L) treatment with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP; Sarkozy and Sehn. Ann Lymphoma 2019); these pts have limited curative options. Glofitamab (Glofit) is a T-cell engaging bispecific antibody with a novel 2:1 (CD20:CD3) format that allows bivalent binding to CD20 on B cells; this enables combination with anti-CD20 antibodies, including rituximab. Glofit monotherapy has shown durable responses in pts with relapsed/refractory DLBCL (Dickinson et al. NEJM 2022). In the safety run-in and expansion phases of the ongoing NP40126 trial (NCT03467373), Glofit + R-CHOP demonstrated promising efficacy and manageable safety in pts with 1L DLBCL (Topp et al. ASH 2022). Here, we report durability of response beyond 12 months in Glofit + R-CHOP-treated pts with 1L DLBCL from the NP40126 trial. Methods: Pts received R-CHOP for 6-8 three-weekly cycles. Intravenous Glofit was given with step-up dosing during Cycle (C)2 (Day [D]8, 2.5mg; D15, 10mg) and at the target dose (30mg) from C3D8 onwards. Glofit maintenance was allowed for up to one year. Efficacy was analyzed in all pts who had been on the study long enough to have a protocol scheduled end-of-treatment response assessment. Safety was analyzed in all pts who received at least one dose of any study drug. Response was assessed by PET-CT using Lugano criteria (Cheson et al. JCO 2014). Cytokine release syndrome (CRS) events were graded using the American Society for Transplantation and Cellular Therapy criteria (Lee et al. Biol Blood Marrow Transplant 2019) and other adverse events (AEs) by the Common Terminology Criteria for Adverse Events (v4.0). Hospitalization was not mandated for Glofit. Results: As of April 4, 2023, 56 pts were enrolled in this cohort. Median age was 68 years (range: 21-84), 54 pts (96.4%) had Ann Arbor stage III/IV disease, and median International Prognostic Index (IPI) score was 3 (IPI 1: 3.6% [2/56], IPI 2: 33.9% [19/56], IPI 3: 35.7% [20/56], IPI 4: 23.2% [13/56], IPI 5: 3.6% [2/56]). The cell of origin was germinal center B-cell (GCB) in 25 (44.6%) pts and non-GCB in 11 (19.6%) pts. After 17.1 (range: 0-26) months of median follow-up, the best overall response rate was 92.9% (52/56) and the complete metabolic response (CMR) rate was 83.9% (47/56). Median time to CMR was 1.8 months (95% confidence interval [CI]: 1.6-4.7). Most CMRs (44/47; 93.6%) were ongoing at data cut-off ( Figure). Among complete responders, the Kaplan-Meier estimated probability of ongoing responses at 12 months was 91.5% (95% CI: 82.2-100). Median duration of response and duration of complete response were not reached at data cut-off. The incidence of AEs and serious AEs (SAEs) were similar compared with earlier analyses. Grade (Gr) ≥3 AEs occurred in 42 (75.0%) pts and Gr ≥3 AEs related to Glofit in 14 (25.0%) pts. SAEs were reported in 20 (35.7%) pts and SAEs related to Glofit in six (10.7%) pts. Gr 5 AEs were reported in four (7.1%) pts (COVID-19 pneumonia, n=3; infusion related reaction associated with rituximab, n=1). AEs leading to dose interruption of Glofit occurred in 12 (21.4%) pts. Median dose intensity was 100% for all R-CHOP components. AEs leading to discontinuation of Glofit occurred in one (1.8%) patient. CRS events were reported in six (10.7%) pts: Gr 1, n=4; Gr 2, n=2; no Gr 3/4 CRS events were reported. All CRS events occurred during C2-3. Tocilizumab was used in two (33.3%) pts with CRS. Neurologic AEs (NAEs) occurred in 23 (41.1%) pts (most common NAEs (&amp;gt;5%) were peripheral neuropathy, n=7 [12.5%]; paraesthesia, n=5 [8.9%]; insomnia, n=4 [7.1%]; headache, n=3 [5.4%]); Gr 3 NAEs included cerebrovascular accident (n=1) and herpes zoster (n=1). No Glofit-related NAEs consistent with immune effector cell-associated neurotoxicity syndrome were reported. Neutropenia was reported in 26 (46.4%) pts (Gr ≥3 neutropenia: Gr 3, n=5; Gr 4, n=19). Infections and infestations were reported in 27 (48.2%) pts (of which the majority were Gr ≤2 [17/27]); Gr 3, n=7; Gr 5, n=3. Conclusions: Glofit + R-CHOP had a manageable safety profile with a low incidence of CRS, and continued to demonstrate durable responses with an improved CMR rate since the last data cut-off. These findings support the potential for favorable long-term outcomes with Glofit + R-CHOP as 1L treatment of DLBCL. Further analyses, including circulating tumor DNA data, will be presented.

Golcadomide (GOLCA; CC-99282), a Novel CELMoD Agent, Plus R-CHOP in Patients (pts) with Previously Untreated Aggressive B-Cell Lymphoma (a-BCL): Safety and Efficacy Results from Phase 1b Dose Expansion

Introduction Up to 40% of pts with diffuse large B-cell lymphoma (DLBCL) relapse after first-line chemo-immunotherapy with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP). CELMoD agents such as GOLCA potently degrade target proteins Ikaros/Aiolos, resulting in antiproliferative, apoptotic, and immunomodulatory activity. GOLCA preferentially distributes to tissues and lymphoid organs. In a phase 1 study, GOLCA demonstrated a manageable safety profile with promising clinical activity as monotherapy in relapsed/refractory non-Hodgkin lymphoma (Michot et al. Blood 2021). CC-220-DLBCL-001 (NCT04884035) is an ongoing open-label, multicenter, dose escalation and expansion trial to assess safety and preliminary efficacy of CELMoD agents + R-CHOP for untreated a-BCL. GOLCA demonstrated a manageable safety profile in the dose escalation phase (Munoz et al. ICML 2023 abstract 438); we report combined results from the GOLCA dose escalation and expansion phases. Methods Eligible pts were ≥ 18 years, had untreated a-BCL with measurable disease (Lugano 2014), ECOG performance status ≤ 2 and International Prognostic Index (IPI) score 0-5 (2-5 in dose expansion). Pts were treated with R-CHOP plus GOLCA in 21-day (D) cycles (C) for up to 6C, or until disease progression/unacceptable toxicity/study withdrawal/physician decision. During dose escalation, pts received GOLCA at dose levels (DL): 0.2 mg D1-7 (DL-1), 0.4 mg D1-7 (DL1), and 0.4 mg D1-10 (DL2). DL2 met the dose-limiting toxicity threshold and was not continued in the expansion phase. During dose expansion, pts were randomized 1:1 to R-CHOP plus GOLCA at DL-1 or DL1. The primary endpoint for the expansion phase was safety of GOLCA at the recommended phase 2 dose (DL1) (based on adverse events [AEs]); secondary endpoints included overall response rate (ORR) and complete metabolic response (CMR) rate (assessed at end of treatment [EoT] by PET-CT [Lugano 2014]). Circulating tumor DNA (ctDNA) was measured at C1D1, C2D1, C3D1, and EoT using the PhasED-Seq assay. Results Across escalation and expansion, 78 pts were treated (DL-1, n = 35; DL1, n = 37; DL2, n = 6). Median age was 63.0 years, 56.4% were male, most had high-intermediate/high IPI (3-5) score at diagnosis (64.1%), Ann Arbor stage III-IV disease (83.3%), and germinal center B cell as cell of origin (51.3%); 83.3% pts had DLBCL histology. At data extraction (May 25, 2023), across escalation and expansion, 38 pts had treatment ongoing, 31 completed treatment, and 35 continued to follow-up. A total of 3 pts discontinued due to AEs, 1 each at DL-1, DL1, and DL2. In the safety population (n = 78), median GOLCA relative dose intensity (RDI) was 99.4%; 82.1% of pts received RDI ≥ 85%. RDI for CHOP components was &amp;gt; 90%. A total of 73 (93.6%) pts had ≥ 1 treatment-emergent AE (TEAE); 70 (89.7%) pts had ≥ 1 TEAE considered related to GOLCA; 65 (83.3%) pts had ≥ 1 grade 3/4 TEAE, 62 (79.5%) pts had ≥ 1 grade 3/4 TEAE considered related to GOLCA. The most frequently occurring grade 3/4 TEAEs were neutropenia (76.9%) and thrombocytopenia (32.1%) ( Table). A total of 30 (38.5%) pts had serious TEAEs, most frequently febrile neutropenia (preferred term: 11 pts, 14.1%); 12 (15.4%) pts had serious TEAEs of infection or infestation (system organ class); 6 pts (7.7%) had venous thromboembolisms considered related to GOLCA (4 deep vein thrombosis, 1 superficial thrombosis, 1 pulmonary embolism). Treatment-related AEs leading to GOLCA dose reduction or discontinuation occurred in 11 (14.1%) pts and 6 (7.7%) pts, respectively. After a median follow-up time of 4.1 months (range 0.3-12.3) and among all treated pts with EoT response available, 21/25 had CMR; together, 14/14 pts who received GOLCA 0.4 mg (DL1 and DL2) achieved CMR at EoT ( Figure). Among efficacy-evaluable pts (n = 56), ORR was 91.1% (95% CI 80.4-97.0). Pts treated with GOLCA at DL-1 and DL1 who were ctDNA high-risk (≥ 2.5 log hGE/mL) responded to study treatment (CMR-PMR) and had early decreases in ctDNA (Kaplan et al. ASH 2023). Conclusions GOLCA demonstrated a manageable safety profile, showed good combinability with R-CHOP, and did not compromise delivery of curative treatment. Efficacy results and substantial ctDNA decrease indicate robust clinical activity in frontline DLBCL, with a high CMR rate at EoT, particularly among patients treated at DL1. Study support Bristol Myers Squibb.

Glofitamab Plus Polatuzumab Vedotin Continues to Demonstrate Frequent and Durable Responses and Has a Manageable Safety Profile in Patients with ≥2L Relapsed/Refractory DLBCL, Including HGBCL, and in Patients with Prior CAR T-Cell Therapy: Updated Results from a Phase Ib/II Study

Background: Glofitamab (Glofit) is a CD20xCD3 bispecific antibody which engages and redirects T cells to eliminate B cells. Glofit monotherapy recently received FDA and EMA approval for treatment of relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL) after ≥2 prior lines of therapy. Polatuzumab vedotin (Pola) is a CD79b-targeted antibody-drug conjugate that has a complementary mode of action to Glofit, with little toxicity overlap. In this open-label, multicenter Phase Ib/II study (NCT03533283), Glofit+Pola demonstrated durable responses and a manageable safety profile in patients with R/R DLBCL (Hutchings et al. ICML 2023). We present updated results with longer follow-up in patients with R/R DLBCL, including high-grade B-cell lymphoma (HGBCL), and in patients with prior chimeric antigen receptor (CAR) T-cell therapy. Methods: Patients receivedobinutuzumab 1000mg on Cycle (C) 1 Day (D) 1 to mitigate the risk of severe cytokine release syndrome (CRS). Pola 1.8mg/kg was given on C1D2 and D1 of C2-6 (21-day cycles). Glofit was given with step-up dosing in C1 (C1D8 2.5mg; C1D15 10mg; D1 of C2-12 10/30mg) for up to 12 cycles. The primary objective was to establish the recommended Phase II dose of Glofit when combined with Pola; this was previously identified as 30mg based on the dose-escalation phase and the NCT03075696 study (Hutchings et al. ASH 2021; Hutchings et al. J Clin Oncol 2021). Results: At the data cut-off (Jan 25, 2023), 111 patients had received ≥1 dose of study drug (safety population). The median age was 68 (range 23-82) years; 61.3% of patients were male; 50.5% had DLBCL not otherwise specified (NOS), 24.3% had HGBCL, 23.4% had transformed follicular lymphoma (trFL), and 1.8% had primary mediastinal large B-cell lymphoma (PMBCL). Most patients were refractory to their last prior therapy (71.2%). Median number of prior lines of therapy was 2 (range 1-7; 61.3% of patients had received ≥2), 24.3% had received prior CAR T-cell therapy. The overall response rate (ORR) in 109 efficacy-evaluable patients was 78.0%, with a complete metabolic response (CMR) rate of 56.0%. In patients with DLBCL NOS (n=56), ORR and CMR rate were 85.7% and 60.7%, respectively. In patients with trFL (n=26), ORR and CMR rate were 76.9% and 53.8%, respectively. In patients with HGBCL (n=25), ORR and CMR rate were 60.0% and 44.0%, respectively. The two patients with PMBCL achieved a CMR. In patients who had prior CAR T-cell therapy (n=27), ORR was 77.8% and CMR rate was 44.4%. In 61 patients who had a complete response, estimated 6- and 12-month duration of complete response (DOCR) rates were 89.2% and 73.1%, respectively ( Figure). Estimated 6-month and 12-month DOCR rates in patients with DLBCL NOS (n=34) were 84.2% and 59.2%, respectively; with trFL (n=14), were 92.9% and 85.7%; with HGBCL (n=11), both were 100%. In patients with PMBCL (n=2), the estimated 6-month DOCR was 100%. With a median follow-up of 13.0 months, median progression-free survival was 10.4 (95% confidence interval [CI]: 5.8-19.0) months ( Figure). Median overall survival was not reached after a median survival follow-up of 15.2 months. In 108/111 patients who had received ≥1 dose of Glofit, the most common adverse event (AE) was CRS (45.4% [Grade 1, 30.5%; Grade 2, 13.9%]). One patient had Grade 5 CRS in the context of an unresolved infection; the patient declined further CRS management when the event was Grade 3. Of 111 safety-evaluable patients, 27 (24.3%) had peripheral neuropathy (all Grade 1/2, 8 events were resolved). Glofit-related AEs potentially consistent with immune effector cell-associated neurotoxicity syndrome (ICANS) occurred in 3 patients and were all Grade 1/2. Grade 3/4 AEs were reported in 61.3% of patients, with neutropenia the most common event (29.7%). Serious AEs occurred in 58.6% of patients, and Grade 5 AEs occurred in 6.3% of patients (5/7 events due to COVID-19); 9.9% of patients discontinued any treatment due to an AE (6.3% discontinued Pola; 9.0% discontinued Glofit). Conclusions: Glofit+Pola demonstrated high response rates and durable responses in heavily pre-treated patients, the majority of whom were refractory to their last prior therapy, across all histologies, including in patients with HGBCL and those with prior CAR T-cell therapy. The safety profile was manageable and consistent with the individual drugs. The rates of CRS events and AEs potentially consistent with ICANS were low. Updated data will be presented.

Tazemetostat in Combination with R-CHOP in Patients with High-Risk, Frontline Follicular Lymphoma (Epi-RCHOP): A Phase II Study from the Lysa

Background: Tazemetostat (TAZ), an enhancer of zeste homolog 2 (EZH2) inhibitor, is approved by the US Food and Drug Administration for the treatment of patients with relapsed/refractory (R/R) follicular lymphoma (FL) whose disease has mutant (MT) EZH2 and who have received ≥2 prior therapies or with R/R FL who have no satisfactory alternative treatment options. We previously reported that the RP2D of TAZ in combination with R-CHOP was 800mg BID in the phase 1 part of Epi-RCHOP study (NCT02889523). Here, we report results of the phase 2 part evaluating TAZ with R-CHOP + rituximab maintenance in a cohort of previously untreated high-risk FL patients. Methods: patients were eligible if aged 18-80 years, had histologically confirmed FL grade 1-3A, high-risk FLIPI (score of 3-5) and were in need of treatment according to GELF criteria. Induction treatment consisted in 6 cycles of RCHOP every 21 days and TAZ 800mg BID every day, starting on day 2 of cycle 1, plus 2 additional 21 days cycles of rituximab+TAZ (cycle 7 and 8). Responses were assessed at end of induction (EOI), and responders then received maintenance 1 (TAZ 6 mo + rituximab 12 mo) and maintenance 2 (12 mo of rituximab alone).The primary efficacy endpoint was PET-based complete response rate based on local assessment at the end of induction or at permanent treatment discontinuation, as determined by Cheson IWG 2014 Lugano Classification (Deauville scale 1-3); in addition bone marrow biopsy (BMB) was mandatory at EOI if involved at baseline and complete metabolic response (CMR) patients with missing assessment at EOI classified as partial responders. Sample size calculation was made with the expectation of an increase of 13% in CR, with an H0 hypothesis of 67% and an H1 assumption of 80%, leading to a theorical sample size of 62 pts, assuming a drop out of 10%. Initial assumption was that CR rate should be &amp;gt;76.4% to consider the combination eligible for further clinical evaluation in high risk FL patients. Results: As of June 14, 2022, 62 patients were enrolled between Aug2020 and Apr2022 across 20 centers (including a drop-out of 12 patients, 70 were enrolled in France, 4 in Belgium). Disease characteristics included: males 61.3%, median age 64.5 years, FLIPI 3/4/5 in 61.3%/32.3%/6.5%, EZH2 mutated 17.3% (n=9/46 assessed had EZH2 mutation; 16 undertermined), BM involvement 68.3%, circulating FL cells in 21%, and increased LDH in 50%. Fifty eight (93%) patients completed induction and initiated maintenance 1, 44 (71%) initiated maintenance 2. Fourteen patients permanently discontinued treatment: 4 before EOI not related to PD (2 COVID19 disease, 1 late onset neutropenia and 1 stopped therapy but accepted FU), and 9 after EOI (5 PD, 2 COVID19 disease, 1 neutropenia, 1 paralytic ileus and 1 patient's refusal). At EOI, 79% (95%CI 66.8; 88.3%) achieved complete metabolic response (CMR) and 16.2% PMR for an overall metabolic response rate of 95.2%, however, according to the stringent protocol definition, 16 patients who achieved CMR had no BMB assessment at EOI and were downgraded to PR leading to 53.2% CR and 41.9% PR rate at EOI. Complete response rates were significantly higher in EZH2 mutants (8/9 CMR 88.9%) versus 17/37 (45.9%) in EZH2 wild-type (WT) patients (Fisher exact test p=0.027). Figure 1 shows the AEs reported by more than 10% of patients. The most common grade 3-4 TEAEs were neutropenia (53.2%, only 3.2% febrile), thrombocytopenia (17.7%), anemia (16.1%). Serious AEs occurred in 14 patients, the two most frequent being Covid19 disease (6.5%) and gastrointestinal hypomotility (6.5%). This latter AE was the most frequent non-hematologic event (40.3%), followed by peripheral neuropathy (35.5%). After amending vincristine dose (Oct2020), 30 digestive AEs were reported (16 related to TAZ, mostly grade 1-2, only 1 grade 3, no sequelae). No SPM was observed. With a median follow-up of 19 months, 7 relapses (5 EZH2 WT and 2 undetermined) including 5 needing subsequent treatment and 2 deaths occurred (1 Covid19 disease, 1 after PD). Median PFS and median DOR were not reached and appeared to be similar irrespective of EZH2 status, 18-months PFS and OS rates were 89.3% and 98.3% respectively. Conclusions: Although the primary endpoint was not met due to missing BM assessments, TAZ + RCHOP combination demonstrated a promising complete metabolic response rate of 79% in this high-risk frontline FL population, with a manageable safety profile, after vincristine dose was reduced.